375 Ketamine Inhibits Cortical Spreading Depolarization in Acute Brain Injury: A Prospective Randomized Multiple Crossover Trial

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 288-289 ◽  
Author(s):  
Andrew Phillip Carlson ◽  
Mohammad Abbas ◽  
Rob Alunday ◽  
Fares Qeadank ◽  
C William Shuttleworth
Keyword(s):  
Brain Injury ◽  
Large Scale ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Fold Increase ◽  
Increased Risk ◽  
Trial Testing ◽  
Dose Dependent Fashion ◽  
Surrogate Measure ◽  
Dose Dependent

Abstract INTRODUCTION Retrospective clinical data support a therapeutic effect of ketamine in suppression of CSD. Animal and slice data strongly support this targeted efficacy on CSD. We present the results of the first prospective clinical trial testing the role of ketamine used for clinical sedation on occurrence of CSD after brain injury. METHODS 10 subjects with aneurysmal subarachnoid hemorrhage (SAH) or severe traumatic brain injury (TBI) or were recruited. A 1 × 6 ECog strip was placed at the time of craniotomy and subjects were then placed on a randomized alternating 6 hour schedule of ketamine or other sedation agent. Ketamine dose was adjusted to clinical effect and left at a subanesthetic basal dose if no sedation was required (0.1mg/kg/h.) CSD was scored using standard criteria, blinded to ketamine dosing. Occurrence of CSD was then compared to the hourly dose of ketamine to determine the effect of ketamine on CSD occurrence. RESULTS >Successful ECog recordings were obtained in all 10 subjects 8 with SAH and 2 with TBI. There was a total of 1642 hours of observations with adequate ECog 833 off ketamine and 809 on ketamine. Hours on doses of less than 1.15 mg/kg/h were associated with a highly significant increased risk of CSD compared with hours on doses of 1.15 mg/kg/h or more (OR = 13.838, 95% CI = 1.99-1000). A decrease of 0.15 mg/kg/h in dose was found to be associated with two-fold increase in the odds of CSDs (OR = 1.973, 95% CI = 1.265-3.503). There was no significant effect of ketamine on the mean duration of depression after CSD (F = 2.62, P = 0.11). CONCLUSION Ketamine effectively inhibits CSD after acute neurologic injury (SAH and TBI) in a dose dependent fashion. These data also demonstrate the feasibility of using CSD as a surrogate measure in future studies prior to large-scale studies of CSD directed therapy on outcome.

CCR1 Inhibition Impairs Osteoclast Activity and Interaction with Myeloma Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3494-3494
Author(s):  
Sonia Vallet ◽  
Noopur Raje ◽  
Kenji Ishitsuka ◽  
Teru Hideshima ◽  
Klaus Podar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Fold Increase ◽  
Pit Formation ◽  
Inflammatory Protein ◽  
Healthy Donors ◽  
Direct Cytotoxicity ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Modest Effect

Abstract Multiple Myeloma (MM) is characterized by increased osteoclasts (OC) activity leading to severe bone disease. Several inducers of OC number and activity have been identified, including several key chemokines. In particular, macrophage inflammatory protein-1α (MIP-1α) and RANTES activate CCR1 and CCR5, resulting in increased osteoclastogenesis (Oba et al. Exp Hematol. 2005) and increased OC motility (Yu X. J Bone Miner Res. 2004) These studies underscore the role of CCR1 in promoting osteoclastogenesis. Here we demonstrate the effects of inhibition of CCR1 with a specific receptor antagonist (MLN3897, Millenium Pharmaceuticals) on normal mature OC. Mature OC were obtained by stimulating PBMC of healthy donors with RANKL and MCSF (50 ng/ml) for three weeks. OC expressed high levels of CCR1 and secreted both MIP-1α (1 ng/ml +/− 1.8) and RANTES (12 pg/ml +/− 0.66), suggesting an autocrine effect of these chemokines. Analyzing the bone resorptive ability with a pit formation assay, we observed that MLN3897 impaired OC function in a dose-dependent fashion (at 10 nM: 20% of reduction in resorbed area, at 100 nM: 50% of reduction). We then studied the effects of CCR1 inhibition on OC viability by analyzing nuclear integrity with Hoechst33258 staining. After 12 hours of cytokine-deprivation, MLN3897 enhanced OC nuclear fragmentation and condensation, suggesting a role for CCR1 ligands in OC survival. We next studied the interactions between OC and MM cells. Because OC secrete several chemoattractants, we studied their ability to stimulate RPMI8226 MM cell migration. We first confirmed high expression levels of CCR1 on RPMI8226 MM cells by flow cytometry (86% compared to isotype control). Inhibition of CCR1 with MLN3897 did not induce any direct cytotoxicity or growth arrest of these cells. We then studied the effects of OC on RPMI8226 MM cells. We observed that OC potently stimulated migration of RPMI8226 MM cells (8-fold increase), which was almost completely blocked by treatment with MLN3897. In contrast, MIP-1α alone induced only a modest effect on migration: the highest effective concentration (0.5 ng/ml) induced only a 2-fold increase. Neutralizing MIP-1α antibody partially reversed these effects, suggesting that other factors may contribute to this migratory effect. Our data therefore demonstrate that CCR1 inhibition by MLN3897 impairs mature OC survival and activity. Although MLN3897 does not have any direct antiMM activity, it affects MM-OC interactions and inhibits MM cell migration to OC. Ongoing studies are further characterizing the effects of CCR1 inhibition on MM-OC interactions in order to provide the framework for its clinical evaluation in MM.

