tbuckley/cabot-search huggingface dataset:
Differential roles of microglia and monocytes in the inflamed central nervous system
Authors: Ryo Yamasaki, Haiyan Lu, Oleg Butovsky, Nobuhiko Ohno, Anna M. Rietsch, Ron Cialic, Pauline M. Wu, Camille E. Doykan, Jessica Lin, Anne C. Cotleur, Grahame Kidd, Musab M. Zorlu, Nathan Sun, Weiwei Hu, LiPing Liu, Jar-Chi Lee, Sarah E. Taylor, Lindsey Uehlein, Debra Dixon, Jinyu Gu, Crina M. Floruta, Min Zhu, Israel F. Charo, Howard L. Weiner, Richard M. Ransohoff
Journal: The Journal of Experimental Medicine (2014)

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
Effect of penicillamine on complement in vitro and in vivo.
Authors: O J Mellbye, E Munthe
Journal: Annals of the Rheumatic Diseases (1977)

In most normal human sera the addition of penicillamine to a final concentration of 0-2 mmol/l and subsequent dialysis caused a slight reduction in serum haemolytic complement (CH50). At 200 mmol/l, CH50 activity was no longer demonstrable. Even high concentrations of penicillamine were needed to inhibit the ability of immunoglobulin to fix complement to preformed or forming immune complexes. This indicated that the reduction of CH50 observed in serum was due to an effect on the complement factors. In vivo, a dose of 240 mg penicillamine caused a slight transient reduction in CH50 in rabbit serum, while 1000 mg penicillamine had no effect on serum CH50 in patients with rheumatoid arthritis. In arthritis patients there was, however, some evidence for removal of complement deposits in synovial tissue during penicillamine treatment. Since it is theoretically possible that concentrations high enough to cause reduction of complement activity can be achieved locally in synovial tissue, the effect on complement may be one of the mechanisms by which penicillamine exerts its effect in rheumatoid arthritis.
The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion
Authors: Noritoshi Kato, Yukio Yuzawa, Tomoki Kosugi, Akinori Hobo, Waichi Sato, Yuko Miwa, Kazuma Sakamoto, Seiichi Matsuo, Kenji Kadomatsu
Journal: Journal of the American Society of Nephrology (2009)

E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg−/−) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg−/− mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg−/− neutrophils showed reduced binding to E-selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg−/− neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg−/− neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg+/+ neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion.
Familial gynecomastia with increased extraglandular aromatization of plasma carbon19-steroids.
Authors: G D Berkovitz, A Guerami, T R Brown, P C MacDonald, C J Migeon
Journal: Journal of Clinical Investigation (1985)

We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-17 beta in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17 beta and of estradiol-17 beta to estrone were normal. Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.
Effects of preventive home visits to elderly people living in the community: systematic review
Authors: J. C M van Haastregt
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To assess the effects of preventive home visits to elderly people living in the community. <b>Design:</b> Systematic review. <b>Setting:</b> 15 trials retrieved from Medline, Embase, and the Cochrane controlled trial register. <b>Main outcome measures:</b> Physical function, psychosocial function, falls, admissions to institutions, and mortality. <b>Results:</b> Considerable differences in the methodological quality of the 15 trials were found, but in general the quality was considered adequate. Favourable effects of the home visits were observed in 5 out of 12 trials measuring physical functioning, 1 out of 8 measuring psychosocial function, 2 out of 6 measuring falls, 2 out of 7 measuring admissions to institutions, and 3 of 13 measuring mortality. None of the trials reported negative effects. <b>Conclusions:</b> No clear evidence was found in favour of the effectiveness of preventive home visits to elderly people living in the community. It seems essential that the effectiveness of such visits is improved, but if this cannot be achieved consideration should be given to discontinuing these visits.
Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK
Authors: Pablo B. Martínez de Morentin, Ismael González-García, Luís Martins, Ricardo Lage, Diana Fernández-Mallo, Noelia Martínez-Sánchez, Francisco Ruíz-Pino, Ji Liu, Donald A. Morgan, Leonor Pinilla, Rosalía Gallego, Asish K. Saha, Andries Kalsbeek, Eric Fliers, Peter H. Bisschop, Carlos Diéguez, Rubén Nogueiras, Kamal Rahmouni, Manuel Tena-Sempere, Miguel López
Journal: Cell Metabolism (2014)

Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
Pneumocystis carinii pneumonia and reticuloses
Authors: K. R. Humphries, H. Ngan, K. James
Journal: Thorax (1968)

Three cases of <i>Pneumocystis carinii</i> pneumonia occurring in the course of diseases of the lymphoreticular system are described. One case was diagnosed in life and unsuccessfully treated with pentamidine isethionate. Incidence of the pneumonia is associated with a depressed immune response and may be more frequent than is usually realized in patients with reticuloses who are receiving corticosteroid and cytotoxic drugs.
Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus
Authors: Mari Rodriguez de Evgrafov, Heidi Gumpert, Christian Munck, Thomas T. Thomsen, Morten O.A. Sommer
Journal: Molecular Biology and Evolution (2015)

