tbuckley/cabot-search huggingface dataset:
Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model
Authors: Gerhard Leinenga, Jürgen Götz
Journal: Science Translational Medicine (2015)

Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD.
Activin-A Overexpression in the Murine Lung Causes Pathology That Simulates Acute Respiratory Distress Syndrome
Authors: Eirini Apostolou, Athanasios Stavropoulos, Alexandros Sountoulidis, Charoula Xirakia, Stavros Giaglis, Evdokia Protopapadakis, Konstantinos Ritis, Spyros Mentzelopoulos, Arja Pasternack, Martyn Foster, Olli Ritvos, George E. Tzelepis, Evangelos Andreakos, Paschalis Sideras
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Activin-A is up-regulated in various respiratory disorders. However, its precise role in pulmonary pathophysiology has not been adequately substantiated in vivo.To investigate in vivo the consequences of dysregulated Activin-A expression in the lung and identify key Activin-A-induced processes that contribute to respiratory pathology.Activin-A was ectopically expressed in murine lung, and functional, structural, and molecular alterations were extensively analyzed. The validity of Activin-A as a therapeutic target was demonstrated in animals overexpressing Activin-A or treated with intratracheal instillation of LPS. Relevancy to human pathology was substantiated by demonstrating high Activin-A levels in bronchoalveolar lavage (BAL) samples from patients with acute respiratory distress syndrome (ARDS).Overexpression of Activin-A in mouse airways caused pulmonary pathology reminiscent of acute lung injury (ALI)/ARDS. Activin-A triggered a lasting inflammatory response characterized by acute alveolar cell death and hyaline membrane formation, sustained up-regulation of high-mobility group box 1, development of systemic hypercoagulant state, reduction of surfactant proteins SpC, SpB, and SpA, decline of lung compliance, transient fibrosis, and eventually emphysema. Therapeutic neutralization of Activin-A attenuated the ALI/ARDS-like pathology induced either by ectopic expression of Activin-A or by intratracheal instillation of LPS. In line with the similarity of the Activin-A-induced phenotype to human ARDS, selective up-regulation of Activin-A was found in BAL of patients with ARDS.Our studies demonstrate for the first time in vivo the pathogenic consequences of deregulated Activin-A expression in the lung, document novel aspects of Activin-A biology that provide mechanistic explanation for the observed phenotype, link Activin-A to ALI/ARDS pathophysiology, and provide the rationale for therapeutic targeting of Activin-A in these disorders.
FLT3 K663Q is a novel AML-associated oncogenic kinase: determination of biochemical properties and sensitivity to Sunitinib (SU11248)
Authors: M M Schittenhelm, K W H Yee, J W Tyner, L McGreevey, A D Haley, A Town, D J Griffith, T Bainbridge, R M Braziel, A-M O'Farrell, J M Cherrington, M C Heinrich
Journal: Leukemia (2006)
Myeloid Cell−Specific ABCA1 Deletion Protects Mice From Bacterial Infection
Authors: Xuewei Zhu, Marlena M. Westcott, Xin Bi, Mingxia Liu, Kymberly M. Gowdy, Jeongmin Seo, Qiang Cao, Abraham K. Gebre, Michael B. Fessler, Elizabeth M. Hiltbold, John S. Parks
Journal: Circulation Research (2012)

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in eliminating excess free cholesterol from tissues by effluxing cellular free cholesterol and phospholipids to lipid-poor apolipoprotein AI. Macrophage ABCA1 also dampens proinflammatory myeloid differentiation primary-response protein 88-dependent toll-like receptor signaling by reducing cellular membrane free cholesterol and lipid raft content, indicating a role of ABCA1 in innate immunity. However, whether ABCA1 expression has a role in regulating macrophage function in vivo is unknown.We investigated whether macrophage ABCA1 expression impacts host defense function, including microbial killing and chemotaxis.Myeloid cell-specific ABCA1 knockout (MSKO) vs wild-type mice were infected with Listeria monocytogenes (Lm) for 36 hours or 72 hours before euthanasia. Lm-induced monocytosis was similar for wild-type and MSKO mice; however, MSKO mice were more resistant to Lm infection, with significantly less body weight loss, less Lm burden in liver and spleen, and less hepatic damage 3 days postinfection. In addition, Lm-infected MSKO mouse livers had: (1) greater monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 expression; (2) more monocyte/macrophage infiltration; (3) less neutral lipid accumulation; and (4) diminished expression of lipogenic genes. MSKO macrophages showed enhanced chemotaxis toward chemokines in vitro and increased migration from peritoneum in response to lipopolysaccharide in vivo. Lm infection of wild-type macrophages markedly reduced expression of ABCA1 protein, as well as other cholesterol export proteins (such as ATP-binding cassette transporter G1 and apolipoprotein E).Myeloid-specific ABCA1 deletion favors host response to and clearance of Lm. Macrophage Lm infection reduces expression of cholesterol export proteins, suggesting that diminished cholesterol efflux enhances innate immune function of macrophages.
Blood Flow and Tissue Space of the Left Coronary Artery in Man
Authors: GERALD A. KLASSEN, JAI B. AGARWAL, PAUL H. TANSER, STANLEY P. WOODHOUSE, DEREK MARPOLE
Journal: Circulation Research (1970)