Induction of cell—cell adhesion by monovalent antibodies in a germ cell culture

Development ◽  
1985 ◽  
Vol 90 (1) ◽  
pp. 211-222
Author(s):  
Wai Chang Ho ◽  
Kathleen B. Bechtol
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Germ Cell ◽  
Germ Cells ◽  
Antigen Expression ◽  
Fab Fragment ◽  
Cell Age ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Four monoclonal antibodies, XT-I, MT-23, MT-24 and MT-29, that bind the XT-1-differentiation-antigen of male germ cells have been used to investigate the biological role of the XT-1-molecule of germ cells in short-term primary culture. Cultures from 10 days postpartum mice demonstrate increasing numbers of antigen-positive germ cells and increased antigen expression per cell with succeeding days of culture. Treatment of the antigen-positive cultures with three of the monoclonal antibodies, XT-I, MT-23 and MT-24, increases germ cell-germ cell adhesion in a dose-dependent fashion. Treatment with the fourth monoclonal antibody, MT-29, does not induce cell adhesion. The monovalent, Fab fragment of XT-I-antibody also elicits tight cell adhesion, thus ruling out antibody cross linking of molecules or cells. Saturating or near saturating amounts of the positive antibodies are required to produce adhesion, a result consistent with perturbation of a function that is performed by the sum of action of many of the XT-1-molecules on the cell. The ability of germ cells to undergo antibody-elicited tight adhesion is dependent on germ cell age and/or XT-1-antigen concentration. We hypothesize that the XT- 1-molecule is involved in regulation of cell adhesion, an event which must occur in normal development.

cAMP-stimulated rise of [Ca2+]i in rabbit connecting tubules: role of peritubular Ca

1990 ◽  
Vol 258 (3) ◽  
pp. F751-F755 ◽  
Author(s):  
J. E. Bourdeau ◽  
B. K. Eby
Keyword(s):  
Parathyroid Hormone ◽  
Ethylene Glycol ◽  
Cell Activation ◽  
Proximal Tubules ◽  
Tetraacetic Acid ◽  
Luminal Membrane ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Parathyroid hormone (PTH) increases cytosolic free Ca concentration ([ Ca2+]i) by mechanisms that depend on extracellular Ca in both cultured renal proximal tubules and isolated rabbit connecting tubules (CNTs). In CNTs 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) mimics this action, implicating cAMP as a second messenger, and part of the rise, due to increased luminal membrane Ca entry, is likely related to Ca absorption. In cultured proximal tubules the rise in [Ca2+]i, presumably mediated by increased Ca entry across the basolateral plasmalemma, activates gluconeogenesis and shortens microvilli. In the present study we examined cAMP-mediated Ca entry across the basolateral membranes of CNT cells, an effect potentially related to cell activation. Single CNTs were dissected from rabbit kidneys and loaded with fura-2. [Ca2+]i was measured by dual-wavelength excitation during perfusion of isolated segments in vitro. With 1.8 or 2.0 mM Ca in the lumen and the bath, suffusate 8-BrcAMP increased [Ca2+]i within minutes in a dose-dependent fashion. The increase persisted as long as 8-BrcAMP was present and reversed on its withdrawal. With 0.1 microM Ca in the lumen and the bath, 8-BrcAMP, but not ionomycin, failed to increase [Ca2+]i, implying that extracellular Ca is the major source. In tubules perfused with 2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid to eliminate luminal Ca, but suffused with 1.8 or 2.0 mM Ca, 8-BrcAMP increased [Ca2+]i (though less so than with Ca in the lumen), implying Ca entry across basolateral cell membranes. This rise in [Ca2+]i was attenuated markedly by the presence of 50 microM LaCl3 in the bath.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a potential role of glucagon during eye growth regulation in chicks

