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Selected AbstractsComparison of the effects of early handling and early deprivation on maternal care in the ratDEVELOPMENTAL PSYCHOBIOLOGY, Issue 4 2001Christopher R. Pryce Abstract It has been reported in the rat that postnatal manipulations can induce robust and persistent effects on offspring neurobiology and behavior, mediated in part via effects on maternal care. There have, however, been few studies of the effects of postnatal manipulations on maternal care. Here, we describe and compare the effects on maternal behavior on postnatal days 1,12 of two manipulations, early handling (EH, 15-min isolation per day) and early deprivation (ED, 4-hr isolation per day), relative to our normal postnatal husbandry procedure. Maternal behavior was measured at five time points across the dark phase of the reversed L:D cycle. EH yielded an increase in arched-back nursing across several time points but did not affect any other behavior. ED stimulated a bout of maternal behavior such that licking and arched-back nursing were increased at the time of dam,litter reunion, although not at any other time point. Neither EH nor ED affected weaning weight significantly. Importantly, within-treatment variation was high relative to these between-treatment effects. © 2001 John Wiley & Sons, Inc. Dev Psychobiol 38: 239,251, 2001 [source] Accumulation and DNA damage in fathead minnows (Pimephales promelas) exposed to 2 brominated flame-retardant mixtures, Firemaster® 550 and Firemaster® BZ-54ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2010Jonathan S. Bearr Abstract Firemaster® 550 and Firemaster® BZ-54 are two brominated formulations that are in use as replacements for polybrominated diphenyl ether (PBDE) flame retardants. Two major components of these mixtures are 2,3,4,5-tetrabromo-ethylhexylbenzoate (TBB) and 2,3,4,5-tetrabromo-bis(2-ethylhexyl) phthalate (TBPH). Both have been measured in environmental matrices; however, scant toxicological information exists. The present study aimed to determine if these brominated flame-retardant formulations are bioavailable and adversely affect DNA integrity in fish. Fathead minnows (Pimephales promelas) were orally exposed to either FM 550, FM BZ54, or the nonbrominated form of TBPH, di-(2-ethylhexyl) phthalate (DEHP) for 56 d and depurated (e.g., fed clean food) for 22 d. At several time points, liver and blood cells were collected and assessed for DNA damage. Homogenized fish tissues were extracted and analyzed on day 0 and day 56 to determine the residue of TBB and TBPH and the appearance of any metabolites using gas chromatography-electron-capture negative ion mass spectrometry (GC/ECNI-MS). Significant increases (p,<,0.05) in DNA strand breaks from liver cells (but not blood cells) were observed during the exposure period compared with controls, although during depuration these levels returned to control. Both parent compounds, TBB and TBPH, were detected in tissues at approximately 1% of daily dosage along with brominated metabolites. The present study provides evidence for accumulation, metabolism, and genotoxicity of these new formulation flame retardants in fish and highlights the potential adverse effects of TBB- and TBPH-formulated fire retardants to aquatic species. Environ. Toxicol. Chem. 2010;29:722,729. © 2009 SETAC [source] Arterial blood gas parameters of normal foals born at 1500 metres elevationEQUINE VETERINARY JOURNAL, Issue 1 2010E. S. HACKETT Summary Reasons for performing study: Arterial blood gas analysis is widely accepted as a diagnostic tool to assess respiratory function in neonates. To the authors' knowledge, there are no published reports of arterial blood gas parameters in normal neonatal foals at altitude. Objective: To provide information on arterial blood gas parameters of normal foals born at 1500 m elevation (Fort Collins, Colorado) in the first 48 h post partum. Hypothesis: Foals born at 1500 m will have lower PaO2 and PaCO2 than foals born at sea level due to low inspired oxygen and compensatory hyperventilation occurring at altitude. Methods: Sixteen foals were studied. Arterial blood gas analysis was performed within 1 h of foaling and subsequent samples were evaluated at 3, 6, 12, 24 and 48 h post partum. Data were compared to those previously reported in healthy foals born near sea level. Results: Mean PaO2 was 53.0 mmHg (7.06 kPa) within 1 h of foaling, rising to 67.5 mmHg (9.00 kPa) at 48 h post partum. PaCO2 was 44.1 mmHg (5.88 kPa) within one hour of foaling, falling to 38.3 mmHg (5.11 kPa) at 48 h. Both PaO2 and PaCO2 were significantly lower in foals born at 1500 m elevation than