Using a constant infusion of two indicators, T-1824 bound to albumin and tritiated water, flow and transit time were measured in the left coronary system of intact man. Indicators were infused for 6 minutes into the left coronary artery with sampling from the coronary sinus in a region that drained exclusively the inflow of the left coronary artery and from the brachial artery for recirculation. The degree of heterogeneity of myocardial perfusion could be defined by the time required for the curve to reach a plateau. A correlation coefficient of 0.966 was found between the two indicator-measured blood flows. The average myocardial hematocrit was calculated and found to be similar to the arterial. In the presence of myocardial disease, total flow of the left coronary artery was increased. When this was divided by tissue volume, the blood flow per unit volume of tissue was decreased in the presence of the idiopathic cardiomyopathy.
Letrozole is Superior to Anastrozole in Suppressing Breast Cancer Tissue and Plasma Estrogen Levels
Authors: Jürgen Geisler, Hilgegunn Helle, Dagfinn Ekse, Nhat K. Duong, Dean B. Evans, Yngve Nordbø, Turid Aas, Per E. Lønning
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E1), estradiol (E2), and estrone sulfate (E1S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor–positive breast cancers. Experimental Design: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. Results: Letrozole suppressed pretreatment tumor levels of E2, E1, and E1S by 97.6%, 90.7%, and 90.1%, respectively. These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E2, E1, and E1S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E2 (average suppression by 95.2% versus 92.8%; P = 0.018), E1 (98.8% suppression versus 96.3%; P = 0.003), and E1S (98.9% suppression versus 95.3%; P = 0.003). Conclusion: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.
Maintenance of serum potassium with sodium zirconium cyclosilicate (<scp>ZS</scp>‐9) in heart failure patients: results from a phase 3 randomized, double‐blind, placebo‐controlled trial
Authors: Stefan D. Anker, Mikhail Kosiborod, Faiez Zannad, Ileana L. Piña, Peter A. McCullough, Gerasimos Filippatos, Peter van der Meer, Piotr Ponikowski, Henrik S. Rasmussen, Philip T. Lavin, Bhupinder Singh, Alex Yang, Prakash Deedwania
Journal: European Journal of Heart Failure (2015)
Clinical and social outcomes of adolescent self harm: population based birth cohort study
Authors: B. Mars, J. Heron, C. Crane, K. Hawton, G. Lewis, J. Macleod, K. Tilling, D. Gunnell
Journal: BMJ (2014)

<b>Objectives</b> To investigate the mental health, substance use, educational, and occupational outcomes of adolescents who self harm in a general population sample, and to examine whether these outcomes differ according to self reported suicidal intent. <b>Design</b> Population based birth cohort study. <b>Setting</b> Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort of children born in 1991-92. <b>Participants</b> Data on lifetime history of self harm with and without suicidal intent were available for 4799 respondents who completed a detailed self harm questionnaire at age 16 years. Multiple imputation was used to account for missing data. <b>Main outcome measures</b> Mental health problems (depression and anxiety disorder), assessed using the clinical interview schedule-revised at age 18 years, self reported substance use (alcohol, cannabis, cigarette smoking, and illicit drugs) at age 18 years, educational attainment at age 16 and 19 years, occupational outcomes at age 19 years, and self harm at age 21 years. <b>Results</b> Participants who self harmed with and without suicidal intent at age 16 years were at increased risk of developing mental health problems, future self harm, and problem substance misuse, with stronger associations for suicidal self harm than for non-suicidal self harm. For example, in models adjusted for confounders the odds ratio for depression at age 18 years was 2.21 (95% confidence interval 1.55 to 3.15) in participants who had self harmed without suicidal intent at age 16 years and 3.94 (2.67 to 5.83) in those who had self harmed with suicidal intent. Suicidal self harm, but not self harm without suicidal intent, was also associated with poorer educational and employment outcomes. <b>Conclusions</b> Adolescents who self harm seem to be vulnerable to a range of adverse outcomes in early adulthood. Risks were generally stronger in those who had self harmed with suicidal intent, but outcomes were also poor among those who had self harmed without suicidal intent. These findings emphasise the need for early identification and treatment of adolescents who self harm.
Direct myocardial effects of cocaine
Authors: N C Morcos, A Fairhurst, W L Henry
Journal: Cardiovascular Research (1993)

