tbuckley/cabot-search huggingface dataset:
Short Communication: Flecainide Exerts an Antiarrhythmic Effect in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia by Increasing the Threshold for Triggered Activity
Authors: Nian Liu, Marco Denegri, Yanfei Ruan, José Everardo Avelino-Cruz, Andrea Perissi, Sara Negri, Carlo Napolitano, William A. Coetzee, Penelope A. Boyden, Silvia G. Priori
Journal: Circulation Research (2011)

Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide.To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2(R4496C+/-) knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia.Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2(R4496C+/-) mice. Cellular studies were performed with isolated RyR2(R4496C+/-) myocytes. Isoproterenol caused the appearance of spontaneous Ca(2+) transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca(2+) transient amplitude, decay, or sarcoplasmic reticulum Ca(2+) content. Moreover, it did not affect the frequency of spontaneous Ca(2+) sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na(+) channel blockade.Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2(R4496C+/-) mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca(2+) homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na(+) channel availability and by an increase in the threshold for triggered activity.
The role of vitamin D3 in the local inflammatory process in sarcoidosis (SA)
Authors: Anna Kowalska, Elzbieta Puscinska, Anna Goljan-Geremek, Agnieszka Skoczylas, Justyna Czerniawska, Adriana Rozy, Paulina Jagus, Joanna Chorostowska-Wynimko, Dorota Gόrecka
Journal: European Respiratory Journal (2011)

Background: SA is an inflammatory disease characterized by granulomas that can produce 1.25(OH)2D hormone. No reports are available in the literature on the role of vitamin D3 derivatives in the local inflammation.

Aims: To assess the role of vitamin D3 derivatives in the local inflammatory process in SA based on the determination of their concentration in the bronchoalveolar lavage fluid (BALF) as well as in exhaled breath condensate (EBC).

Material and Methods: In 108 pts (48 women, 60 men; (mean±SD) age 44.3±9.5 yrs, BMI=27.5±4.8) with SA stage I-IV we measured 1.25(OH)2D (pg/m), 25(OH)D (ng/ml) in serum, EBC and BALF.

Results: Results are shown below:

View this table:

Table 1





View this table:

Table 2





No correlation was found between 25OHD or 1.25(OH)2D and CD8 lymphocyte count or BALF CD4/CD8.

Conclusions: 1. It is possible to measure vitamin D3 derivates concentration in BALF and EBC. 2. Many correlations found between macrophage, lymphocyte and neutrophil counts in BALF and concentration of 1.25D and 25D in serum, BALF and EBC suggest an important role of vitamin D derivates in local and systemic inflammatory process in SA.

Supported by: Polish Ministry of Science grant No 1594/P01/2007/32
Detection of leukemic cells in the CD34+CD38− bone marrow progenitor population in children with acute lymphoblastic leukemia
Authors: Aswathi A. George, Janet Franklin, Keith Kerkof, Ami J. Shah, Mary Price, Eleanor Tsark, David Bockstoce, Dapeng Yao, Nancy Hart, Sherri Carcich, Robertson Parkman, Gay M. Crooks, Kenneth Weinberg
Journal: Blood (2001)
Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response.
Authors: M Pasparakis, L Alexopoulou, V Episkopou, G Kollias
Journal: The Journal of Experimental Medicine (1996)

