tbuckley/cabot-search huggingface dataset:
Intravital Microscopy on Atherosclerosis in Apolipoprotein E–Deficient Mice Establishes Microvessels as Major Entry Pathways for Leukocytes to Advanced Lesions
Authors: Einar E. Eriksson
Journal: Circulation (2011)

There has been considerable speculation about the role of lesion microvessels in the accumulation of leukocytes in atherosclerosis. However, direct study of microvascular recruitment of leukocytes in lesions has not been performed, and the quantitative role for this route of entry is unclear.Here, microvascular recruitment of leukocytes was studied in advanced lesions in 12- to 24-month-old apolipoprotein E-deficient (ApoE(-/-)) mice. Histology and transmission electron microscopy demonstrated the presence of mainly adventitial, but also intimal, microvessels. Interactions between leukocytes and endothelium occurred in lesion venules. Leukocyte rolling was largely P-selectin dependent; however, residual rolling was mediated by L-selectin and endothelial P-selectin glycoprotein ligand 1. Leukocyte adhesion was significant and was attenuated in mice treated with antibodies against P-selectin, CD18, or both before preparation for intravital microscopy, suggesting acute activation of these 2 molecules by surgical trauma. Nonetheless, the density of firmly arrested leukocytes was 100-fold higher in lesion venules compared with the arterial lumen even in mice pretreated with antibodies against P-selectin and CD18, indicating strong recruitment of cells from venules that is unrelated to experimental manipulation. Fluorescent myelomonocytic cells in ApoE(-/-) mice carrying a knock-in mutation for enhanced green fluorescent protein (EGFP) in the lysozyme M locus (ApoE(-/-)/lysM(EGFP/EGFP) mice) were distributed specifically around lesion venules, but not around arterioles or capillaries, further indicating ongoing extravasation from venules into plaque tissue.These findings provide strong data for microvascular recruitment of leukocytes in atherosclerosis and indicate roles for L-selectin and P-selectin glycoprotein ligand 1 in this process.
The Role of Notch in Promoting Glial and Neural Stem Cell Fates
Authors: Nicholas Gaiano, Gord Fishell
Journal: Annual Review of Neuroscience (2002)

▪ Abstract The Notch signaling pathway has long been known to influence cell fate in the developing nervous system. However, this pathway has generally been thought to inhibit the specification of certain cell types in favor of others, or to simply maintain a progenitor pool. Recently, this view has been challenged by numerous studies suggesting that Notch may play an instructive role in promoting glial development. This work has inspired a new look at the role of Notch signaling in specifying cell fate. It has also prompted further consideration of the emerging view that in some contexts glia may be multipotent progenitors. This review examines the role of Notch during gliogenesis in both fruit flies and vertebrates, as well as evidence in vertebrates that some glia may be stem cells.
Breast implants and illness: a model of psychological factors
Authors: D M Dush
Journal: Annals of the Rheumatic Diseases (2001)

Studies of disease outcomes have not produced an explanation or an intervention for the symptoms and complaints that some women have attributed to breast implants. Reviews of the literature have found no increased risk of specific systemic disease, and no treatment recommendations have emerged. However, similar symptoms in fibromyalgia, chronic fatigue, and other contexts have been considered to be stress or behaviourally mediated, and a number of promising behavioural interventions have been developed. Aetiological, research, and treatment implications may follow from the consideration of such symptoms within a behavioural medicine model that allows for the interaction of physical and psychological influences. In the case of implants, a mass somatisation model may also help to discern the potential effects of litigation and other social influences.
Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats
Authors: Mitugi Yasuda, Ichiro Shimizu, Masako Shiba, Susumu Ito
Journal: Hepatology (1999)

As a model for the analysis of the fibrosuppressive role of estradiol, hepatic fibrosis was induced in male and female rats by the administration of a single dose of dimethylnitrosamine (DMN). The fibrotic response of the male liver after DMN treatment was significantly stronger than that of the female liver. In the male DMN model, estradiol reduced hepatic mRNA for type I and III procollagens and the tissue inhibitor of metalloproteinase–1 (TIMP–1), as well as deposition of type I and III collagen protein total hepatic collagen and malondialdehyde (MDA), a product of lipid peroxidation. Concomitant administration of a neutralizing antibody against rat estradiol enhanced fibrogenesis, as judged by the same parameters. Ovariectomy in the female model had a fibrogenic effect, inducing the hepatic expression of both types of procollagen and TIMP–1; in addition, the number of α–smooth muscle actin (α–SMA)-positive cells in the liver increased; estradiol replacement was fibrosuppressive in the castrated–female model. In rat hepatic stellate cells incubated in primary culture with estradiol, cell number, type I collagen production, and α–SMA expression were all reduced. These findings suggest that estradiol suppressed the induction of hepatic fibrosis, and may in part underlie the more rapid progression in males of hepatic fibrosis and its complications.
Pulmonary gas exchange responses to histamine and methacholine challenges in mild asthma
Authors: A.L. Echazarreta, F.P. Gómez, J. Ribas, E. Sala, J.A. Barberà, J. Roca, R. Rodriguez-Roisin
Journal: European Respiratory Journal (2001)

