tbuckley/cabot-search huggingface dataset:
Upfront triple therapy for pulmonary arterial hypertension: is three a crowd or critical mass?
Authors: Michael D. McGoon
Journal: European Respiratory Journal (2014)

Upfront triple therapy may be the most reliable treatment strategy that we can offer PAH patients http://ow.ly/ugPbgEven the most enthusiastic reviews about progress in the pharmacotherapeutic management of pulmonary arterial hypertension (PAH) either begin or conclude with the sad acknowledgement that no treatment strategy comes close to being considered a ''cure.''There is little doubt, however, that the cumulative discovery, clinical testing, approval and integration of an expanding armamentarium of medications has led to improvement in patients' general well-being and life expectancy.Based on survival as a benchmark, the state of patients with PAH, as well as those with more narrowly and homogeneously defined idiopathic/ heritable/toxin-induced PAH, has progressively improved from when no specific drug treatment was available, to when calcium channel blockers were used, to the introduction and use of intravenous epoprostenol, to the current era, in which multiple drugs are available and are frequently employed in combination [1][2][3][4][5][6][7][8].Whereas median survival in 1986 for idiopathic PAH (then called primary pulmonary hypertension) was 2.8 years [2], it now exceeds 7 years [1].
Deletion of ABCA1 and ABCG1 Impairs Macrophage Migration Because of Increased Rac1 Signaling
Authors: Tamara A. Pagler, Mi Wang, Mousumi Mondal, Andrew J. Murphy, Marit Westerterp, Kathryn J. Moore, Frederick R. Maxfield, Alan R. Tall
Journal: Circulation Research (2010)

Reduced plasma cholesterol and increased high-density lipoprotein (HDL) levels promote regression of atherosclerosis, in a process characterized by lipid unloading and emigration of macrophages from lesions. In contrast free cholesterol loading of macrophages leads to imbalanced Rac1/Rho activities and impaired chemotaxis.To study the role of HDL and the ATP-binding cassette transporters ABCA1 and ABCG1 in modulating the chemotaxis of macrophages.Abca1(-/-)Abcg1(-/-) mouse macrophages displayed profoundly impaired chemotaxis both in a Transwell chamber assay and in the peritoneal cavity of wild-type (WT) mice. HDL reversed impaired chemotaxis in free cholesterol-loaded WT macrophages but was without effect in Abca1(-/-)Abcg1(-/-) cells, whereas cyclodextrin was effective in both. Abca1(-/-)Abcg1(-/-) macrophages had markedly increased Rac1 activity and increased association of Rac1 with the plasma membrane (PM). Their defective chemotaxis was reversed by a Rac1 inhibitor. To gain a better understanding of the role of transporters in PM cholesterol movement, we measured transbilayer PM sterol distribution. In WT macrophages, the majority of cholesterol was located on the inner leaflet, whereas on upregulation of transporters by liver X receptor activation, PM sterol was shifted to the outer leaflet, where it could be removed by HDL. Abca1(-/-)Abcg1(-/-) macrophages showed increased PM sterol content and defective redistribution of sterol to the outer leaflet.Deletion of ABCA1 and ABCG1 causes an increased cholesterol content on the inner leaflet of the PM, associated with increased Rac1 PM localization, activation, and impairment of migration. ABCA1 and ABCG1 facilitate macrophage chemotaxis by promoting PM transbilayer cholesterol movement and may contribute to the ability of HDL to promote regression of atherosclerosis.
Proinflammatory cytokine production and cartilage damage due to rheumatoid synovial T helper-1 activation is inhibited by interleukin-4.
Authors: J A van Roon, J L van Roy, A Duits, F P Lafeber, J W Bijlsma
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVES--To investigate the role of T helper-1 cell (Th1) activation in the induction of proinflammatory cytokine production and cartilage damage by rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMNC) and the subsequent possible beneficial role of the T helper-2 cell (Th2) cytokine interleukin-4 (IL-4) in the inhibition of this process. METHODS--SFMNC were stimulated with bacterial antigen (hsp60) to activate Th1 cells. Th1 and Th2 specific cytokine profiles (interferon gamma (IFN gamma) and IL-4) and proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha) in the conditioned media were analysed. In addition, the conditioned media were tested for their ability to induce cartilage damage. The same parameters were measured in the presence of IL-4. RESULTS--Stimulation of SFMNC with bacterial antigen resulted in an increase in IFN gamma, IL-1, and TNF alpha production which was accompanied by the induction of cartilage damage. Th1 activation could be inhibited by IL-4 as shown by a reduction of IFN gamma. This was accompanied by a decrease in IL-1 and TNF alpha production and inhibition of cartilage damage. CONCLUSIONS--Th1 activation is a possible mechanism by which inflammation in RA joints is enhanced. The Th2 cytokine IL-4 inhibits this Th1 activity and may diminish inflammation and induction of cartilage damage in RA joints.
Tumour necrosis factor and anti-tumour necrosis factor approach to inflammatory demyelinating diseases of the central nervous system
Authors: K. W Selmaj
Journal: Annals of the Rheumatic Diseases (2000)