As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent drugs should be the focus of future resistance evolution work.
Open Clinic-Based Peanut Food Challenges are a Viable and Safe Method of Evaluating Clinical Sensitivity and Tolerance
Authors: J.E. Conner, S.A. Lowe, L.A. Crandall, M.B. Ho, C.M. Lee, M. Feuling, C. Sova, M. Vasudev
Journal: Journal of Allergy and Clinical Immunology (2012)
Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial
Authors: A.J. Zurita, D.J. George, N.D. Shore, G. Liu, G. Wilding, T.E. Hutson, M. Kozloff, P. Mathew, C.S. Harmon, S.L. Wang, I. Chen, E. Chow Maneval, C.J. Logothetis
Journal: Annals of Oncology (2011)
Possible mechanisms underlying the development of cachexia in COPD
Authors: P. D. Wagner
Journal: European Respiratory Journal (2008)

About 25% of patients with chronic obstructive pulmonary disease (COPD) will develop cachexia (fat-free body mass index <17 kg.m(-2) (males) or <14 kg.m(-2) (females)). This is associated with approximately 50% reduction in median survival. The pathogenetic mechanism has been variously suggested to result from the following: 1) energy imbalance; 2) disuse atrophy; 3) tissue hypoxia from arterial hypoxaemia; 4) systemic inflammation; and 5) anabolic hormonal insufficiency. Genetic polymorphisms implicate inflammatory cytokines, especially interleukin (IL)-1beta, but IL-6 and tumour necrosis factor (TNF)-alpha do not show polymorphisms in these patients. Early reports of elevated TNF-alpha levels suggested a role for inflammation, but recent studies have not shown elevated levels of either IL-6 or TNF-alpha. Therapeutic trials of nutritional support, hormonal supplementation, anti-TNF-alpha immunotherapy, ghrelin and antioxidants have been conducted, but only a few have shown any benefits in muscle structure and function. Considerably more mechanistic knowledge is needed before therapeutic recommendations can be made. At this time, it is not possible to attribute cachexia in COPD unequivocally to inflammation or any other cause, and much more research is needed. To date, studies have been predominantly cross-sectional, with measurements made only after cachexia has developed. Future research should target prospective observation, studying patients as cachexia progresses, since once cachexia is established, inflammatory cytokine levels may not be abnormal.
Effect of Serotonin on Glycogen Metabolism in Isolated Rat Liver*
Authors: Robert A. Levine, Leroy A. Pesch, Gerald Klatskin, Nicholas J. Giarman
Journal: Journal of Clinical Investigation (1964)

In the invertebrate liver fluke, Fasciola hepatica, there is evidence that 5-hydroxytryptamine (serotonin) increases glycolysis (1, 2), glycogenolysis (1), and phosphorylase activity (3).However, previous studies in mammalian liver, in vitro and in vivo, have yielded conflicting results concerning the effect of serotonin on hepatic glycogen content, hepatic phosphorylase, and blood glucose.Some investigators have reported a hyperglycemic action that they have attributed either to liberation of epinephrine from the adrenal medulla (4, 5) or to a direct glycogenolytic effect in the liver (6, 7).Others have found that serotonin either has no effect on blood glu- cose or produces hypoglycemia (8-11).To investigate the direct action of serotonin on hepatic glycogen metabolism, we employed the technique of isolated liver perfusion.The re- sults of our studies indicate that exogenous or endogenous serotonin causes glycogenolysis, hyperglycemia, and stimulation of hepatic phosphorylase activity in the isolated perfused rat liver.
Mechanism of Renal Handling of Angiotensin II in the Dog
Authors: SUZANNE OPARIL, MICHAEL D. BAILIE
Journal: Circulation Research (1973)

The mechanism of renal handling of angiotensin II was studied in vivo in the renal circulation of the intact anesthetized dog and in vitro in whole blood using 14 C-5-Ile-angiotensin II, l -Asp- 125 I-angiotensin II, and d -Asp- 125 I-angiotensin II. Seventy-five percent of a 600-pmole bolus of 14 C-angiotensin II was degraded in a single passage through the kidney as measured by radioactive tracer and radioimmunoassay techniques. The metabolic products were 14 C-5-Ile (59%), 5-Ile-8-Phe (15%), and 3-Val-8-Phe (2%); recovery of the injected radioactive material was 99%. The degradation rate of 14 C-angiotensin II in whole dog blood in vitro was only 17%/min. Similar metabolic patterns were seen in vivo and in vitro. Sixty-six percent of the injected l -Asp- 125 I-angiotensin II was metabolized, but only 23% of the d -Asp- 125 I-angiotensin II was metabolized in a single passage through the kidney. These observations indicate that, under the conditions of these experiments, (1) angiotensin II is rapidly metabolized in the dog kidney by multiple enzymes, including an aminopeptidase, (2) circulating plasma enzymes do not account for the renal handling of angiotensin II, and (3) angiotensin II is not sequestered in the kidney.
Comprehensive analysis of microRNA-regulated protein interaction network reveals the tumor suppressive role of microRNA-149 in human hepatocellular carcinoma via targeting AKT-mTOR pathway
Authors: Yanqiong Zhang, Xiaodong Guo, Lu Xiong, Lingxiang Yu, Zhiwei Li, Qiuyan Guo, Zhiyan Li, Boan Li, Na Lin
Journal: Molecular Cancer (2014)