Histamine (HIST) produces greater changes in bronchial and pulmonary vasculature, and so may produce more gas exchange abnormalities, than methacholine (MTH) after inhalational challenge. The goals of this study were to compare the effects of HIST and MTH challenge on pulmonary gas exchange in patients with mild asthma at an equivalent degree of bronchoconstriction. Eleven patients were studied (mean±sem age, 22±1 yr; forced expiratory volume in one second (FEV 1 ), 91±5% pred) using a randomized, double-blind cross-over design. Respiratory system resistance ( R rs ), arterial blood gases, and ventilation-perfusion distributions were measured before and after HIST/MTH challenges when cumulative doses caused a 30% fall in FEV 1 . Compared with baseline, HIST and MTH provoked similar moderate to severe increases in R rs (p&lt;0.005 each), and mild to moderate decreases in arterial oxygen tension ( P a,O 2 ) due to ventilation-perfusion abnormalities (dispersion of pulmonary blood flow -log SDQ-, 0.40±0.03–0.71±0.08 and 0.47±0.04–0.89±0.06; normal values &lt;0.60–0.65), respectively, similar to those shown in mild to moderate acute asthma, without differences between them. For the same degree of airflow obstruction, both histamine and methacholine bronchoprovocations induce, in patients with mild asthma, very similar disturbances in ventilation-perfusion distribution and respiratory system resistance, suggesting similar mechanisms of airway narrowing.
Idiopathic pulmonary fibrosis trials: recommendations for the jury
Authors: S.D. Nathan, R.M. du Bois
Journal: European Respiratory Journal (2011)

Idiopathic pulmonary fibrosis (IPF) is a disease with a dismal prognosis and a median survival of only 2–3 yrs. There are no licensed medical therapies in the USA and the only care options that are endorsed by the most recent consensus guidelines are lung transplantation and enrolment in a clinical trial [1]. Although the past decade has seen numerous trials in IPF being undertaken and completed, the outcomes have mostly been disappointing with only one or two exceptions [2, 3]. Despite this, valuable insights about the natural history and course of the disease have been gained from the well-characterised patient data sets of these trials. However, these studies have raised many questions and fuelled the continuing debate on how future IPF trials should be designed. There are many considerations and challenges involved in the implementation and completion of IPF studies. The complex nature of the pathogenic process, the highly variable disease course, the possibility of inadequate drug deposition in the targeted area and the uncertainty about the most appropriate end-points may all confound the interpretation of clinical trial results.

It is believed that IPF is the result of derangements of the alveolar epithelial membrane followed by an inappropriate wound healing response, for reasons that remain unknown. These perturbations occur at unpredictable intervals with great inter-individual variability over many years. Therefore, at clinical presentation, the pathology consists of a combination of relatively unaffected areas, together with more advanced, established fibrosis and various degrees of histopathology between these extremes. Each stage of this dynamic disease process is marked by simultaneous cellular derangements, activated pathways and dysregulated cytokines co-localising with upstream initiators and downstream consequences. This intricate network of mediators and pathways may be accompanied by autocrine and escape pathways that limit the ability of a unimechanistic agent …
Highly effective treatment of acquired immunodeficiency syndrome–related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology
Authors: Richard F. Little, Stefania Pittaluga, Nicole Grant, Seth M. Steinberg, Mark F. Kavlick, Hiroaki Mitsuya, Genoveffa Franchini, Martin Gutierrez, Mark Raffeld, Elaine S. Jaffe, Gene Shearer, Robert Yarchoan, Wyndham H. Wilson
Journal: Blood (2003)
THE ETIOLOGIC AGENTS OF VARICELLA AND HERPES ZOSTER
Authors: Thomas H. Weller, Helen M. Witton
Journal: The Journal of Experimental Medicine (1958)

