tbuckley/cabot-search huggingface dataset:
Relevance of compartmentalization of T-cell subsets for clinical improvement in psoriasis: effect of immune-targeted antipsoriatic therapies
Authors: R.G. van Lingen, J.E.M. Körver, P.C.M. van de Kerkhof, M.A.M. Berends, D.W.A. van Rens, A.M. Langewouters, J.B.M. Boezeman, M.M.B. Seyger, E.M.G.J. de Jong
Journal: British Journal of Dermatology (2008)

Therapies targeting the T cell-mediated pathology of psoriasis have been found to achieve remarkable clinical improvement and have confirmed the crucial role of the immune system either in peripheral blood (PB) or in skin. No analyses of T-cell counts in both compartments have been conducted in order to confirm or refute the hypothesized shifts between them.To gain more insight in the dynamics of compartmentalization of T cells between PB and lesional skin of patients with psoriasis, in response to immune-targeted antipsoriatic therapies.Eighteen patients with psoriasis received either efalizumab (n = 9) or etanercept (n = 9) for 12 weeks. Biopsies were taken for immunohistochemical analysis of T-cell subsets and simultaneously T-cell subsets were isolated from PB specimens by flow cytometry.The Psoriasis Area and Severity Index declined significantly after 12 weeks of etanercept, but not for efalizumab. After treatment with efalizumab, a significantly decreased number of all T-cell subsets was found in the dermis. In the epidermis, CD4+, CD8+, CD25+, CD45RO+ and CD161+ T-cell subsets were significantly decreased. With respect to etanercept, few significant changes in T-cell subsets were found. The percentage of lymphocytes in PB was significantly elevated after efalizumab treatment regardless of responder status.Treatment with efalizumab establishes successful recompartmentalization of T-cell subsets with modest clinical efficacy after 12 weeks, whereas in etanercept-treated patients, a significant clinical response is no guarantee for significant changes in T-cell subsets in the different compartments. Reductions in T-cell subsets cannot be used as predictive markers for the clinical response to therapy. Interference with the studied T-cell populations in its own right seems not to be responsible for the clinical efficacy of efalizumab and etanercept.
Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes
Authors: Rodrigo Martino, Marı́a Dolores Caballero, José Antonio Pérez Simón, Carmen Canals, Carlos Solano, Alvaro Urbano-Ispı́zua, Joan Bargay, Angel Léon, Josep Sarrá, Guillermo F. Sanz, José Marı́a Moraleda, Salut Brunet, Jesús San Miguel, Jorge Sierra
Journal: Blood (2002)
Destruction of Leishmania mexicana amazonensis amastigotes within macrophages by lysosomotropic amino acid esters.
Authors: M Rabinovitch, V Zilberfarb, C Ramazeilles
Journal: The Journal of Experimental Medicine (1986)

Leishmania amastigotes parasitize almost exclusively the mononuclear phagocytes of mammals. The organisms survive and multiply within acidified vacuoles (parasitophorous vacuoles; p.v.) akin to phagolysosomes. Certain amino acid esters are known to accumulate in and disrupt lysosomes. We postulated that, since Leishmania possess lysosome-like organelles, they may be susceptible to the potentially high ester concentrations attained in the p.v. We report here that L-amino acid esters can rapidly destroy intracellular Leishmania at concentrations that do not appear to damage the host cells. L-leu-OMe, which cured greater than or equal to 90% of infected macrophages at 0.8 mM concentrations, was used in most of the experiments. L-leu-OMe was only active after infection, implying inefficient transfer from secondary lysosomes to the p.v. Parasite destruction had several features in common with lysosomal and leukocyte damage induced by the esters, i.e., inactivity of D-amino acid esters, a marked pH dependence and increased killing after ester pulses at lower temperatures. Killing depended on the amino acid and on the ester substitution. The most active of the methyl esters assayed was that of leucine, followed by those of tryptophan, glutamic acid, methionine, phenylalanine, and tyrosine. Methyl esters of seven other amino acids were inactive when tested at up to 10 mM concentrations. Among leucine esters studied, benzyl ester was sixfold more active than the methyl homolog. The dipeptide L-leu-leu-OMe produced 90% cure at 0.08 mM concentrations. Leishmanicidal activity could be related to penetration of the parasites by the esters or to toxic ester hydrolysis products released in the p.v. The first hypothesis is supported by the pH-dependent destruction of isolated amastigotes by the esters. Furthermore, relatively high concentrations of L-leucine, methanol, or benzyl alcohol were not demonstrably toxic to the amastigotes. We postulate that ester concentrations sufficient to damage the intracellular amastigotes may be obtained within the p.v. after exposure of infected macrophages to the esters. Esters preferentially hydrolyzed by parasite enzymes may be expected to be leishmanicidal, but less damaging to the host.
Better Outcome for Women Compared With Men Undergoing Coronary Revascularization
Authors: Alice K. Jacobs, Sheryl F. Kelsey, Maria Mori Brooks, David P. Faxon, Bernard R. Chaitman, Vera Bittner, Michael B. Mock, Bonnie H. Weiner, Larry Dean, Carla Winston, Laura Drew, George Sopko
Journal: Circulation (1998)