To investigate the role of TNF alpha in the development of in vivo immune response we have generated TNF alpha-deficient mice by gene targeting. Homozygous mutant mice are viable and fertile, develop lymph nodes and Peyer's patches and show no apparent phenotypic abnormalities, indicating that TNF alpha is not required for normal mouse development. In the absence of TNF alpha mice readily succumb to L. monocytogenes infections and show reduced contact hypersensitivity responses. Furthermore, TNF alpha knockout mice are resistant to the systemic toxicity of LPS upon D-galactosamine sensitization, yet they remain sensitive to high doses of LPS alone. Most interestingly, TNF alpha knockout mice completely lack splenic primary B cell follicles and cannot form organized follicular dendritic cell (FDC) networks and germinal centers. However, despite the absence of B cell follicles, Ig class-switching can still occur, yet deregulated humoral immune responses against either thymus-dependent (TD) or thymus-independent (TI) antigens are observed. Complementation of TNF alpha functioning by the expression of either human or murine TNF alpha transgenes is sufficient to reconstitute these defects, establishing a physiological role for TNF alpha in regulating the development and organization of splenic follicular architecture and in the maturation of the humoral immune response.
Interleukin 4 receptor signaling in human monocytes and U937 cells involves the activation of a phosphatidylcholine-specific phospholipase C: a comparison with chemotactic peptide, FMLP, phospholipase D, and sphingomyelinase.
Authors: J L Ho, B Zhu, S He, B Du, R Rothman
Journal: The Journal of Experimental Medicine (1994)

Interleukin 4 (IL-4) diminishes cytokine activation of human macrophage. IL-4 binding to monocyte IL-4R is associated with protein kinase C (PKC) translocation to a nuclear fraction. The cleavage of diacyglycerol (DAG), an activator of PKC, from membrane phospholipids was investigated to define the proximal events of IL-4R signaling. IL-4 induced a statistically significant time-and dose-dependent generation of DAG. The IL-4-triggered production of DAG was not derived from phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, since neither cytosolic calcium flux nor liberation of inositol phosphates was detected in response to IL-4. Experiments were performed using [14C-methyl]choline-labeled U937 cells and monocytes to determine whether IL-4R activated phospholipase C (PLC), PLD, or PLA2 to use membrane phosphatidylcholine (PC) to form DAG. IL-4 induced a time- and dose-dependent increase of phosphocholine (pchol) with concomitant degradation of membrane PC (p &amp;lt; 0.05 compared with control). The finding that the peak reduction of PC was equivalent to peak production of pchol suggested that IL-4R signaling involved the activation of a PC-specific PLC. Changes in choline (chol) or lyso-PC and glycerolphosphocholine, the respective products of PC cleavage by PLD or PLA2, were not detected in IL-4-treated cells. In contrast, exogenous PLD induced an increase in chol and concomitant loss of membrane PC. Additional investigation suggested that IL-4R signaling does not involve PLD. In cells labeled with L-lyso-3-PC 1-[1-14C]palmitoyl, PLD but not IL-4, increased the production of phosphatidic acid (PA) and phosphatidyl-ethanol when pretreated with ethanol. Propranolol, an inhibitor of phosphatidate phosphohydrolase, and calyculin A, a phosphatase 1 and 2A inhibitor, blocked DAG production in response to FMLP but not to IL-4. In propranolol pretreated cells, PMA but not IL-4 triggered the production of PA and lowered the amount of DAG. Evidence that PLA2 is not coupled to IL-4R is the detection of arachidonate production in response to FMLP but not to IL-4. Furthermore, IL-4R is not coupled to sphingomyelinase (SMase) since IL-4, unlike exogenous SMase, did not generate ceramide but induced the hydrolysis of PC to pchol that was comparable to exogenous PLC. In summary, IL-4R signaling in monocytes and U937 cells involves PLC and not PLD, PLA2, or SMase, and it uses PC and not PIP2 to form DAG.
Regulation of Splicing Factors by Alternative Splicing and NMD Is Conserved between Kingdoms Yet Evolutionarily Flexible
Authors: Liana F. Lareau, Steven E. Brenner
Journal: Molecular Biology and Evolution (2015)

Ultraconserved elements, unusually long regions of perfect sequence identity, are found in genes encoding numerous RNA-binding proteins including arginine-serine rich (SR) splicing factors. Expression of these genes is regulated via alternative splicing of the ultraconserved regions to yield mRNAs that are degraded by nonsense-mediated mRNA decay (NMD), a process termed unproductive splicing (Lareau et al. 2007; Ni et al. 2007). As all human SR genes are affected by alternative splicing and NMD, one might expect this regulation to have originated in an early SR gene and persisted as duplications expanded the SR family. But in fact, unproductive splicing of most human SR genes arose independently (Lareau et al. 2007). This paradox led us to investigate the origin and proliferation of unproductive splicing in SR genes. We demonstrate that unproductive splicing of the splicing factor SRSF5 (SRp40) is conserved among all animals and even observed in fungi; this is a rare example of alternative splicing conserved between kingdoms, yet its effect is to trigger mRNA degradation. As the gene duplicated, the ancient unproductive splicing was lost in paralogs, and distinct unproductive splicing evolved rapidly and repeatedly to take its place. SR genes have consistently employed unproductive splicing, and while it is exceptionally conserved in some of these genes, turnover in specific events among paralogs shows flexible means to the same regulatory end.
LONG-TERM EFFICACY OF FENOFIBRIC ACID 135 MG IN COMBINATION WITH ROSUVASTATIN 20 MG IN PATIENTS WITH MIXED DYSLIPIDEMIA
Authors: Peter H. Jones, Terry A. Jacobson, Carolyn M. Setze, Darryl J. Sleep, Maureen T. Kelly, Laura A. Williams, James C. Stolzenbach
Journal: Journal of the American College of Cardiology (2010)
Effects of aspirin and Helicobacter pylori on the gastroduodenal mucosal permeability to sucrose.
Authors: A A Rabassa, R Goodgame, F M Sutton, C N Ou, C Rognerud, D Y Graham
Journal: Gut (1996)

A non-invasive marker is needed to identify patients with significant gastrointestinal injury due to non-steroidal anti-inflammatory drugs. Gastrointestinal permeability to sucrose has been suggested as such a test.To assess the utility of sucrose permeability as a marker of gastroduodenal mucosal injury after single and multiple doses of aspirin, to identify the site of increased sucrose permeability, to explore the relation between sucrose permeability and endoscopic findings, and to evaluate whether Helicobacter pylori infection influenced gastroduodenal sucrose permeability.After a fasting urine was obtained, 500 ml of a solution containing 100 g of sucrose was ingested. Urine was collected for five hours and assayed for sucrose by high performance liquid chromatography. Sucrose permeability was also assessed 20 minutes after ingestion of 650 mg of aspirin and eight to 12 hours after a 72 hour course of 650 mg aspirin four times a day. The site of increased permeability was identified after pyloric occlusion with a double balloon tube.Thirty seven healthy volunteers participated. Sucrose permeability (mean (SEM)) increased after both single (195.2 (27) mg and multiple (196.4 (31) mg) doses of aspirin compared with baseline (53.7 (10) mg; p < 0.0005). Balloon pyloric occlusion confirmed that the site of increased sucrose permeability was the stomach. The effect of aspirin on sucrose permeability was similar in those with and without H pylori infection.These results confirm the use of sucrose permeability as a marker of aspirin induced gastroduodenal mucosal injury and identify the stomach as the major site of increased permeability. H pylori infection does not seem to change gastric mucosal sucrose permeability either at baseline or after ingestion of aspirin.
Activated T Cells Secrete an Alternatively Spliced Form of Common γ-Chain that Inhibits Cytokine Signaling and Exacerbates Inflammation
Authors: Changwan Hong, Megan A. Luckey, Davinna L. Ligons, Adam T. Waickman, Joo-Young Park, Grace Y. Kim, Hilary R. Keller, Ruth Etzensperger, Xuguang Tai, Vanja Lazarevic, Lionel Feigenbaum, Marta Catalfamo, Scott T.R. Walsh, Jung-Hyun Park
Journal: Immunity (2014)
On-Line Hemodiafiltration Reduces the Proinflammatory CD14+CD16+ Monocyte-Derived Dendritic Cells
Authors: Julia Carracedo, Ana Merino, Sonia Nogueras, Diana Carretero, Isabel Berdud, Rafael Rami[Combining Acute Accent]rez, Ciro Tetta, Mariano Rodri[Combining Acute Accent]guez, Alejandro Marti[Combining Acute Accent]n-Malo, Pedro Aljama
Journal: Journal of the American Society of Nephrology (2006)