those near sea level at several time points during the first 48 h. Conclusions and potential relevance: Foals at 1500 m elevation undergo hypobaric hypoxia and compensatory hyperventilation in the first 48 h. Altitude specific normal arterial blood values are an important reference for veterinarians providing critical care to equine neonates. [source] Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined directionHEPATOLOGY RESEARCH, Issue 5 2009Tomohiko Ohashi Aim:, Human hepatocytes are known to express an array of inflammatory cytokines and chemokines. In this study, we examined the potential roles of hepatocytes in regulating immune responses in the liver, by assessing the induction of Th1- or Th2-specific chemokines in HepG2 cells after various inflammatory stimulations. Methods:, HepG2 cells were stimulated with IL-1,, IFN-,, IL-4, IL-10, and/or CCL2, harvested at several time points, and served for the analyses of cytokine/chemokine mRNA expressions by semi-quantitative RT-PCR. Results:, (i) IL-1, up-regulated mRNA levels of CXCL8, CXCL10, and CCL2. IFN-, increased those of CXCL9, CXCL10, and CCL5, while IL-4 or IL-10 had no effect. (ii) Addition of IL-4 to the culture of IFN-,-stimulated cells, down-regulated CXCL9 and CXCL10 mRNA levels. (iii) Addition of IFN-, to the culture of IL-1,-stimulated cells, further up-regulated CXCL9 and CXCL10 mRNA levels. Addition of IL-4 decreased CXCL8 and CXCL10 levels, and increased CCL2 level in IL-1,-stimulated cells. (iv) CCL2 induced IL-4 mRNA expression. Conclusions:, IFN-, augmented mRNA expression of Th1-specific chemokines (CXCL9 and CXCL10) in HepG2 cells. IL-4 had no effect on those of Th2-spesific chemokines (CCL17 and CCL22); however, it was supposed to augment Th2 response indirectly through the induction of CCL2 under the inflammatory condition. The findings suggest that hepatocytes have ability to promote immune responses in the liver toward the direction, initially determined by the cytokine balances in the local inflammatory region. [source] Upregulation of gamma-2 laminin-332 in the mouse ear vesicant wound model,JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 3 2009Yoke-Chen Chang Abstract Epithelial cell migration during wound healing is regulated in part by enzymatic processing of laminin-332 (formerly LN-5), a heterodimer formed from ,, ,, and , polypeptide chains. Under static conditions, laminin-332 is secreted into the extracellular matrix as a proform and has two chains processed to smaller forms, allowing it to anchor epithelial cells to the basement membrane of the dermis. During incisional wounding, laminin ,2 chains in particular are processed to smaller sizes and function to promote epithelial sheet migration over the wound bed. The present study examines whether this same function occurs following chemical injury. The mouse ear vesicant model (MEVM) was used to follow the pathology in the ear and test whether processed laminin-332 enhances epithelial cell migration. Skin biopsies of sulfur mustard (SM) exposed ears for several time points were analyzed by histology, immunohistochemistry, real-time PCR, and Western blot analysis. SM exposure greatly increased mRNA levels for laminin-,2 in comparison to the other two chains. Protein production of laminin-,2 was upregulated, and there was an increase in the processed forms. Protein production was in excess of the amount required to form heterotrimeric laminin-332 and was associated with the migrating epithelial sheet, suggesting a potential role in wound healing for monomeric laminin-,2. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:172,184, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20275 [source] Troglitazone prevents fatty changes of the liver in obese diabetic ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2000Dong Mei Jia Abstract Background and Aims: Troglitazone is a newly developed antidiabetic drug and is indicated to be useful for the treatment of patients with type II diabetes mellitus. Recently, however, it became clear that troglitazone could cause liver dysfunction in some patients. In addition, a relationship between the activation of the peroxisome proliferator-activated receptor gamma receptor by troglitazone and colon tumorigenesis has been suggested. The present study was undertaken to examine the effects of long-term administration of troglitazone on the liver and intestine in genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and control Long-Evans Tokushima Otsuka (LETO) rats. Methods: A troglitazone-rich diet (200 mg/100 g normal chow) or a standard rat chow, free of troglitazone (control), was given to OLETF and LETO rats from 12 or 28 weeks of age until 72 weeks of age. Serum levels of glucose, insulin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined at several time points. In addition, histology of the liver and intestine and serum levels of cholesterol and triglycerides were examined at 72 weeks of age. Results: Troglitazone prevented age-related increases in fasting glucose and insulin concentrations in OLETF rats, but had no significant influences on serum levels of AST and ALT in both strains of rats. The liver weights in the control OLETF rats were significantly heavier than in the LETO rats. Troglitazone significantly reduced serum cholesterol and triglyceride levels and the liver weight. However, it had no influence on the large intestine weight and the number of colonic polyps in both OLETF and LETO rats. Sections of the liver from the untreated OLETF rats showed mild fatty changes in the central zone of the hepatic lobule, whereas those from the troglitazone-treated OLETF rats appeared normal with no fat deposition in the hepatocytes. Troglitazone in LETO rats also caused no significant histopathologic changes of the liver tissue. Conclusion: Our present study demonstrated that long-term administration of troglitazone prevents the progress of the metabolic derangement and fatty changes of the liver in genetically determined obese diabetes. [source] Differential regulation of blood vessel formation between standard and delayed bone healingJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 9 2009Jasmin Lienau Abstract Blood vessel formation is a prerequisite for bone healing. In this study, we tested the hypothesis that a delay in bone healing is associated with an altered regulation of blood vessel formation. A tibial osteotomy was performed in two groups of sheep and stabilized with either a rigid external fixator leading to standard healing or with a highly rotationally unstable one leading to delayed healing. At days 4, 7, 9, 11, 14, 21, and 42 after surgery, total RNA was extracted from the callus. Gene expressions of vWF, an endothelial cell marker, and of several molecules related to blood vessel formation were studied by qPCR. Furthermore, histology was performed on fracture hematoma and callus sections. Histologically, the first blood vessels were detected at day 7 in both groups. mRNA expression levels of vWF, Ang1, Ang2, VEGF, CYR61, FGF2, MMP2, and TIMP1 were distinctly lower in the delayed compared to the standard healing group at several time points. Based on differential expression patterns, days 7 and 21 postoperatively were revealed to be essential time points for vascularization of the ovine fracture callus. This work demonstrates for the first time a differential regulation of blood vessel formation between standard and mechanically induced delayed healing in a sheep osteotomy model. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fracturesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2006Takahiro Niikura Abstract Nonunion is a challenging problem that may occur following certain bone fractures. However, there has been little investigation of the molecular basis of nonunions. Bone morphogenetic proteins (BMPs) play a significant role in osteogenesis. However, little is known about the expression patterns of BMPs in abnormal bone healing that results in nonunion formation. These facts prompted us to investigate and compare the gene expression patterns of BMPs and their antagonists in standard healing fractures and nonunions using rat experimental models. Standard closed healing fractures and experimental atrophic nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of standard healing fracture and fibrous tissue of nonunion (n,=,4 per each time point and each group). Gene expression of BMPs, BMP antagonists, and other regulatory molecules were studied by methods including Genechip® microarray and real-time quantitative RT-PCR. Gene expression of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMBI were significantly lower in nonunions compared to standard healing fractures at several time points. Downregulation in expression of osteogenic BMPs may account for the nonunions of fracture. The balance between BMPs and their endogenous antagonists is critical for optimal fracture healing. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1463,1471, 2006 [source] Effects of Lidocaine Infusion during Experimental Endotoxemia in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2010J.R. Peiró Background: The clinical efficacy of IV infusion of lidocaine for treatment of equine endotoxemia has not been studied. Hypothesis: Lidocaine infusion after exposure to lipopolysaccharide (LPS) will inhibit the inflammatory response and have inhibitory effects on the hemodynamic and cytokine responses to endotoxemia. Animals: Twelve horses. Methods: Two equal groups (n = 6): saline (GI) and lidocaine (GII). In all animals, endotoxin (500 ng/kg body weight [BW]) was injected intraperitoneally over 5 minutes. Twenty minutes later, animals received a bolus of GI or GII (1.3 mg/kg BW) over 5 minutes, followed by a 6-hour continuous rate infusion of GI or GII (0.05 mg/kg BW/min). Treatment efficacy was judged from change in arterial blood pressure, peripheral blood and peritoneal fluid (PF) variables (total and differential cell counts, enzyme activities, and cytokine concentrations), and clinical scores (CS) for behavioral evidence of abdominal pain or discomfort during the study. Results: Compared with the control group, horses treated with lidocaine had significantly lower CS and serum and PF tumor necrosis factor-, (TNF-,) activity. At several time points in both groups, total and differential cell counts, glucose, total protein and fibrinogen concentrations, and alkaline phosphatase, creatine kinase, and TNF-, activities were significantly different from baseline values both in peripheral blood and in PF. Conclusions and Clinical Importance: Lidocaine significantly decreased severity of CS and inhibited TNF-, activity in PF. [source] Modifications and oxidation of lipids and proteins in human serum detected by thermochemiluminescenceLUMINESCENCE: THE JOURNAL OF BIOLOGICAL AND CHEMICAL LUMINESCENCE, Issue 2 2003Sergei Shnizer Abstract Detection of electronically excited species (EES) in body fluids may constitute an important diagnostic tool in various pathologies. Examples of such products are triplet excited carbonyls (TEC), which can be a source for photon emission in the 400,550,nm range. The aim of the present study was to determine the actual contribution of lipid and protein components (protein carbonyls) to photon emission generated by thermochemiluminescence (TCL) during the heating of biological fluids. In this study, a new TCL Photometer device, designed by Lumitest Ltd, Israel, was used. Samples were heated to a constant temperature of 80,±,0.5°C for 280,s and photon emission was measured at several time points. In order to compare the results of TCL measurements to conventional methods of detecting lipid and protein oxidation, each examined sample was also heated in a waterbath at 80°C for 10,280,s. Lipid and protein oxidation were subsequently measured using conventional methods. The TCL of four polyunsaturated fatty acids (PUFA) with three to six double bonds was measured. The elevation of the PUFA TCL amplitude correlated with the increase in the number of double bonds of PUFA. A correlation between the increase in TCL intensity and protein carbonyl generation in bovine serum albumin (BSA) was also observed. In the venous blood serum, our study showed that an increase of TCL intensity during heating reflected the cleavage of TEC of lipid origin. Our study suggests that biological molecules such as proteins, lipids and other molecules, which may become unstable during heating, are capable of generating EES. We demonstrated that a TCL curve can be used as a kinetic model for measuring oxidative processes, which reflects modifications of different molecules involved in the oxidative stress phenomena. Copyright © 2003 John Wiley & Sons, Ltd. [source] Ex vivo assessment of mouse cervical remodeling through pregnancy via 23Na MRSNMR IN BIOMEDICINE, Issue 8 2010Xiang Xu Abstract Preterm birth occurs in 12.5% of births in the United States and can lead to risk of infant death or to lifelong serious health complications. A greater understanding by which the two main processes, uterine contraction and cervical remodeling are regulated is required to reduce rates of preterm birth. The cervix must undergo extensive remodeling through pregnancy in preparation for parturition, the process of labor and delivery of young. One key aspect of this dynamic process is a change in the composition and abundance of glycosaminoglycans (GAGs) and proteoglycans within the extracellular matrix, which influences the loss of tensile strength or stiffness of the cervix during labor. 