Background —Numerous studies have shown that women undergoing coronary revascularization procedures do so at a higher risk for an adverse outcome compared with men. However, the impact of advances in technology and improvements in techniques on in-hospital and long-term outcome after revascularization in women is unclear. Methods and Results —We evaluated 1829 patients with symptomatic multivessel coronary disease randomized to CABG or PTCA in the Bypass Angioplasty Revascularization Investigation (BARI), of whom 27% were women. As expected, women were older (64.0 versus 60.5 years), with more congestive heart failure (14% versus 7%), hypertension (68% versus 42%), treated diabetes mellitus (31% versus 15%), and unstable angina (67% versus 61%) than men but had similar preservation of left ventricular function and extent of multivessel disease. Women assigned to surgery received the same number of total grafts but fewer internal mammary artery grafts (72% versus 85%, P &lt;0.01), and those assigned to angioplasty had more intended lesions (76% versus 71%, P &lt;0.01) successfully dilated than men. At an average of 5.4 years’ follow-up, crude mortality rates were similar in women (12.8%) and men (12.0%). The Cox regression model adjusting for baseline differences revealed that women had a significantly lower risk of death (relative risk, 0.60; 95% CI, 0.43 to 0.84; P =0.003) but not a significantly lower risk of death plus myocardial infarction (relative risk, 0.84; 95% CI, 0.66 to 1.07; P =0.16) than men. Conclusions —Although the unadjusted mortality rate suggests that women and men undergoing CABG and PTCA have a similar 5-year mortality, women have higher risk profiles; consequently, contrary to previous reports, female sex is an independent predictor of improved 5-year survival after we control for multiple risk factors.
Safety of Early Discharge for Low-Risk Patients With Febrile Neutropenia: A Multicenter Randomized Controlled Trial
Authors: James A. Talcott, Beow Y. Yeap, Jack A. Clark, Robert D. Siegel, Elizabeth Trice Loggers, Charles Lu, Paul A. Godley
Journal: Journal of Clinical Oncology (2011)