Multiple sclerosis is a primary demyelinating disease in which an inflammatory cell infiltrate represents a characteristic pathological feature of active lesions within the central nervous system (CNS). As the search for anti-myelin antibodies in multiple sclerosis has thus far been unsuccessful, the possibility is raised that cell mediated immune mechanisms orchestrate the pathogenesis of this disease.1 In cellular immune mechanisms cytokines play a particularly important part. Tumour necrosis factors (TNFs) form a unique family of cytokines that are very pleiotropic in nature.2 TNFs demonstrate immunoregulatory activity but they are also involved in the effector arm of cellular immune responses. TNF increases antigen and mitogen induced T lymphocyte activation,3 as well as increasing the generation of cytotoxic T cells.4 Studies both in vitro and in vivo have suggested a role for TNFs in the pathology of multiple sclerosis. In this report, I will summarise data for and against involvement of TNFs in the mechanisms of multiple sclerosis and attempt to apply an anti-TNF approach for future therapeutic strategy for this disease.

An initial interest of TNFα involvement in the pathomechanisms of multiple sclerosis was generated after demonstration that TNFα was capable of inducing delayed onset myelin dilatation and subsequent gradual myelin degradation in organotypic nerve tissue cultures.5 The organotypic nerve tissue cultures have been established from spinal cord tissue explanted from mice embryos. Several cytokines, TNFα, interferon γ, interleukin 1, interleukin 2, interleukin 6 were added to spinal cord cultures at a time when myelination was well advanced. The cultures were examined in living state and after fixation by light and electron microscopy. In the living state, cultures exposed to TNFα showed selective damage to myelin. By light microscopy, myelinated fibres exhibited dilatations of myelin sheath. These swellings were regularly spaced along affected fibres and appeared …
Loss of CD55 Is Associated with Aggressive Breast Tumors
Authors: Zahra Madjd, Lindy G. Durrant, Richard Bradley, Ian Spendlove, Ian O. Ellis, Sarah E. Pinder
Journal: Clinical Cancer Research (2004)

Abstract Purpose: CD55 is a complement regulatory protein expressed by cells to protect them from bystander attack by complement. CD55 is overexpressed on some tumor cell lines, and in colorectal carcinomas, it has been shown to be an indicator of poor prognostic. Experimental Design: A large set of samples (480) from patients with primary operable breast cancer followed for 4–192 months were included in the present study. The prognostic significance of CD55 was then investigated in these tumors using an anti-CD55 monoclonal antibody (RM1) that we raised against a synthetic peptide and a standard immunohistochemistry method. Results: Ninety-five percent of the breast carcinomas expressed CD55 (RM1) with intensity ranging from weak (51%) to strong (6%). High expression of CD55 was significantly associated with low-grade (grades 1 or 2; P = 0.001), lymph node negativity (P = 0.031), and good prognosis tumors (Nottingham Prognostic Index &amp;lt; 3.4; P &amp;lt; 0.001). Survival analysis showed CD55 overexpression was associated with a more favorable outcome and loss of CD55 being associated with poor survival (P = 0.001). Intensity of CD55 expression was significantly correlated (P = 0.002) with intensity of CD59 expression (as shown in a previous study) in these series of patients. Conclusions: In conclusion, we found that loss of both CD55 and CD59 in breast carcinomas is associated with a worse prognosis.
Choice, optimal foraging, and the delay-reduction hypothesis
Authors: Edmund Fantino, Nureya Abarca
Journal: Behavioral and Brain Sciences (1985)