2002 ◽  
Vol 19 (6) ◽  
pp. 755-766 ◽  
Author(s):  
MARITA P. FELDKAEMPER ◽  
FRANK SCHAEFFEL
Keyword(s):  
Visual Processing ◽  
Growth Regulation ◽  
Amacrine Cells ◽  
Early Gene ◽  
Eye Growth ◽  
Dose Dependent Fashion ◽  
High Concentrations ◽  
Dose Dependent ◽  
Glucagon Antagonist

Eye growth and refraction are regulated by visual processing in the retina. Until now, the messengers released by the retina to induce these changes are largely unknown. Previously, it was found that glucagon amacrine cells respond to defocus in the retinal image and even to its sign. The expression of the immediate-early gene product ZENK increased in this cell population in eyes wearing plus lenses and decreased in minus lens-treated chicks. Moreover, it was shown that the amount of retinal glucagon mRNA increased during treatment with positive lenses. Therefore, it seems likely that these cells contribute to the visual regulation of ocular growth and that glucagon may act as a stop signal for eye growth. The purpose of the present study was to accumulate further evidence for a role of glucagon in the visual control of eye growth. Chicks were treated with plus and minus lenses after injection of different amounts of the glucagon antagonist des-His1-Glu9-glucagon-amide or the agonist Lys17,18,Glu21-glucagon, respectively. Refractive development and eye growth were recorded by automated infrared photorefraction and A-scan ultrasound, respectively. The glucagon antagonist inhibited hyperopia development, albeit only in a narrow concentration range, and at most by 50%, but not myopia development. In contrast, the agonist inhibited myopia development in a dose-dependent fashion. At high concentrations, it also prevented hyperopia development.

scholarly journals Communicating Increased Risk: An Empirical Investigation of the National Weather Service’s Impact-Based Warnings

2016 ◽  
Vol 8 (3) ◽  
pp. 219-232 ◽  
Author(s):  
Mark A. Casteel
Keyword(s):  
Qualitative Research ◽  
Central Region ◽  
Behavioral Intentions ◽  
Large Scale ◽  
Empirical Investigation ◽  
Severe Weather ◽  
Plant Manager ◽  
Decision Points ◽  
Increased Risk

Abstract In 2014, following a Central Region pilot assessment, the National Weather Service implemented large-scale use of an experimental product of enhanced severe weather warnings known as impact-based warnings (IBWs). The overarching goal of these IBWs is to improve the threat warning process and motivate appropriate responses by using event tags and additional text that provides more specificity about the magnitude of the storm and its potential consequences. These IBWs are designed to be used by individuals in the field to make more effective decisions. Although qualitative research has shown overall satisfaction with IBWs (Harrison et al. 2014; Losego et al. 2013), little published experimental research has been conducted on these new enhanced warnings. The research reported here therefore empirically investigates the effectiveness of the new IBW experimental product. In three experiments, participants adopted the role of a plant manager and read both IBWs and non-IBWs. At three different decision points, participants made decisions about shutting down the plant and having employees shelter in place. The results of all three experiments show that the IBWs produced higher likelihoods of closing the plant and sheltering in place, but only after the additional IBW text (providing information about the hazard, source, and impact) was presented. Interestingly, participant background knowledge of tornadoes and severe weather had little impact on their shelter in place decisions. The results support the conclusion that the additional enhanced text in IBWs promotes a higher stated likelihood of sheltering in place, at least as measured by behavioral intentions.