Febrile neutropenia commonly complicates cancer chemotherapy. Outpatient treatment may reduce costs and improve patient comfort but risk progression of undetected medical problems.By using our validated algorithm, we identified medically stable inpatients admitted for febrile neutropenia (neutrophils < 500/μL) after chemotherapy and randomly assigned them to continued inpatient antibiotic therapy or early discharge to receive identical antibiotic treatment at home. Our primary outcome was the occurrence of any serious medical complication, defined as evidence of medical instability requiring urgent medical attention.We enrolled 117 patients with 121 febrile neutropenia episodes before study termination for poor accrual. We excluded five episodes as ineligible and three because of inadequate documentation of the study outcome. Treatment groups were clinically similar, but sociodemographic imbalances occurred because of block randomization. The median presenting absolute neutrophil count was 100/μL. Hematopoietic growth factors were used in 38% of episodes. The median neutropenia duration was 4 days (range, 1 to 15 days). Five outpatients were readmitted to the hospital. Major medical complications occurred in five episodes (8%) in the hospital arm and four (9%) in the home arm (95% CI for the difference, -10% to 13%; P = .56). No study patient died. Patient-reported quality of life was similar on both arms.We found no evidence of adverse medical consequences from home care, despite a protocol designed to detect evidence of clinical deterioration. These results should reassure clinicians who elect to treat rigorously characterized low-risk patients with febrile neutropenia in suitable outpatient settings with appropriate surveillance for unexpected clinical deterioration.
Response to: ‘Paying attention to carpal tunnel contents lesions: ultrasound for evaluation of carpal tunnel syndrome’ by zhu and Liu
Authors: Christian Dejaco, Martin Stradner, Dorothea Zauner, Werner Seel, Nicole Elisabeth Simmet, Alexander Klammer, Petra Heitzer, Kerstin Brickmann, Judith Gretler, Florentine Fürst-Moazedi, Rene Thonhofer, Rusmir Husic, Josef Hermann, Winfried B Graninger, Stefan Quasthoff
Journal: Annals of the Rheumatic Diseases (2014)

Our and several previous studies demonstrated a high diagnostic value of ultrasound for carpal tunnel syndrome (CTS).1 ,2 Among the various abnormalities within the carpal tunnel reported, the increase of the cross-sectional area (CSA) of the median nerve is the most commonly studied ultrasound abnormality.3 Additionally, ultrasound allows the identification of secondary causes of CTS, such as synovitis, tenosynovitis, calcified masses or tophaceous gout, as pointed out by zhu et al. 4 We acknowledge that the diagnostic value of ultrasound is not perfect, as some patients may suffer from CTS despite a normal ultrasound result and, …
Complex regulation of calcium current in cardiac cells. Dependence on a pertussis toxin-sensitive substrate, adenosine triphosphate, and an alpha 1-adrenoceptor.
Authors: E C Keung, J S Karliner
Journal: Journal of Clinical Investigation (1990)

We investigated regulation of the cardiac L-type calcium channel by intracellular ATP and by alpha 1-adrenergic agonism using single adult guinea pig ventricular cells and the whole-cell patch clamp method. Inclusion of 5 mM ATP in the patch clamp pipette prevented calcium current rundown but did not increase the maximal magnitude of the slow inward calcium current (ICa). During beta 1-adrenergic blockade with 10 microM (-)-propranolol, cells preincubated with 1 microgram/ml pertussis toxin for 2-5 h exhibited a rapid twofold increase in ICa after rupture of the membrane patch when 5 mM ATP was present in the patch clamp pipette. In the absence of ATP, the increase in ICa did not occur. In pertussis toxin-treated cells, 100 microM (-)-phenylephrine inhibited the augmentation of ICa. This inhibitory effect was blocked by 100 nM terazosin, a selective alpha 1-antagonist. The inhibitory effect of alpha 1-adrenergic agonism was not mediated by cAMP-dependent phosphodiesterase since incubation with 100 microM (-)-phenylephrine did not augment the activity of this enzyme. We conclude that regulation of the L-type calcium channel in cardiac cells is complex, and is dependent on a pertussis toxin-sensitive substrate, ATP, and an alpha 1-adrenergic receptor. The marked increase in ICa after pertussis toxin treatment in the presence of ATP indicates significant inhibition of ICa by a pertussis toxin substrate, presumably the guanine nucleotide inhibitory protein (Gi) in the basal state. The inhibitory action of (-)-phenylephrine in pertussis toxin-treated cells is consistent with modulation of ICa by an alpha 1-adrenergic receptor not coupled to Gi.
TCT-127 Trans-Auricular Intra-Pericardial Tricuspid Annuloplasty (TRAIPTA)
Authors: Toby Rogers, Kanishka Ratnayaka, William H. Schenke, Anthony Z. Faranesh, Merdim Sonmez, Dominique N. Franson, Robert J. Lederman
Journal: Journal of the American College of Cardiology (2013)
Cingulate Cortex Anatomical Abnormalities in Children and Adolescents With Bipolar Disorder
Authors: Simerjit Kaur, Roberto B. Sassi, David Axelson, Mark Nicoletti, Paolo Brambilla, E. Serap Monkul, John P. Hatch, Matcheri S. Keshavan, Neal Ryan, Boris Birmaher, Jair C. Soares
Journal: American Journal of Psychiatry (2005)