The aim was to determine whether cocaine has a direct effect on the myocardium which is independent of coronary vasospasm.Cocaine was introduced into the perfusate of the isolated rabbit ventricular septal preparation in the concentration range 10(-5) to 10(-3)M while holding coronary flow of oxygenated Krebs solution constant at 3.0 ml.min-1 by a perfusion pump. The septa were obtained from white male New Zealand rabbits and were paced at 48 beats.min-1. Mechanical and enzymatic measurements were performed.Developed tension (T), maximum contraction velocity (+dT/dt), and maximum relaxation velocity (-dT/dt) were all depressed to approximately the same degree at each different cocaine concentration and averaged 4, 48, and 95% at 10(-5), 10(-4), and 10(-3)M cocaine respectively, with an ED50 = 9 x 10(-5)M. Relaxation time (tR/T) was prolonged, but the ED50 was greater (by 1.5 times) than for the other mechanical parameters. Simultaneously, an increase in excitation threshold dysrhythmia developed which resulted in 17, 50, and 90 beats missed per 100 stimulations at 10(-5), 10(-4), and 10(-3)M cocaine respectively. Resting tension (RT) was not altered. Coronary flow rate was not reduced in presence of cocaine because of the constant delivery pump. T, +dT/dt, -dT/dt and modulation of the excitation threshold completely recovered after washout of cocaine.Cocaine has acute direct, though reversible, depressant effects on the myocardium, including depression of function and modulation of excitation threshold, which are independent of its effect on coronary flow.
Interaction between airway calibre and exhaled NO: The allergen challenge model
Authors: Amaryllis Haccuria, Sébastien Michiels, Alain Michils, Alain Van Muylem
Journal: European Respiratory Journal (2013)

Background : High fractionated exhaled nitric oxide (FENO) detected in asthma patients reflects increased airway inflammation. However, FENO may be affected by airway calibre reduction, thus introducing a bias in FENO use for asthma control.  Aim: to assess the impact on FENO of changes in both airway calibre and inflammation using the allergen challenge model.  Methods: FEV 1  (forced expired volume in one second) and FENO were measured during early (EAR) and late (LAR) responses to a house dust mite challenge in 15 mild allergic asthmatics. Ventilation distribution using single breath washout test with inert gases (He and SF 6 ) was also performed to identify the sites of airway constriction, since different constriction sites result in different FENO reductions.  Results: In EAR, mean FEV 1  fall was 36.8%, FENO decreased by 22% (p=0.002) and SHe was greater than ΔSSF 6  (+189.4% and +82.2%, p=0.001).  In LAR, for a FEV 1  fall of 31.7%, FENO decreased by 28.7% (p=0.002) with the same ΔSHe, ΔSSF 6  pattern (+155.8% vs +76%, p=0.001).  8 hours after EAR, whereas FEV 1  was still lowered (p  At 24 hours, when FEV 1  returned to baseline, FENO increased by 38.7% (p=0.04).  Conclusion: In mild allergic asthma, changes in airway calibre significantly modulate changes in FENO levels resulting from concomitant changes in airway inflammation. Therefore, correct interpretation of FENO changes in asthma patients may require integration of changes in airway calibre occurring concomitantly. Airway constriction and inflammatory processes after allergen exposure seem to involve similar regions of the bronchial tree, mainly the conductive airways.
Activation markers of peripheral blood mononuclear cells in late pregnancy and after delivery: a pilot study
Authors: M Ostensen
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To study the putative shift of a Th1 to a Th2 immune response in pregnancy and its reversal post partum in healthy women and patients with rheumatoid arthritis (RA). <b>Methods:</b> Peripheral blood mononuclear cells (PBMC) were examined by FACS analysis for the expression of activation markers CD25 and HLA-DR and chemokine receptors CXCR3 and CCR4 on CD4+ and CD8+ T cells in four healthy women and four patients with RA. Samples were analysed once in the third trimester and six and 12 weeks post partum. Eight healthy non-pregnant women served as controls. <b>Results:</b> No reduction of CD25 and HLA-DR+ T cells occurred in the third trimester, but a significant increase was observed post partum in healthy women and an even greater increase in patients. Proportions of T cells expressing the CXCR3 or CCR4 marker were similar in patients and controls during pregnancy, whereas a significant increase occurred post partum. The ratio of CXCR3+ to CCR4+ cells remained unchanged during the observation period and did not differ significantly from that in non-pregnant controls. <b>Conclusion:</b> A shift from a Th1 to a Th2 immune response was not detected in the circulation of healthy pregnant women or pregnant patients. The significant increase of T cell activation after pregnancy warrants further investigation into the mechanisms of adjustment of the immune system post partum and its clinical correlates in rheumatic patients.
NF-κB Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase
Authors: Simone de Haij, Astrid C. Bakker, Reinier N. van der Geest, Guy Haegeman, Wim Vanden Berghe, Jamil Aarbiou, Mohamed R. Daha, Cees van Kooten
Journal: Journal of the American Society of Nephrology (2005)