It is not known whether high convective transport may have a role in modulating the chronic inflammation of hemodialysis (HD) patients. The aim of this study was to evaluate the effect of on-line hemodiafiltration (OL-HDF) on proinflammatory peripheral monocytes: Percentage of CD14+CD16+ cells and their telomere length and spontaneous or bacterial DNA-induced production of cytokines (TNF-alpha and IL-6). In a prospective, crossover study, 31 patients who were on high-flux HD (HF-HD) were evaluated. Patients underwent the following sequence of treatments (4 mo each): HF-HD (basal), OL-HDF (period 1), HF-HD (period 2), OL-HDF (period 3), and HF-HD (period 4). The dialysis characteristics were similar in the two modalities; the only difference was a higher convective transport in the OL-HDF than in the HF-HD. All patients who were on OL-HDF periods showed a significantly lower number of CD14+CD16+ cells than on HF-HD (18.5 +/- 2.3 basal versus 13.6 +/- 2.9 period 1 and 13.9 +/- 2.3 period 3; P = 0.001). By contrast, HF-HD restored the number of CD14+CD16+ cells to the basal values (19.2 +/- 2.8 and 18.6 +/- 1.4, periods 2 and 4, respectively; NS). During OL-HDF periods, the reduction of CD14+CD16+ was paralleled by a decreased number of short telomere cells. Spontaneous or bacterial DNA-induced production of cytokines (TNF-alpha and IL-6) was increased in HF-HD as compared with OL-HDF. In conclusion, these results demonstrate that as compared with HF-HD, OL-HDF markedly reduces the number of proinflammatory CD14+CD16+ cells and the production of TNF-alpha and IL-6. Future studies are needed to assess the possible therapeutic effect of convective transport on chronic inflammation that is associated with HD.
The “tank top sign”: a unique pattern of skin fibrosis seen in pansclerotic morphea
Authors: N S Sherber, F Boin, L K Hummers, F M Wigley
Journal: Annals of the Rheumatic Diseases (2009)

Pansclerotic morphea is a rare form of localised scleroderma in which inflammation in the dermis and subcutaneous fat leads to diffuse cutaneous sclerosis.1 It typically presents in childhood, but cases of adult-onset pansclerotic morphea have been reported, generally associated with a progressive course and poor response to traditional immunosuppressive therapy.2

Between 2000 and 2008, three men with pansclerotic morphea presented to the Johns Hopkins Scleroderma Center with striking similarity in the distribution of fibrotic plaques on the upper chest that spared the areolae and lateral pectoral region and involved the whole back. This gave the appearance that each patient was wearing a “tank top” …
Gangrene developing after minor surgery in a patient with undiagnosed systemic lupus erythematosus and lupus anticoagulant.
Authors: B K Jindal, M F Martin, A Gayner
Journal: Annals of the Rheumatic Diseases (1983)

We report a case of progressive peripheral ischaemia and gangrene as a presenting feature of systemic lupus erythematosus. It developed in a previously asymptomatic 40-year-old woman following minor surgery to her toe. Eventually she required a below-knee amputation and despite systemic corticosteroids continued to deteriorate, presenting later with signs of systemic intravascular thromboses. Histopathology and immunofluorescence on vessels repeatedly failed to demonstrate any evidence for vasculitis. A full coagulation screen confirmed the presence of 9lupus9 anticoagulant. A plasma exchange was performed to remove circulating immunoglobins and she made a rapid and sustained recovery. Peripheral gangrene has not previously been described in association with lupus anticoagulant. We would suggest that in all cases of systemic thrombosis or unexplained peripheral vascular ischaemia lupus anticoagulant should be considered.
Low-level laser therapy (LLLT) for discogenic back pain
Authors: N Malliaropoulos, A Akritidou, I Tsifountoudis, K Tsitas
Journal: British Journal of Sports Medicine (2011)

The aim of this study was to investigate the effect of low-level laser therapy (LLLT) on low back pain documented by history, clinical examination, MRI findings of the Lumbar Spine and patients' pain scores. 39 individuals with diagnosis of low back pain were enrolled in randomised, double-blind, placebo-controlled trial, but 32 participants completed the therapeutic protocol. After enrolment, symptomatic individuals were randomly assigned to receive LLLT, or identical placebo, for 6 weeks. MRI was performed at baseline of therapy. The subjective low back pain was recorded at baseline and after treatment on a visual analogue scale. After LLLT, low back pain in both groups showed significant change over the experimental period and there was a significant difference (before treatment and after treatment) in discogenic back pain between the two groups. Pain estimation on the visual analogue scale had improved significantly in all test situations (after night rest, daily activities) after LLLT when compared with that of the placebo group. Additionally when the difference in pain scores was compared between the two groups the change was statistically significant. In summary, while MRI findings are able to depict the morphologic changes related to discogenic back pain, 905 nm gallium-arsenide infrared laser may contribute to healing and pain reduction in discogenic low back pain.
Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma
Authors: Paulo C. Rodriguez, Claudia P. Hernandez, David Quiceno, Steven M. Dubinett, Jovanny Zabaleta, Juan B. Ochoa, Jill Gilbert, Augusto C. Ochoa
Journal: The Journal of Experimental Medicine (2005)

Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting l-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell–produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE2. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.
Response to: ‘Biologic discontinuation studies: a systematic review of methods’ by van der Maas<i>et al</i>
Authors: Kazuki Yoshida, Yoon-Kyoung Sung, Arthur Kavanaugh, Sang-Cheol Bae, Michael E Weinblatt, Mitsumasa Kishimoto, Kazuo Matsui, Shigeto Tohma, Daniel H Solomon
Journal: Annals of the Rheumatic Diseases (2013)

We would like to thank van der Maas and colleagues1 for their interest in, and useful feedback on, our review.2 They raise several important points. First, regarding the interpretation of the studies included in the review, we focused on studies examining discontinuation of biologic disease modifying antirheumatic drugs (DMARDs) that examined patient outcomes. Thus, we had difficulty in …
Lactadherin and clearance of platelet-derived microvesicles
Authors: Swapan K. Dasgupta, Hanan Abdel-Monem, Polly Niravath, Anhquyen Le, Ricardo V. Bellera, Kimberly Langlois, Shigekazu Nagata, Rolando E. Rumbaut, Perumal Thiagarajan
Journal: Blood (2008)
A paediatric emergency
Authors: Frances da Cunha
Journal: BMJ (2004)

It was an ordinary evening surgery when a mother brought in her 2 week old baby, saying that he was “not himself, not feeding, sleepy… perhaps, I'm being fussy… fine until this morning,” alternating between platitudes and anxiety. One glance was sufficient to realise that the baby required immediate attention. I had a sudden, automatic change to a clinical “hospitaloid” approach; no patient centred consultation, but an urgent demand to ascertain facts and assess the sick baby.

He was feverish, breathing satisfactory, awake, with no localising signs, no grunting, no rash or meningism, but probably septicaemic. As I explain to …
A randomized, controlled trial of weekly administration of lymphoblastoid interferon in patients with chronic hepatitis C
Authors: Tatehiro Kagawa, Toshio Morizane, Hidetsugu Saito, Shingo Miyaguchi, Satoshi Tsunematsu, Shinichirou Tada, Ferdinand M. Guevara, Naoki Kumagai, Kanji Tsuchimoto, Tetsu Watanabe, Masaharu Tsuchiya
Journal: Journal of Hepatology (1993)