In vivo imaging studies have suggested anatomical and functional abnormalities in the anterior cingulate in adults with mood disorders. This anatomical magnetic resonance imaging study examined the cingulate cortex in children and adolescents with bipolar disorder and matched healthy comparison subjects.Sixteen patients (mean age=15.5 years, SD=3.4) with DSM-IV bipolar disorder and 21 matched healthy comparison subjects (mean age=16.9 years, SD=3.8) were studied. Three-dimensional gradient echo imaging was performed (TR=25 msec, TE=5 msec, slice thickness=1.5 mm) in a 1.5-T GE Signa magnet. Cingulate volumes were compared by using analysis of covariance, with age and intracranial volume as covariates.The patients with bipolar disorder had significantly smaller mean volumes relative to the healthy subjects in the left anterior cingulate (mean=2.49 cm(3 [SD=0.28] versus 3.60 cm3 [SD=0.12], respectively), left posterior cingulate (2.53 cm3 [SD=0.32] versus 2.89 cm3 [SD=0.09]), and right posterior cingulate (2.19 cm3 [SD=0.13] versus 2.28 cm3 [SD=0.08]). No significant between-group difference was found for the right anterior cingulate (2.64 cm3 [SD=0.21] versus 2.71 cm3 [SD=0.10]).The findings indicate smaller cingulate volumes in children and adolescents with bipolar disorder, suggesting that such abnormalities may be present early in the illness course.
Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome
Authors: Kazuyuki Shimizu
Journal: American Journal of Hematology (1998)

A 64-year-old woman presented with cardiomegaly, Sweet's syndrome, and refractory anemia (RA), and died of sudden cardiac arrest. The autopsy revealed a perivascular and myocardial infiltration by neutrophils, which could be responsible for the cardiomegaly and probably had caused disturbances in the conduction system leading to sudden cardiac arrest. Myocardial infiltration by functionally defective neutrophils can develop in a patient with myelodysplastic syndrome (MDS) without peripheral neutrophilia or leukemic blood picture and needs a special diagnostic and therapeutic consideration. Am. J. Hematol. 58:337–338, 1998. © 1998 Wiley-Liss, Inc.
Molecular Phylogeny, Biogeography, and Habitat Preference Evolution of Marsupials
Authors: Kieren J Mitchell, Renae C Pratt, Laura N Watson, Gillian C Gibb, Bastien Llamas, Marta Kasper, Janette Edson, Blair Hopwood, Dean Male, Kyle N Armstrong, Matthias Meyer, Michael Hofreiter, Jeremy Austin, Stephen C Donnellan, Michael S Y Lee, Matthew J Phillips, Alan Cooper
Journal: Molecular Biology and Evolution (2014)

Marsupials exhibit great diversity in ecology and morphology. However, compared with their sister group, the placental mammals, our understanding of many aspects of marsupial evolution remains limited. We use 101 mitochondrial genomes and data from 26 nuclear loci to reconstruct a dated phylogeny including 97% of extant genera and 58% of modern marsupial species. This tree allows us to analyze the evolution of habitat preference and geographic distributions of marsupial species through time. We found a pattern of mesic-adapted lineages evolving to use more arid and open habitats, which is broadly consistent with regional climate and environmental change. However, contrary to the general trend, several lineages subsequently appear to have reverted from drier to more mesic habitats. Biogeographic reconstructions suggest that current views on the connectivity between Australia and New Guinea/Wallacea during the Miocene and Pliocene need to be revised. The antiquity of several endemic New Guinean clades strongly suggests a substantially older period of connection stretching back to the Middle Miocene and implies that New Guinea was colonized by multiple clades almost immediately after its principal formation.
Glucocorticoids Attenuate T Cell Receptor Signaling
Authors: François Van Laethem, Erika Baus, Lesley A. Smyth, Fabienne Andris, Françoise Bex, Jacques Urbain, Dimitris Kioussis, Oberdan Leo
Journal: The Journal of Experimental Medicine (2001)