Tubular epithelial cells (TEC) play an important role in tubulointerstitial inflammation, a hallmark of most renal diseases, via production of cytokines and chemokines. In this study, the role of mitogen-activated protein kinases (MAPK) in regulation of the proinflammatory cytokine IL-6 in cultured human TEC in response to the leukocyte-derived factors IL-1, TNF-alpha, IL-17, and CD40L was investigated. IL-6 production induced by IL-1, TNF-alpha, and IL-17 was specifically inhibited by the c-jun NH(2)-terminal kinase (JNK) inhibitor SP600125, but not by a selective inhibitor of p38 MAPK, and was moderately increased when the ERK1/2 pathway was inhibited. Also for CD40L stimulation, inhibition of JNK resulted in a pronounced inhibition of IL-6 production. Although stimulation of TEC induced activation of activator protein-1 (AP-1), the down-stream target of JNK, reporter assays demonstrated that mutation of the AP-1 binding site in the IL-6 promoter did not affect gene transcription. Furthermore, IL-1-induced transcriptional activation of the IL-6 promotor was repressed by SP600125 or by co-transfection of a dominant-negative expression plasmid of c-jun even in the absence of a functional AP-1 binding site. This suggests that IL-6 production by renal epithelial cells is regulated by JNK, via a mechanism, however, independent of the AP-1 binding site. The data rather suggest that the JNK pathway may interfere with other signaling pathways, involving NF-kappaB and possibly ERK.
Adenosine as an important mediator of post-ischaemic neuronal stunning
Authors: J Pernow
Journal: Cardiovascular Research (2001)

See article by Burgdorf et al. [11] (pages 713–720) in this issue. 

A brief period of ischaemia is known to induce a prolonged period of reversible myocardial dysfunction despite normalized electrocardiogram and absence of histological signs of necrosis. This was first described by Heyndrickx and co-workers [1] who found that myocardial function was depressed for several hours following a 15-min period of coronary artery occlusion in dogs. Braunwald and Kloner [2] subsequently named this phenomenon ‘myocardial stunning’. Although the exact mechanism underlying myocardial stunning is not fully understood, results from several studies indicate that it can be mediated by increased myocyte calcium levels and oxygen-derived free radicals during ischaemia and the initial part of reperfusion [3–5].

In addition to the reduced myocardial contractility, there is also evidence of a long-lasting impairment of neurotransmission in the post-ischaemic heart, a phenomenon known as ‘neuronal stunning’. Martins et al. [6] demonstrated that myocardial contractile function induced by sympathetic nerve stimulation was depressed in ischaemic myocardium. It was later described that the myocardial segment shortening evoked by sympathetic nerve stimulation in dogs was markedly reduced following coronary artery occlusion [7,8]. On the other hand, the response to administration of exogenous noradrenaline was unaffected by ischaemia, which indicates that the sympathetic neurotransmission but not the post-junctional response to noradrenaline was impaired. Neuronal stunning affects not only myocardial contractile function but also regulation of the coronary vasculature. … 

* Tel.: +46-8-5177-5876; fax: +46-8-311-044 john.pernow{at}ks.se
Early human IgH gene assembly in Epstein-Barr virus-transformed fetal B cell lines. Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements.
Authors: K G Nickerson, J Berman, E Glickman, L Chess, F W Alt
Journal: The Journal of Experimental Medicine (1989)

We have analyzed the phenotypic characteristics and IgH gene rearrangements in a panel of EBV-transformed B lineage cell lines from human fetal liver and bone marrow. Some lines contained only populations of immature, Ig- Be cells, while others contained mixed populations of mature and immature B cells. The majority of identifiable IgH rearrangements involved joining of the most JH-proximal D segment, DQ52, to various JH segments, implying that DQ52 is a preferred target for initial DJH rearrangements. Three other rearrangements involving VH-related sequences were also characterized. Two involved VHDJH joining using VH3 genes, although one of these had a very unusual DJH structure. The third consisted of inverted 3' signal sequences and flanking regions of a VH4 gene appended to a JH. The mechanisms by which the later rearrangement could have occurred and its potential physiological significance are discussed.