Chorioamnionitis reduces placental endocrine functions: the role of bacterial lipopolysaccharide and superoxide anion

1997 ◽  
Vol 155 (3) ◽  
pp. 401-410 ◽  
Author(s):  
T Okada ◽  
N Matsuzaki ◽  
K Sawai ◽  
T Nobunaga ◽  
K Shimoya ◽  
...  
Keyword(s):  
Manganese Superoxide Dismutase ◽  
Northern Blot Analysis ◽  
Inflammatory Responses ◽  
Placental Lactogen ◽  
Manganese Superoxide ◽  
Histologic Chorioamnionitis ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Stimulation Of

Chorioamnionitis has been shown to be one of the most important factors in inducing preterm delivery. The present study was undertaken to examine the effects of chorioamnionitis on placental endocrine functions. Preterm placentas with histologic chorioamnionitis produced smaller amounts of human chorionic gonadotropin (hCG) and human placental lactogen (hPL) than those without chorioamnionitis (P < 0.001). To examine the mechanism involved in the suppression of placental endocrine functions induced by chorioamnionitis, we initially confirmed the expression of lipopolysaccharide (LPS) receptor, i.e. the CD14 molecule, on trophoblasts by Northern blot analysis and immunohistochemistry. We then stimulated purified trophoblasts with LPS, which is the major agent which induces inflammatory responses in the host via the LPS receptor. The trophoblasts stimulated with LPS produced reduced amounts of hCG, hPL, and progesterone in a time- and dose-dependent fashion in spite of the induced manganese-superoxide dismutase (SOD) synthesis. Stimulation of trophoblasts with hypoxanthine and xanthine oxidase resulted in suppressed hCG production, while the simultaneous addition of SOD into the culture medium reversed the suppression of hCG production. LPS in the placenta with chorioamnionitis might directly stimulate trophoblasts through the LPS receptor (CD14), thus reducing placental endocrine functions. Superoxide anions which exogenously act on trophoblasts might be generated by simultaneous stimulation of neutrophils and monocytes at the feto-maternal interface by LPS, and additively reduce placental endocrine functions.

scholarly journals Identification of a new metalloproteinase inhibitor that forms tight-binding complexes with collagenase

1990 ◽  
Vol 269 (1) ◽  
pp. 183-187 ◽  
Author(s):  
T E Cawston ◽  
V A Curry ◽  
I M Clark ◽  
B L Hazleman
Keyword(s):  
Connective Tissue ◽  
Culture Media ◽  
Tight Binding ◽  
Gel Filtration ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Metalloproteinase Inhibitor ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Extracellular Activity

Connective-tissue cells produce a family of metalloproteinases which, once activated, can degrade all the components of the extracellular matrix. These potent enzymes are all inhibited by the tissue inhibitor of metalloproteinases (TIMP), and it was thought that the levels of this inhibitor controlled the extracellular activity of these enzymes. We recently detected a new metalloproteinase inhibitor present in culture media of WI-38 fibroblasts. The inhibitor, named ‘large inhibitor of metalloproteinases’ (LIMP), can be separated from TIMP by gel filtration on Ultrogel AcA 44, where it is eluted with an apparent Mr of 76,000. A portion of this inhibitor-containing peak binds to concanavalin A-Sepharose, indicating that at least some of the inhibitor contains carbohydrate. LIMP inhibits collagenase (MMP-1), stromelysin (MMP-3) and gelatinase (MMP-2) in a dose-dependent fashion. Collagenase forms tight-binding complexes with LIMP, which can be separated from free collagenase on gel-filtration columns. The complex is eluted with Mr 81,600 (AcA 44) or Mr 60,000 (Superose 12). This complex is larger than that formed between collagenase and TIMP, which has Mr 52,800 (Aca 44) or 41,000 (Superose 12). Polyclonal antibody to TIMP does not recognize LIMP by immunoblotting, and will not block the inhibition of collagenase by LIMP, showing that LIMP is not a multimeric form of TIMP. The role of this new inhibitor in connective-tissue breakdown studies and its relationship to previously described inhibitors of metalloproteinases is discussed.