Our previous study identified AKT1, AKT2 and AKT3 as unfavorable prognostic factors for patients with hepatocellular carcinoma (HCC). However, limited data are available on their exact mechanisms in HCC. Since microRNAs (miRNAs) are implicated in various human cancers including HCC, we aimed to screen miRNAs targeting AKTs and investigate their underlying mechanisms in HCC by integrating bioinformatics prediction, network analysis, functional assay and clinical validation. Five online programs of miRNA target prediction and RNAhybrid which calculate the minimum free energy (MFE) of the duplex miRNA:mRNA were used to screen optimized miRNA-AKT interactions. Then, miRNA-regulated protein interaction network was constructed and 5 topological features ('Degree', 'Node-betweenness', 'Edge-betweenness', 'Closeness' and 'Modularity') were analyzed to link candidate miRNA-AKT interactions to oncogenesis and cancer hallmarks. Further systematic experiments were performed to validate the prediction results. Six optimized miRNA-AKT interactions (miR-149-AKT1, miR-302d-AKT1, miR-184-AKT2, miR-708-AKT2, miR-122-AKT3 and miR-124-AKT3) were obtained by combining the miRNA target prediction and MFE calculation. Then, 103 validated targets for the 6 candidate miRNAs were collected from miRTarBase. According to the enrichment analysis on GO items and KEGG pathways, these validated targets were significantly enriched in many known oncogenic pathways for HCC. In addition, miRNA-regulated protein interaction network were divided into 5 functional modules. Importantly, AKT1 and its interaction with mTOR respectively had the highest node-betweenness and edge-betweenness, implying their bottleneck roles in the network. Further experiments confirmed that miRNA-149 directly targeted AKT1 in HCC by a miRNA luciferase reporter approach. Then, re-expression of miR-149 significantly inhibited HCC cell proliferation and tumorigenicity by regulating AKT1/mTOR pathway. Notably, miR-149 down-regulation in clinical HCC tissues was correlated with tumor aggressiveness and poor prognosis of patients. This comprehensive analysis identified a list of miRNAs targeting AKTs and revealed their critical roles in HCC malignant progression. Especially, miR-149 may function as a tumor suppressive miRNA and play an important role in inhibiting the HCC tumorigenesis by modulating the AKT/mTOR pathway. Our clinical evidence also highlight the prognostic potential of miR-149 in HCC. The newly identified miR-149/AKT/mTOR axis might be a promising therapeutic target in the prevention and treatment of HCC.
Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children
Authors: Savvas Savvatianos, Anastasios P. Konstantinopoulos, Åse Borgå, George Stavroulakis, Jonas Lidholm, Magnus P. Borres, Emmanouil Manousakis, Nikolaos G. Papadopoulos
Journal: Journal of Allergy and Clinical Immunology (2015)
A STUDY OF THE ANTIDEPRESSANT EFFECTS OF PARGYLINE
Authors: MILTON H. MILLER, LEIGH M. ROBERTS, CARL H. FELLNER
Journal: American Journal of Psychiatry (1964)

The evaluation of antidepressant medication in an office practice setting is complicated by the somewhat unpredictable course of the illness, the long time interval before medications can become effective, and by the difficulty in weighing subjective findings. Our clinical impression, however, is that pargyline may demonstrate a low order of clinical effectiveness as an antidepressant agent. It would not appear to be as dependable or as effective as some of the other antidepressant medications which are available. The low order of antidepressant effects may have some importance clinically in the use of pargyline as an anti-hypertensive drug since some other blood pressure reducing agents now in use in medical practice have a predilection for the production of depression. Further clinical study will be necessary to determine whether this inference holds. Importantly, physicians prescribing this medication for its antihypertensive effects should be aware of the fact that this is a monoamine oxidase inhibitor which must be prescribed with care. It should probably never be given along with other monoamine oxidase inhibitors or imipramine.
Cell and Molecular Determinants of<i>In Vivo</i>Efficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts
Authors: Santi Suryani, Hernan Carol, Triona Ni Chonghaile, Viktoras Frismantas, Chintanu Sarmah, Laura High, Beat Bornhauser, Mark J. Cowley, Barbara Szymanska, Kathryn Evans, Ingrid Boehm, Elise Tonna, Luke Jones, Donya Moradi Manesh, Raushan T. Kurmasheva, Catherine Billups, Warren Kaplan, Anthony Letai, Jean-Pierre Bourquin, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock
Journal: Clinical Cancer Research (2014)

Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity.The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity.ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%).These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy.