tbuckley/cabot-search huggingface dataset:
Cryothermal Ablation of the Slow Pathway for the Elimination of Atrioventricular Nodal Reentrant Tachycardia
Authors: Allan C. Skanes, Marc Dubuc, George J. Klein, Bernard Thibault, Andrew D. Krahn, Raymond Yee, Denis Roy, Peter Guerra, Mario Talajic
Journal: Circulation (2000)

Background —We report the first successful slow pathway ablation using a novel catheter-based cryothermal technology for the elimination of atrioventricular nodal reentrant tachycardia (AVNRT). Methods and Results —Eighteen patients with typical AVNRT underwent cryoablation. Reversible loss of slow pathway (SP) conduction during cryothermy (ice mapping) was demonstrated in 11 of 12 patients. Because of time constraints, only 2 sites were ice mapped in 1 patient. Seventeen of 18 patients had successful cryoablation of the SP. One patient had successful ice mapping of the SP, but inability to cool beyond −38°C prevented successful cryoablation. A single radiofrequency lesion at this site eliminated SP conduction. No patient has had recurrent AVNRT over 4.9±1.7 months of follow-up. During cryoablation, accelerated junctional tachycardia was not seen and was therefore not available to guide lesion delivery. Adherence of the catheter tip during cryothermy (cryoadherence) allowed atrial pacing to test for SP conduction. Cryoablation in the anterior septum produced inadvertent transient PR prolongation consistent with loss of fast pathway conduction in 1 patient and transient (6.5 seconds) 2:1 AV block in another. On rewarming, the PR interval returned to normal, and the AV nodal effective refractory period was unchanged in both. Accelerated junctional tachycardia was seen on rewarming in both but not during cryothermy. Conclusions —Cryothermal ablation of the SP was achieved in patients with this novel technique. Successful ice mapping of both the SP and fast pathway was demonstrated. The ability to test the functionality of specific ablation sites before production of a permanent lesion may eliminate inadvertent AV block.
Differential regulation of the bone morphogenic protein antagonist chordin in human normal and osteoarthritic chondrocytes
Authors: G Tardif
Journal: Annals of the Rheumatic Diseases (2006)

To investigate the distribution of the bone morphogenic protein (BMP) antagonist chordin in normal and osteoarthritic cartilage and synovial membranes, and its regulation in chondrocytes and synovial fibroblasts by inflammatory and growth factors.Localisation of chordin in tissues was undertaken by immunohistochemistry and gene regulation was determined by real time polymerase chain reaction.In normal cartilage, chordin was found at low levels (mean (SD), 7.6 (1.3)%), mainly in the very superficial layers. In osteoarthritis, chordin was also found in the superficial layers (8.9 (1.1)%), though at a significantly higher level (24.7 (1.5)%) in the last two thirds of the cartilage. In contrast to normal cells, chordin mRNA and protein levels were significantly downregulated (p<0.01) in osteoarthritic chondrocytes by all the growth factors tested. Interferon gamma stimulated chordin expression in normal but not in osteoarthritic chondrocytes (p<0.0002), while interleukin 1 beta and tumour necrosis factor alpha did not affect the expression level. However, no difference was found in either the distribution or regulation of chordin in normal and osteoarthritic synovial membranes or synovial fibroblasts.The differential distribution and regulation of chordin in normal and osteoarthritic cartilage and chondrocytes suggests an involvement of this antagonist in the osteoarthritic process.
TLR4 activation mediates kidney ischemia/reperfusion injury
Authors: Huiling Wu, Gang Chen, Kate R. Wyburn, Jianlin Yin, Patrick Bertolino, Josette M. Eris, Stephen I. Alexander, Alexandra F. Sharland, Steven J. Chadban
Journal: Journal of Clinical Investigation (2007)

Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage.
Abstract 194: E-selectin mediates targeted delivery of mesenchymal stem cells to tumor
Authors: Cuixia Yang, Danjuan Li, Bo Wang, Omaida C. Velazquez, Zhao-Jun Liu
Journal: Cancer Research (2014)