Abstract Behaving organisms are continually choosing. Recently the theoretical and empirical study of decision making by behavioral ecologists and experimental psychologists have converged in the area of foraging, particularly food acquisition. This convergence has raised the interdisciplinary question of whether principles that have emerged from the study of decision making in the operant conditioning laboratory are consistent with decision making in naturally occurring foraging. One such principle, the “parameter-free delay-reduction hypothesis, ” developed in studies of choice in the operant conditioning laboratory, states that the effectiveness of a stimulus as a reinforcer may be predicted most accurately by calculating the decrease in time to food presentation correlated with the onset of the stimulus, relative to the length of time to food presentation measured from the onset of the preceding stimulus. Since foraging involves choice, the delay-reduction hypothesis may be extended to predict aspects of foraging. We discuss the strategy of assessing parameters of foraging with operant laboratory analogues to foraging. We then compare the predictions of the delay-reduction hypothesis with those of optimal foraging theory, developed by behavioral ecologists, showing that, with two exceptions, the two positions make comparable predictions. The delay-reduction hypothesis is also compared to several contemporary pscyhological accounts of choice. Results from several of our experiments with pigeons, designed as operant conditioning simulations of foraging, have shown the following: The more time subjects spend searching for or traveling between potential food sources, the less selective they become, that is, the more likely they are to accept the less preferred outcome; increasing time spent procuring (“handling”) food increases selectivity; how often the preferred outcome is available has a greater effect on choice then how often the less preferred outcome is available; subjects maximize reinforcement whether it is the rate, amount, or probability of reinforcement that is varied; there are no significant differences between subjects performing under different types of deprivation (open vs. closed economies). These results are all consistent with the delay-reduction hypothesis. Moreover, they suggest that the technology of the operant conditioning laboratory may have fruitful application in the study of foraging, and, in doing so, they underscore the importance of an interdisciplinary approach to behavior.
Sequence Variations of MicroRNAs in Human Cancer: Alterations in Predicted Secondary Structure Do Not Affect Processing
Authors: Sven Diederichs, Daniel A. Haber
Journal: Cancer Research (2006)

Abstract Expression levels of microRNAs (miRNAs) are globally reduced in cancer compared with matched normal tissues, and miRNA function has recently been implicated in tumorigenesis. To test whether epigenetic silencing contributes to miRNA suppression in tumors, lung cancer cells were treated with inhibitors of DNA methylation or histone deacetylation. No significant alteration in miRNA expression was detected using microarray profiling. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). No mutations were detected within any of the short mature miRNA sequences. In addition to previously reported polymorphisms, 1 sequence variant in a precursor miRNA and 15 variants in primary miRNA (pri-miRNA) transcripts were identified. Despite pri-miRNAs having dramatic changes in the predicted secondary folding structure flanking putative cleavage sites, processing and miRNA maturation were not affected in vivo. Thus, genetic variants in miRNA precursors are common in cancer cells but are unlikely to have physiologic significance. (Cancer Res 2006; 66(12): 6097-104)
Mixed linear model approach adapted for genome-wide association studies
Authors: Zhiwu Zhang, Elhan Ersoz, Chao-Qiang Lai, Rory J Todhunter, Hemant K Tiwari, Michael A Gore, Peter J Bradbury, Jianming Yu, Donna K Arnett, Jose M Ordovas, Edward S Buckler
Journal: Nature Genetics (2010)
Severe asthma after inadvertent ingestion of oxprenolol.
Authors: I P Williams, F J Millard
Journal: Thorax (1980)

We report a case in which the accidental ingestion of 80 mg of oxprenolol resulted in a respiratory-cardiac arrest.The report draws attention to the dangers of ,a blockers in asthmatics, and to the rapidity with which serious sequaelae may follow their administra- tion.Case report
EXPERIMENTAL DISSEMINATED ENCEPHALOMYELITIS IN WHITE MICE
Authors: Peter K. Olitsky, Robert H. Yager
Journal: The Journal of Experimental Medicine (1949)

Disseminated encephalomyelitis was readily induced in mice of the Swiss strain by means of repeated intramuscular and subcutaneous injections of apparently normal mouse brain mixed with an adjuvant. The latter consisted of autoclaved virulent tubercle bacilli and heavy liquid petrolatum, a modification of the Freund adjuvant. The syndrome and the histopathological picture of the induced malady were essentially similar to those in monkeys, rabbits, and guinea pigs, previously reported by others. Certain exceptional characteristics of the affection, as occurring in mice, suggest that they may be the animals of choice for its study as well as for that of other encephalitides. Not only were the signs indicative of marked involvement of the central nervous system but also of the respiratory mechanism, and only a few injections of mouse brain-adjuvant mixture were required to evoke the neurological symptom complex in almost every animal.
Exercise testing and exercise prescription for special cases--theoretical basis and clinical application
Authors: David A. Brodie
Journal: British Journal of Sports Medicine (1987)