The preparation of antigenic materials capable of specific fixation of complement in the presence of convalescent phase sera from patients with varicella and herpes zoster is described. Satisfactory antigens were obtained by the repetitive harvest and subsequent concentration of the pooled nutrient fluids from bottle cultures of human embryonic skin-muscle tissue or of monkey kidney tissue infected with varicella or herpes zoster viruses. Specific fixation of complement was also demonstrated with antigens prepared from extracts of the infected cell sheets harvested from bottle cultures. In individuals with varicella, complement-fixing antibody usually appeared in the serum 4 or 5 days after the development of the exanthem and further significant increases in titer were characteristically observed during the 2nd week of illness. The complement-fixing antibody response in herpes zoster tended to follow the same pattern as in varicella, with the exception that in sera from some individuals relatively high titers were present in the acute phase specimen. Complement-fixing antigens prepared from varicella strains or from a zoster strain reacted to essentially the same degree with convalescent sera from the homologous and the heterologous clinical entities. The varicella-zoster antigens did not fix complement in the presence of paired sera obtained from a limited number of individuals with primary infections due to herpes simplex virus or from individuals with generalized vaccinia infection. Specific inhibition in vitro of the focal cytopathic process produced by the varicella-zoster viruses was demonstrated. This was accomplished by the incorporation of the sera under test as constituents of nutrient media of the cultures, either prior to or at the time of their inoculation with virus. The neutralization of focal cytopathogenicity thus obtained was relative in degree and never absolute; it was therefore assayed by repetitive counts of the number of focal lesions per culture in the various test groups. Inhibition of varicella-zoster viral cytopathogenicity occurred in the presence of convalescent serum from either clinical entity. The results of the immunologic studies with the viruses of herpes zoster and varicella as propagated in vitro are considered as providing further evidence in support of the concept of the close relationship and probable identity of the two agents.
Role of<i>Helicobacter pylori</i>CagL in modulating gastrin expression
Authors: Timothy L Cover
Journal: Gut (2012)

Helicobacter pylori is a Gram-negative bacterium that is highly adapted for persistent colonisation of the human stomach. Although most H pylori -infected people remain asymptomatic, the presence of this organism is a risk factor for gastric adenocarcinoma, peptic ulcer disease and gastric lymphoma. There is a high level of genetic heterogeneity among H pylori strains and the risk of gastric disease is determined, in part, by characteristics of the H pylori strain(s) with which a person is infected.1 One of the most extensively studied genetic features of disease-associated H pylori strains is the cag pathogenicity island (PAI). This 40 kb region of chromosomal DNA, comprising about 27 genes, may be present, incomplete or absent in H pylori strains.

CagA, the first cag PAI-encoded protein to be studied in detail, is a highly antigenic protein that is translocated into gastric epithelial cells. Within gastric epithelial cells, CagA undergoes phosphorylation by host cell tyrosine kinases and interacts with multiple host proteins, leading to cytoskeletal rearrangements, disruption of cellular junctions, altered cellular adhesion and polarity and increased cell proliferation. Experiments in animal models indicate that CagA has an important role in the pathogenesis of gastric cancer and therefore, CagA has been termed a bacterial oncoprotein.2 CagA is translocated into host cells by a process that requires about 17 genes within the cag PAI, several of which are homologous to genes encoding components of type IV secretion systems (T4SS) in other Gram-negative bacterial species. …
Understanding controlled trials: What is a patient preference trial?
Authors: D. Torgerson, B. Sibbald
Journal: BMJ (1998)

A common problem in randomised controlled trials arises when patients (or their clinicians) have such strong treatment preferences that they refuse randomisation.1 The absence of these patients from trials may restrict generalisation of the results, as participants may not be representative. A further potential source of bias exists when patients with strong treatment preferences are recruited and randomised. When it is not possible to blind patients to their treatment allocation they may suffer resentful demoralisation2 if they do not receive their preferred treatment and may comply poorly. On the other hand, patients receiving their preferred treatment may comply better than average. There may therefore be a treatment effect which results from patient preferences and not from therapeutic efficacy. The effects of resentful demoralisation are …
Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs.
Authors: G J Gross, J A Auchampach
Journal: Circulation Research (1992)