Abstract Objectives. Tumor tissue produces abundant stromal cell-derived factor-1α (SDF-1α/CXCL12) that promotes recruitment of circulating stem/progenitor cells. We have recently found that SDF-1α induces elevated expression of CD162 and CD44, both are E-selectin ligands, on luminal endothelial cells lining capillaries. We thus postulate that highly expressed E-selectin ligands on tumor endothelium can serve as docking molecules to mediate specific homing of E-selectin-expressing circulating stem cells to tumor tissues. Here, we tested the role of E-selectin in mediating and facilitating homing of mesenchymal stem cells (MSC), which are modified to overexpress E-selectin, to SDF-1α−rich melanoma tissue. Methods. MSC from C57 BL6 and E-selectin-/- mice were enriched by culturing bone marrow cells in MesenCultTM medium. MSC were genetically labeled with luciferase (Luc2) or GFP in vitro. MSC from C57 BL6 mice were engineered to stably overexpress E-selectin (E-selectin+). Human melanoma cells were engineered to overexpress SDF-1α. 2 x 10^6 SDF-1α+/melanoma cells were pre-engrafted into NSG mice via tail-vein or subcu to form lung metastatic foci or skin melanoma, respectively. After 7-10 days, 1 x 10^6 E-selectin+ or E-selectin-/- MSC were injected into tumor-bearing mice through tail-vein or subcu, respectively. Homing of injected MSC to melanoma was assessed at various time points by IVIS (for Luc2+/MSC) and flow cytometry (for GFP+/MSC), respectively. Results. There were significantly increased numbers of engineered E-selectin-overexpressing MSC homing to melanoma tissues via systemic and local approaches, compared to control MSC or E-selectin-/-/MSC (p&amp;lt;0.05). Conclusions. E-selectin is an effective adhesion molecule in mediating tumor selective homing of MSC. Our study provides a useful method for targeted delivery of cells to tumor and may have therapeutic potential for developing stem cell-based cancer treatment. Citation Format: Cuixia Yang, Danjuan Li, Bo Wang, Omaida C. Velazquez, Zhao-Jun Liu. E-selectin mediates targeted delivery of mesenchymal stem cells to tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2014-194
On the mechanism of impaired distal acidification in hyperkalemic renal tubular acidosis
Authors: W Schlueter, T Keilani, M Hizon, B Kaplan, D C Batlle
Journal: Journal of the American Society of Nephrology (1992)

It has been postulated that a distinctive type of hyperkalemic distal renal tubular acidosis (DRTA), referred to as voltage-dependent DRTA, results from diminished potassium and hydrogen ion secretion in the distal nephron, which is due to a suboptimal voltage (lumen negative) as a result of impaired sodium reabsorption. To test for the presence of a voltage-dependent DRTA, we used amiloride (20 mg oral, single dose) and bumetanide (2 mg oral, single dose) to inhibit and to stimulate voltage-dependent potassium and hydrogen ion secretion, respectively. Eighteen patients with hyperkalemic DRTA and seven controls with a comparable degree of renal impairment were studied. Patients were subdivided in two groups on the basis of their ability to lower their urine pH during spontaneous acidosis. Patients in Group I lowered their urine pH to the level of controls (5.29 +/- 0.06 and 5.37 +/- 0.11, respectively) whereas patients in Group II could not lower their urine pH below 5.5 (6.38 +/- 0.11). Patients in Group I and Group II had a similar degree of metabolic acidosis and hyperkalemia whereas controls had neither acidosis or hyperkalemia. Most patients in Group II and all patients in Group I had low plasma aldosterone levels. The administration of amiloride resulted in an increase in urine pH and a decrease in potassium excretion in all three groups. The finding that amiloride, presumably by obliterating the transtubular voltage as a result of blockade of sodium transport, inhibited potassium excretion to about the same extent in both groups of patients and in controls argues against the existence of a voltage-dependent defect. Bumetanide produced a fall in urine pH below 5.5 and an increase in potassium excretion in controls and Group I patients. In Group II patients, bumetanide failed to elicit a fall in urine pH below 5.5 but resulted in an increase in potassium excretion similar to that seen in controls and Group I patients. These findings suggest that a derangement other than a voltage-dependent defect is responsible for the inability, characteristic of Group II patients, to lower their urine pH. It was concluded that the impairment in urinary acidification observed in patients with this subtype of hyperkalemic DRTA is due to a defect in collecting tubule hydrogen secretion that results from H+ ATPase dysfunction rather than from a voltage-dependent defect.
Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling
Authors: Louis M. Luttrell, Diane Gesty-Palmer
Journal: Pharmacological Reviews (2010)

Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective "biased agonists" is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.
Level of FEV1 as a predictor of all-cause and cardiovascular mortality: an effect beyond smoking and physical fitness?
Authors: J. Sunyer
Journal: European Respiratory Journal (2005)

In 1970, Higgins and Keller 1 showed that low spirometric values predict mortality independently of smoking in the general population of Tecumseh, MI, USA. Furthermore, in the general population of Renfrew and Paisley, Scotland, a forced expiratory volume in one second (FEV1) level in the lowest quintile explains a substantial fraction of all-cause mortality occurring in the subsequent 15 yrs (31% in males and 26% in females) 2. This observation was mainly mediated through a higher risk of dying from cardiovascular conditions, as it has also been observed in a number of other cohorts. In line with this, a significant association has also been reported between baseline levels of lung function and the incidence of coronary heart disease 3 and stroke 4; and, furthermore, annual decline of FEV1, independent of baseline FEV1, has also been related to cardiovascular mortality 5.

Recent evidence suggests that individuals in the community with moderate airflow limitation may have co-existing systemic inflammation 6, and …
Dynamic interaction between cardiac myosin isoforms modifies velocity of actomyosin sliding in vitro.
Authors: M Sata, S Sugiura, H Yamashita, S Momomura, T Serizawa
Journal: Circulation Research (1993)

To study the functional significance of cardiac isomyosin heterogeneity, active sliding of actin-myosin was studied using two different types of in vitro motility assay systems: (1) a sliding actin filament assay, in which fluorescently labeled actin filaments were made to slide on a myosin layer attached to a glass coverslip, and (2) a myosin-coated bead assay, in which myosin-coated latex beads were made to slide on actin cables of an alga. Two different isomyosins were obtained from 3-week-old (V1) and hypothyroid (V3) rat hearts and were mixed to form solutions with various mixing ratios [V1/(V1 + V3)]. For these myosin mixtures, both ATPase activity and sliding velocity of actin-myosin were determined. As the relative content of V1 increased, both ATPase activity and velocity increased. However, in contrast to the linear relation between the mixing ratio and ATPase activity, the relation between the mixing ratio and sliding velocity was sigmoid, suggesting the existence of mechanical interaction between different isomyosins. To clarify the nature of this interaction, sliding velocity was measured for mixtures of V1 and p-N,N'-phenylene-dimaleimide-treated V1 myosin (pPDM-M). A convex relation was observed between the relative content of pPDM-M and velocity. Because pPDM-M is known to form a noncycling and weakly bound crossbridge with actin, it is expected to exert a constant internal load on V1, in contrast to the actively cycling V3. In conclusion, in actomyosin sliding, different isomyosins mechanically interact when they coexist. The interaction may be a dynamic one that cannot be explained by a simple load effect.
p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation
Authors: Dennis Sohn, Frank Essmann, Klaus Schulze-Osthoff, Reiner U. Jänicke
Journal: Cancer Research (2006)