23Na NMR spectroscopy has previously been validated as a method to quantify GAGs in tissues. In the current study, the Na+ concentration was measured at several time points through pregnancy in mouse cervices using 23Na NMR spectroscopy. The Na+ concentration increased progressively during pregnancy and peaked one day before birth followed by a rapid decline after birth. The same trend was seen in GAGs as measured by a biochemical assay using independent cervix samples over the course of pregnancy. We suggest that monitoring the Na+ concentration via 23Na NMR spectroscopy can serve as an informative physiological marker in evaluating the stages of cervical remodeling ex vivo and warrants further investigation to determine its utility as a diagnostic tool for the identification of women at risk for impending preterm birth. Copyright © 2010 John Wiley & Sons, Ltd. [source] HPA axis safety of fluticasone furoate nasal spray once daily in children with perennial allergic rhinitisPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 3 2009Ita Tripathy The effects of intranasal corticosteroids (INSs) on the hypothalamic,pituitary,adrenal (HPA) axis should be assessed for any to be marketed INS. The objective of this study was to assess the effects of fluticasone furoate nasal spray (FFNS) on cortisol production (as a measure of HPA axis function) following 6 wk of treatment with FFNS 110 ,g once daily (QD) compared with placebo in pediatric patients with perennial allergic rhinitis (PAR). In this double-blind, parallel-group study, patients (n = 112) aged 2,11 yr with a 1-yr history of PAR (6 months for patients aged 2,3 yr) were randomized in a 1:1 ratio to either placebo or FFNS. Serum cortisol (SC) concentrations and urinary cortisol (UC) excretion were measured over a 24-h period at the randomization (baseline) and final treatment (week 6) visits for HPA axis evaluation in a domiciled environment (overnight in the clinic). Plasma samples were collected for FFNS at several time points over the 24 h after the final dose for pharmacokinetic analyses. FFNS was non-inferior to placebo with respect to change from baseline (expressed as a ratio) in 24-h SC weighted mean. The lower limit of the two-sided 95% confidence interval (CI) for the treatment ratio was greater than the pre-specified non-inferiority margin of 0.8 (treatment ratio = 0.97, 95% CI 0.88,1.07). UC excretion over 24 h at baseline and end of treatment was similar between treatment groups; no patients had 24-h excretion levels below normal range after 6 wk of treatment. Plasma concentrations of FFNS were generally non-quantifiable (<10 pg/ml). Results of the current study indicate that FFNS 110 ,g QD has no significant effect on HPA axis function in 2- to 11-yr-old pediatric patients with PAR. [source] The effect of postoperative fasting on vomiting in children and their assessment of painPEDIATRIC ANESTHESIA, Issue 5 2009OLIVER C. RADKE MD PhD DEAA Summary Background:, Mandatory postoperative food intake has been shown to increase nausea and vomiting, and so postoperative fasting has become common practice even if patients request food or drink. Objective:, We sought to investigate whether postoperative fasting reduces the incidence of postoperative vomiting in children when compared with a liberal regimen in which they are allowed to eat and drink upon request. Methods:, One hundred forty-seven children scheduled for outpatient surgery were randomized to one of two groups. After anesthesia, patients in the ,fasting' group were expected to fast for 6 h. The children in the ,liberal' group were allowed to eat and drink according to their own needs. The incidence of vomiting and the children's well-being were recorded at several time points over a 24-hour period. Parents were also asked to rate, on a scale of 0,6, how much their children were bothered by fasting, pain, and nausea/vomiting. Results:, Age (4.8 ± 2.6 years), weight (20 ± 9 kg) and gender (73% boys) were comparable between the groups. The incidence of vomiting was 15% in the liberal and 22% in the fasting group (P = 0.39) and, between 1 and 12 h after extubation, children in the liberal group were significantly happier (P < 0.001). Children in the liberal group were significantly less bothered by their pain than those in the fasting group (P < 0.001). Conclusion:, Postoperative fasting did not reduce the incidence of vomiting after general anesthesia in children when compared with a liberal regimen. Furthermore, the ability to eat and drink at will decrease the bothersome aspects of pain and lead to happier patients. [source] Predictors of Cardiovascular Response to Methamphetamine Administration in Methamphetamine-Dependent IndividualsTHE AMERICAN JOURNAL ON ADDICTIONS, Issue 2 2008Gilles Fleury MD The goal of the present investigation was to determine predictors of cardiovascular response to methamphetamine administrated in the laboratory. Heart rate (HR) and blood pressure (BP) were measured at baseline and at several time points following the administration of methamphetamine or saline placebo. One-way