This text makes a magnificent contribution to the literature on exercise testing.It does so by presenting a collection of individual chapters, written by authorities in the field, each one considering a different aspect of testing or special population.Each of the chapters is presented economically yet in depth, well referenced and up-to-date.The first section on general considerations includes general principles, sexual dimorphism, aspects of age and environment.The second section on special cases includes rheumatoid arthritis, diabetes, dyslipoproteinemia, obesity, respiratory and cardiovascular conditions, and pregnancy.Sadly my review copy contained a serious printing error which duplicated two chapters and omitted two others.I was, therefore, not able to examine the special cases of rheumatoid arthritis and diabetes, but trust the printers have corrected this problem.It is difficult to fault such an authoritative text and for any serious student of exercise testing and prescription, particularly considerations of special subjects, this book would be a valuable addition to their library.
Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons
Authors: Hiroshi Yamamoto, Charlotte E. Lee, Jacob N. Marcus, Todd D. Williams, J. Michael Overton, Marisol E. Lopez, Anthony N. Hollenberg, Laurie Baggio, Clifford B. Saper, Daniel J. Drucker, Joel K. Elmquist
Journal: Journal of Clinical Investigation (2002)

Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo.
Gabapentin for Neuropathic Cancer Pain: A Randomized Controlled Trial From the Gabapentin Cancer Pain Study Group
Authors: Augusto Caraceni, Ernesto Zecca, Cesare Bonezzi, Edoardo Arcuri, Ricardo Yaya Tur, Marco Maltoni, Marco Visentin, Giovanna Gorni, Cinzia Martini, Walter Tirelli, Massimo Barbieri, Franco De Conno
Journal: Journal of Clinical Oncology (2004)

Purpose To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain. Patients and Methods One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opiod analgesics. Results Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P = .0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P = .0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%). Conclusion Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids.
CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: a review
Authors: M C Béné, G Castoldi, W Knapp, G M Rigolin, L Escribano, P Lemez, W-D Ludwig, E Matutes, A Orfao, F Lanza, M van't Veer
Journal: Leukemia (2003)
Can Trained Dogs Detect a Hypoglycemic Scent in Patients With Type 1 Diabetes?
Authors: Ky Dehlinger, Kristin Tarnowski, Jody L. House, Evan Los, Kathryn Hanavan, Bryan Bustamante, Andrew J. Ahmann, W. Kenneth Ward
Journal: Diabetes Care (2013)

In persons with type 1 diabetes (T1D), hypoglycemia is common and sometimes serious. Anecdotal reports suggest that dogs can detect hypoglycemia in their human companions. The current study was undertaken to assess whether dogs can detect hypoglycemia by scent alone.

The study was approved by the Human Institutional Review Board and the Animal Care and Use Committee at Legacy Research Institute (Portland, OR). Three patients with T1D were enrolled (age 25–57 years; duration of diabetes 2–21 years; none were hypoglycemic unaware). These people were unfamiliar to the dogs that were studied. For each of two hypoglycemic periods (capillary blood specimens ≤60 mg/dL), each subject collected two sterile cotton swab samples by rubbing them on the skin of both arms. Additional samples were collected during two normoglycemic episodes (capillary glucose 100–150 mg/dL). This procedure was chosen …
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial
Authors: G Comi, V Martinelli, M Rodegher, L Moiola, O Bajenaru, A Carra, I Elovaara, F Fazekas, HP Hartung, J Hillert, J King, S Komoly, C Lubetzki, X Montalban, KM Myhr, M Ravnborg, P Rieckmann, D Wynn, C Young, M Filippi
Journal: The Lancet (2009)
No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans
Authors: Véronique Bolduc, Pierre Chagnon, Sylvie Provost, Marie-Pierre Dubé, Claude Belisle, Marianne Gingras, Luigina Mollica, Lambert Busque
Journal: Journal of Clinical Investigation (2007)

Skewing of X chromosome inactivation (XCI) can occur in normal females and increases in tissues with age. The mechanisms underlying skewing in normal females, however, remain controversial. To better understand the phenomenon of XCI in nondisease states, we evaluated XCI patterns in epithelial and hematopoietic cells of over 500 healthy female mother-neonate pairs. The incidence of skewing observed in mothers was twice that observed in neonates, and in both cohorts, the incidence of XCI was lower in epithelial cells than hematopoietic cells. These results suggest that XCI incidence varies by tissue type and that age-dependent mechanisms can influence skewing in both epithelial and hematopoietic cells. In both cohorts, a correlation was identified in the direction of skewing in epithelial and hematopoietic cells, suggesting common underlying skewing mechanisms across tissues. However, there was no correlation between the XCI patterns of mothers and their respective neonates, and skewed mothers gave birth to skewed neonates at the same frequency as nonskewed mothers. Taken together, our data suggest that in humans, the XCI pattern observed at birth does not reflect a single heritable genetic locus, but rather corresponds to a complex trait determined, at least in part, by selection biases occurring after XCI.