Single or multiple brief periods of ischemia (preconditioning) have been shown to protect the myocardium from infarction after a subsequent more prolonged ischemic insult. To test the hypothesis that preconditioning is the result of opening ATP-sensitive potassium (KATP) channels, a selective KATP channel antagonist, glibenclamide, was administered before or immediately after preconditioning in barbital-anesthetized open-chest dogs subjected to 60 minutes of left circumflex coronary artery (LCX) occlusion followed by 5 hours of reperfusion. Preconditioning was elicited by 5 minutes of LCX occlusion followed by 10 minutes of reperfusion before the 60-minute occlusion period. Glibenclamide (0.3 mg/kg i.v.) or vehicle was given 10 minutes before the initial ischemic insult in each of four groups. In a fifth group, glibenclamide was administered immediately after preconditioning. In a final series (group 6), a selective potassium channel opener, RP 52891 (10 micrograms/kg bolus and 0.1 micrograms/mg/min i.v.) was started 10 minutes before occlusion and continued throughout reperfusion. Transmural myocardial blood flow was measured at 30 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk. There were no significant differences in hemodynamics, collateral blood flow, or area at risk between groups. The ratio of infarct size to area at risk in the control group (28 +/- 6%) was not different from the group pretreated with glibenclamide in the absence of preconditioning (31 +/- 6%). Preconditioning produced a marked reduction (p less than 0.002) in infarct size (28 +/- 6% to 6 +/- 2%), whereas glibenclamide administered before or immediately after preconditioning completely abolished the protective effect (28 +/- 6% and 30 +/- 8%, respectively). RP 52891 also produced a significant (p less than 0.03) reduction (28 +/- 6% to 13 +/- 3%) in infarct size. These results suggest that myocardial preconditioning in the canine heart is mediated by activation of KATP channels and that these channels may serve an endogenous myocardial protective role.
Urine Collagen Fragments and CKD Progression—The Cardiovascular Health Study
Authors: Joachim H. Ix, Mary L. Biggs, Kenneth Mukamal, Luc Djousse, David Siscovick, Russell Tracy, Ronit Katz, Joseph A. Delaney, Paulo Chaves, Dena E. Rifkin, Jan M. Hughes-Austin, Pranav S. Garimella, Mark J. Sarnak, Michael G. Shlipak, Jorge R. Kizer
Journal: Journal of the American Society of Nephrology (2015)

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m2, and median urine PIIINP was 2.6 (interquartile range, 1.4–4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.
Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency
Authors: Vanessa Sancho-Shimizu, Rebeca Pérez de Diego, Lazaro Lorenzo, Rabih Halwani, Abdullah Alangari, Elisabeth Israelsson, Sylvie Fabrega,, Annabelle Cardon, Jerome Maluenda, Megumi Tatematsu, Farhad Mahvelati, Melina Herman, Michael Ciancanelli, Yiqi Guo, Zobaida AlSum, Nouf Alkhamis, Abdulkarim S. Al-Makadma, Ata Ghadiri, Soraya Boucherit, Sabine Plancoulaine, Capucine Picard, Flore Rozenberg, Marc Tardieu, Pierre Lebon, Emmanuelle Jouanguy, Nima Rezaei, Tsukasa Seya, Misako Matsumoto, Damien Chaussabel, Anne Puel, Shen-Ying Zhang, Laurent Abel, Saleh Al-Muhsen, Jean-Laurent Casanova
Journal: Journal of Clinical Investigation (2011)

Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.
Clinical predictors of pulmonary hypertension in sarcoidosis
Authors: J. M. Bourbonnais, L. Samavati
Journal: European Respiratory Journal (2008)

Pulmonary hypertension (PH) adversely affects outcome in sarcoidosis and is an important predictor of mortality in these patients. Early and accurate diagnosis of this complication may improve outcome. The current authors hypothesised that integration of 6-min walk test (6MWT) as part of the evaluation leads to an earlier diagnosis of this complication. A total of 162 patients with sarcoidosis underwent 6MWT. Demographic and pulmonary function results were analysed. Patients were further assessed by echocardiography and right heart catheterisation when clinically indicated. Patients with sarcoidosis-associated PH had significantly decreased results on pulmonary function testing. They also walked shorter distances and desaturated to lower levels on 6MWT. On logistic regression analyses, significant predictors of PH were oxygen saturation <90% on 6MWT (odds ratio (OR) 12.1, 95% confidence interval (CI) 3.66-19.73) and diffusing capacity of the lung for carbon monoxide <60% predicted (OR 7.3, 95% CI 1.98-24.82). Moreover, by combining the results of oxygen saturation at 6 min with those of echocardiography, the ability to correctly predict the presence of PH by right heart catheterisation was improved. Patients with diffusing capacity of the lung for carbon monoxide <60% predicted and oxygen desaturation <90% on 6-min walk test have a high likelihood of pulmonary hypertension and should undergo further evaluation for the presence of this disorder.