ANOVA was used to determine the differences between female and male subjects in their cardiovascular response. In male subjects, linear regression and one-way ANOVA were used to determine the influence of potential predictors on cardiovascular response, including age, weight, drug use indicators, concurrent use of other substances, route of administration, and race. Methamphetamine administration provoked significant increases in HR and BP, as compared to placebo. Female gender was associated with larger peak change in diastolic BP following administration. Baseline HR and BP were found to be strong predictors of cardiovascular response to methamphetamine administration in male subjects. Lifetime use and recent use of methamphetamine and nicotine did not predict cardiovascular response to methamphetamine. Recent alcohol use was associated with increased peak change in diastolic BP. Also, current use of cannabis was negatively correlated with peak HR change. Male cannabis users show lower peak change in HR as compared to non-cannabis users. As compared to methamphetamine smokers, intravenous users demonstrated higher peak change in diastolic BP following drug administration. Race did not have a significant effect on cardiovascular response. Taken together, these findings may help in the prevention and treatment of cardiovascular events in a population at high risk of premature morbidity and mortality. [source] 1141638491 Hepatocyte growth factor (HGF) stimulates mammalian target of rapamycin (mTOR) in choriocarcinoma cell lines and human trophoblast cellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006S Busch Introduction:, Hepatocyte growth factor (HGF), interleukin-6 (IL-6) and insulin-like growth factor-II (IGF-II) are involved in the regulation of trophoblast cell migration and invasion. Signal Transducer and Activator of Transcription 3 (STAT3) and Mammalian Target Of Rapamycin (mTOR) signalling regulate cell invasion, growth and proliferation. mTOR plays also a key role during embryogenesis. Knock-out mice embryos die after implantation and blastocysts trophoblast outgrowth is reduced. Aim:, Stimuli which might trigger such invasive behaviour through mTOR should be defined. Methods:, The human choriocarcinoma cell lines JEG-3, JAR, the human choriocarcinoma-trophoblast hybrid AC1-M59 and human term trophoblast cells were stimulated with HGF, IL-6 or IGF-II. At several time points, the phosphorylation level of mTOR and STAT3 were tested by Western blot. STAT3 DNA-binding capacity was analyzed by Electrophorectic Mobility Shift Assay (EMSA). To examine the role of mTOR for invasion and proliferation, mTOR expression was silenced by RNA interference (RNAi). Results:, HGF, IGF-II and IL-6 did neither induce tyrosine (705) phosphorylation of STAT3 nor STAT3 DNA binding capacity as assessed by EMSA. HGF led to an increase of mTOR serine (2448) phosphorylation for all cell types after 15 and 30 min while IL-6 and IGF-II did not induce mTOR phosphorylation. Simultaneously, HGF decreased STAT3 serine (727) phosphorylation. mTOR silencing in AC1-M59 correlates with reduced proliferation and invasion. STAT3 expression was not affected by mTOR knock down. Conclusion:, HGF triggers mTOR activity in trophoblast and trophoblast-like cells. mTOR is a main regulator of crucial trophoblast functions. [source] Synthesis and Characterization of New Liver Targeting 5-Fluorouracil-Cholic Acid ConjugatesARCHIV DER PHARMAZIE, Issue 9 2009Shan Qian Abstract The objective of this work was to develop a liver-specific antihepato carcinoma agent. A series of 5-fluorouracil / cholic acid conjugates (5-FU-cholic acid conjugates) were prepared and tested for their chemical characteristics and bio-distribution properties. The in-vitro stability trial showed 5-FU-cholic acid conjugates could be completely hydrolyzed by heating at 70°C in an acidic solution, pH = 1, for 5 min. The fast and complete hydrolysis of these compounds could be compatible with a fast separation and analysis method to shorten the analysis time. The decomposition speeds of the 5-FU-cholic acid conjugates in different organs of mice at several time points after oral administration were evaluated by measuring the concentrations of regenerated 5-FU in organ tissue. The results were compared with those of the controls, which was a group of mice orally taking 5-FU. The concentrations of 5-FU in mice liver tissue were remarkably increased after oral administration of the prodrugs, and were much larger than if only orally administered 5-FU. The results suggested the feasibility to improve therapeutic efficiency of liver targeting treatments by using cholic acid as