Glucocorticoids (GCs) affect peripheral immune responses by inhibiting T cell immunity at several stages of the activation cascade, causing impaired cytokine production and effector function. The recent demonstration that the thymic epithelium and possibly thymocytes themselves produce steroids suggests that endogenous GCs also play a role in the control of T cell development. As both peripheral responsiveness and thymic differentiation appear to be regulated by the quantity and quality of intracellular signals issued by antigen–major histocompatibility complex-engaged T cell receptor (TCR) complexes, we investigated the effects of GCs on the signaling properties of T cells stimulated by anti-CD3 monoclonal antibodies or agonist peptides. We demonstrate in this work that dexamethasone, a synthetic GC, inhibits the early signaling events initiated upon TCR ligation, such as tyrosine phosphorylation of several TCR-associated substrates including the ζ chain, the ZAP70 kinase, and the transmembrane adapter molecule linker for activation of T cells. Hypophosphorylation was not a consequence of reduced kinase activity of src protein tyrosine kinases, but was correlated with an altered- membrane compartmentalization of these molecules. These observations indicate that in addition to their well-described ability to interfere with the transcription of molecules involved in peripheral responses, GCs inhibit T cell activation by affecting the early phosphorylating events induced after TCR ligation.
High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde
Authors: Hak-Bong Kim, Mi-Ju Kim, Dae-Young Kim, Jae-Won Lee, Jae-Ho Bae, Dong-Wan Kim, Chi-Dug Kang, Sun-Hee Kim
Journal: Molecular Cancer (2011)

Tumor recurrence and metastasis develop as a result of tumors' acquisition of anti-apoptotic mechanisms and therefore, it is necessary to develop novel effective therapeutics against metastatic cancers. In this study, we showed the differential TRAIL responsiveness of human prostate adenocarcinoma PC3 and human colon carcinoma KM12 cells and their respective highly metastatic PC3-MM2 and KM12L4A sublines and investigated the mechanism underlying high susceptibility of human metastatic cancer cells to TRAIL. PC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB), a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer. This study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and combination of TRAIL therapy with agent that inhibits the DNA-PKcs/Akt signaling pathway might be clinically useful for the treatment of relatively TRAIL-insensitive human cancers.
Explanations for the High Risk of Diabetes-Related Amputation in a Caribbean Population of Black African Descent and Potential for Prevention
Authors: Anselm J.M. Hennis, Henry S. Fraser, Ramesh Jonnalagadda, John Fuller, Nish Chaturvedi
Journal: Diabetes Care (2004)

OBJECTIVE—Diabetes-related lower-extremity amputation (LEA) rates are elevated in blacks compared with whites in the U.S., but are lower in African Caribbeans in the U.K., whereas anecdotal reports suggest high rates in the Caribbean. We aimed to establish the incidence and risk factors for diabetes-related LEA in a Caribbean population. RESEARCH DESIGN AND METHODS—We conducted an incident and prospective case-control study of case patients (individuals with diabetes having a LEA) and community-based control subjects (individuals with diabetes without a LEA) in Barbados, West Indies. Participants completed an interview and examination of risk factors for amputation, including footwear use. RESULTS—The overall 1-year incidence of LEA (n = 223) was 173 per 105 population and 936 per 105 population with diabetes (557 per 105 for minor amputation and 379 per 105 for major amputation). Women had higher amputation rates than those reported in the Global Lower Extremity Amputation Study, apart from the U.S. Navajo population. Independent risk factors for all diabetes-related LEAs were poor footwear (odds ratio [OR] 2.71 [95% CI 1.23–5.97]), elevated GHb (1.40 per percent increase [1.26–1.57]), peripheral neuropathy (1.05 per volt increase [1.03–1.08]), and peripheral vascular disease. CONCLUSIONS—Diabetes LEA rates in Barbados are among the highest in the world. Inadequate footwear independently tripled amputation risk. Education of professionals and patients, particularly about footwear and foot care, coupled with improved diabetes clinical care, is key to reducing amputation risk in this population.