Use of antipsychotics and risk of venous thromboembolism in postmenopausal women

2016 ◽  
Vol 115 (06) ◽  
pp. 1209-1219 ◽  
Author(s):  
Jun-Ting Liou ◽  
Yun-Wen Huang ◽  
Chen Lin ◽  
Gwo-Jang Wu ◽  
Che-Li Chu ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Postmenopausal Women ◽  
Safety Issue ◽  
Antipsychotic Agents ◽  
Major Surgery ◽  
High Dose ◽  
Increased Risk ◽  
Dose Dependent Fashion ◽  
Nested Case Control ◽  
Dose Dependent

SummaryDespite continued uncertainty of venous thromboembolism (VTE) caused from antipsychotic agents, this safety issue has not been examined in postmenopausal women, a population with high usages of antipsychotics and at high risk for VTE. We assessed whether antipsychotic use was associated with an increased VTE risk in women after menopause. We conducted a nested case-control study of all Taiwanese women aged ≥ 50 years (n = 316,132) using a nationwide healthcare claims database between 2000 and 2011. All newly diagnosed VTE patients treated with an anticoagulant or thrombectomy surgery were identified as cases (n = 2,520) and individually matched to select controls (n = 24,223) by cohort entry date, age, cancer diagnosis and major surgery procedure. The odds ratios (ORs) and 95 % confidence interval (CI) of VTE associated with antipsychotics were estimated by multivariate conditional logistic regressions. Current use of antipsychotics was associated with a 1.90-fold (95 % CI = 1.64–2.19) increased VTE risk compared with nonuse in postmenopausal women. The VTE risk existed in a dose-dependent fashion (test for trend, p<0.001), with a more than quadrupled risk for high-dose antipsychotics (adjusted OR = 4.60; 95 % CI = 2.88–7.33). Current parenteral administration of antipsychotics also led to a 3.46-fold increased risk (95 % CI = 2.39–5.00). Conversely, there was no increased VTE risk when antipsychotics were discontinued for > 30 days. In conclusion, current use of antipsychotics is significantly associated with a dose-dependent increased risk of VTE in postmenopausal women, especially for those currently taking high-dose or receiving parenteral antipsychotics.

scholarly journals Lymphopenic community acquired pneumonia, an unnoticed phenotype associated to mortality in non immuno-suppressed patients: a retrospective cohort study

2017 ◽  
Author(s):  
Jesus F Bermejo-Martin ◽  
Catia Cilloniz ◽  
Raul Mendez ◽  
Raquel Almansa ◽  
Albert Gabarrus ◽  
...  
Keyword(s):  
Multivariate Regression ◽  
Fold Increase ◽  
Multivariate Regression Analysis ◽  
Community Acquired Pneumonia ◽  
Post Discharge ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Immunological Phenotype ◽  
Hospital Clinic

AbstractBackgroundThe role of neutrophil and lymphocyte counts as predictors of prognosis in Community Acquired Pneumonia (CAP) has not been appropriately studied.MethodsThis was a retrospective study to evaluate by multivariate regression analysis, the association between neutrophil and lymphocyte counts with mortality at 30-days post discharge in two large cohorts of hospitalized patients with CAP and no prior immunosupression: a multicentric with 1550 patients recruited at 14 hospitals in Spain and a unicentric with 2840 patients recruited at the Hospital Clinic-Barcelona.FindingsThe unicentric cohort accounted with a higher proportion of critically ill patients: 586 (20·6%) vs 131 (8·5%) and non survivors 245 (8·6%) vs 74 (4·8%). Lymphopenia (< 1000 lymphocytes/mm3) was present in the 52·8% of the patients in both cohorts. A sub-group of lymphopenic patients, those with lymphocyte counts below decil 3 (677 lymphocytes/mm3 in the multicentric cohort and 651 lymphocytes/mm3 in the unicentric one), showed > 2-fold increase in the risk of mortality, independently of the CURB-65 score, critical illness and receiving an appropriated antibiotic treatment: (OR [CI95%], p) (2·18 [1·21- 3·92], 0·009) and (2·33 [1·61-3·33], <0·001) respectively. Neutrophil counts were not associated with mortality risk.InterpretationLymphopenia is present in a half of the patients with CAP needing of hospitalization, in absence of antecendents of immunosupression. Lymphopenic CAP with lymphocyte counts < 664 lymphocytes/mm3 constitutes a particular immunological phenotype of the disease which is associated to an increased risk of mortality.FundingCibeRes, 2009 Support to Research Groups of Catalonia 911, IDIBAPS, SEPAR, SVN

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