Abstract The role of the cyclin-dependent kinase (CDK) inhibitor p21 as a mediator of p53-induced growth arrest is well established. In addition, recent data provide strong evidence for new emerging functions of p21, including a role as a modulator of apoptosis. The mechanisms, however, by which p21 interferes with the death machinery, especially following ionizing radiation (IR), are largely unknown. Here, we report that IR induced caspase-9 and caspase-3 activation and subsequent apoptosis only in p21-deficient colon carcinoma cells, whereas similar treated wild-type cells were permanently arrested in the G2-M phase, correlating with the induction of cellular senescence. Interestingly, activation of the mitochondrial pathway, including caspase-2 processing, depolarization of the outer mitochondrial membrane, and cytochrome c release, was achieved by IR in both cell lines, indicating that p21 inhibits an event downstream of mitochondria but preceding caspase-9 activation. IR-induced p21 protein expression was restricted to the nucleus, and no evidence for a mitochondrial or cytoplasmic association was found. In addition, p21 did neither interact with caspase-3 or caspase-9, suggesting that these events are not required for the observed protection. Consistent with this assumption, we found that CDK inhibitors potently abrogated IR-induced caspase processing and activation without affecting mitochondrial events. In addition, in vitro caspase activation assays yielded higher caspase-3 activities in extracts of irradiated p21-deficient cells compared with extracts of similar treated wild-type cells. Thus, our results strongly indicate that p21 protects cells from IR-induced apoptosis by suppression of CDK activity that seems to be required for activation of the caspase cascade downstream of the mitochondria. (Cancer Res 2006; 66(23): 11254-62)
Selective Relationship Between Prefrontal<i>N</i>-Acetylaspartate Measures and Negative Symptoms in Schizophrenia
Authors: Joseph H. Callicott, Alessandro Bertolino, Michael F. Egan, Venkata S. Mattay, Frederick J.P. Langheim, Daniel R. Weinberger
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Certain cognitive, behavioral, and emotional deficits (so-called negative symptoms) in patients with schizophrenia have often been attributed to prefrontal cortical pathology, but direct evidence for a relationship between prefrontal neuronal pathology and negative symptoms has been lacking. The authors hypothesized that an in vivo measure of prefrontal neuronal pathology (N-acetylaspartate [NAA] levels) in patients with schizophrenia would predict negative symptoms. METHOD: Proton magnetic resonance spectroscopic imaging (1H-MRSI) and rating scales for negative and positive symptoms were used to study 36 patients with schizophrenia. Magnetic resonance spectra were analyzed as metabolite ratios, and parametric correlations were performed. RESULTS: A regionally selective negative correlation was found between prefrontal NAA-creatine ratio and negative symptom ratings in this group of patients with schizophrenia. CONCLUSIONS: Lower prefrontal NAA—and by inference greater neuronal pathology—predicted more severe negative symptoms in patients with schizophrenia. These data demonstrate a relationship between an intraneuronal measure of dorsolateral prefrontal cortex integrity and negative symptoms in vivo and represent further evidence for the involvement of the dorsolateral prefrontal cortex in negative symptoms associated with schizophrenia.
Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing
Authors: Jingquan Jia, Andrew E. Dellinger, Eric S. Weiss, Anuradha Bulusu, Christel Rushing, Haiyan Li, Leigh A. Howard, Neal Kaplan, Herbert Pang, Herbert I. Hurwitz, Andrew B. Nixon
Journal: Clinical Cancer Research (2015)

In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies.A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies.Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib.Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies.
Endoscopic and Percutaneous Drainage of Symptomatic Walled-Off Pancreatic Necrosis Reduces Hospital Stay and Radiographic Resources
Authors: Michael Gluck, Andrew Ross, Shayan Irani, Otto Lin, Ellen Hauptmann, Justin Siegal, Mehran Fotoohi, Robert Crane, David Robinson, Richard A. Kozarek
Journal: Clinical Gastroenterology and Hepatology (2010)
GENERATION OF CHEMOTACTIC ACTIVITY IN RABBIT SERUM BY PLASMINOGEN-STREPTOKINASE MIXTURES
Authors: Fletcher B. Taylor, Peter A. Ward
Journal: The Journal of Experimental Medicine (1967)

The addition of plasminogen and streptokinase to rabbit serum results in appearance of chemotactic activity which is relatively heat-labile and dialyzable. Generation of this activity requires heat-labile factors in serum, but not the sixth component of complement. The optimal mole ratio for generation of chemotactic activity is 1:1 to 1:3 for plasminogen to streptokinase. Neither material alone is sufficient to generate the activity in fresh serum. Generation of chemotactic activity can be blocked by the presence of ϵ-aminocaproic acid. This plasmin-generated chemotactic factor sediments slowly in a sucrose density gradient during ultracentrifugation. The addition of plasminogen and streptokinase to rabbit serum containing the preformed chemotactic factor (activated trimolecular complex of C'5, C'6, C'7) causes destruction of the chemotactic factor and loss of hemolytic activity of the sixth component of complement. The same mole ratio of reactants for optimal expression of the phenomenon holds as for plasmin generation of chemotactic activity in untreated serum.
Doctoring the Unattractive Areas
Authors: G. M. Jones
Journal: BMJ (1967)

on-coming cars would be cut out, since there would be a 90' rotation.Awareness of on- coming traffic may be achieved by using a Polaroid material of suitable density and efficiency so that not all light is stopped.Fog light would be exempt.If headlight adaptation is made compulsory it leaves the choice of selecting the method of cut-out to the individual driver, should he so desire.Th. most convenient but expensive way would be by incorporating the material between the layers of the windscreen during manufacture, but the alternatives mentioned above would be simpler and cheaper.Head- lights may be adapted by using clip-on polaroid screens or by inserting them on the inside of the glass during assembly.-Iam, etc.,