the vector of drugs. [source] Monosodium urate monohydrate crystal,induced inflammation in vivo: Quantitative histomorphometric analysis of cellular eventsARTHRITIS & RHEUMATISM, Issue 6 2002C. Schiltz Objective To quantify the inflammatory cell response in rat air pouch pseudosynovial membrane during monosodium urate monohydrate (MSU) crystal,induced inflammation. Methods In the rat air-pouch model, we used a computer-assisted histomorphometric method to quantify cell distributions, based on cell linear densities, in histologic sections of membranes from pouches injected with MSU or saline. The volume, white blood cell (WBC) count, and histamine content of the pouch exudates were determined at several time points. Results Injection of 10 mg of MSU crystals into the pouch produced an acute exudate. After peaking at 24 hours, the exudate volume and WBC count decreased spontaneously over the next 3 days, simulating the self-limited course of acute gout. Membrane thickness followed a parallel course. Membrane polymorphonuclear cell (PMN) linear densities were closely correlated with exudate WBC counts, suggesting PMN recruitment from the subintimal synovial membrane. Both monocyte/macrophage and mast cell linear densities increased in the subintimal layer 2 hours after crystal injection (P = 0.038 and P = 0.03, respectively, versus controls), whereas PMN linear densities showed 2 peaks, one at 4 hours and the other 24 hours. The exudate histamine content peaked 6 hours after crystal injection, when mast cell linear densities were minimal in the membranes, suggesting mast cell degranulation. Conclusion An increase in monocyte/macrophage and mast cell densities in the membrane preceded the PMN influx in the pouch membrane and exudate, suggesting that mast cells may be involved in the early phase of MSU crystal,induced inflammation, at least in this rat model. [source] Characterisation of ligand binding to the parathyroid hormone/parathyroid hormone-related peptide receptor in MCF7 breast cancer cells and SaOS-2 osteosarcoma cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2007Majed S. Alokail Abstract Parathyroid hormone-related peptide (PTHrP) and parathyroid hormone (PTH)/PTHrP-receptor, PTH/PTHrP-R, are frequently expressed in mammary carcinomas as well as in bone cells. In this study we compared the ligand binding characteristics of the PTH/PTHrP,R in SaOS-2 human osteosarcoma cells with those in MCF7 breast cancer cells. We used both Scatchard analysis of saturation kinetics for iodinated ligand and the level of expressed receptor protein by visualising the single radio-labelled receptor-ligand complex from isolated membrane preparations from the two cell lines. In MCF7 cells, ligand binding, (receptor number) was increased by prior exposure of the cultured cells to epidermal growth factor (EGF), estradiol (E2), or dexamethasone (DEX), and decreased following calcitriol (1,25 DHCC). In contrast in the SaOS-2 cells, PTH/PTHrP-R number was increased by exposure to E2 and 1,25DHCC and decreased by DEX while EGF had no effect. These data were confirmed when the PTH/PTHrP-R was cross linked with 125I-PTHrP-1-34Tyr, and extended by visualising the intensity of the isolated radiolabelled receptor complex by autoradiography following SDS-PAGE at several time points during the treatment. Copyright © 2005 John Wiley & Sons, Ltd. [source] 2162: New aspects of the Slug Mucosal Irritation (SMI) assay: Detecting ocular stinging, itching and burning sensationsACTA OPHTHALMOLOGICA, Issue 2010J LENOIR Purpose Our eyes are one of the most important senses. They are very sensitive and irritations may occur easily. A screening method for ocular discomfort would be very helpful in the development and refinement of formulations. In the past, the Slug Mucosal Irritation (SMI) assay demonstrated a relation between an increased mucus production (MP) in slugs and an elevated incidence of stinging, itching and burning (SIB) in human eyes. The aim of this study is to compare subjective ocular discomfort caused by shampoos evaluated in volunteers with results of the SIB-procedure. Methods The stinging potency of 1 artificial tear and 10 shampoos was evaluated with the SIB-procedure by placing 3 slugs per treatment group 3 times on 100 µl of the test item. After each 15 min contact period, MP was measured. Evaluation of the results is based upon the total MP during 3 repeated contact periods. Experiments were repeated 3 times. A Human Eye Irritation test with the same test items will be set up (12-period cross-over study, 24 volunteers, study approved by an independent Commission for Medical Ethics, associated with Ghent University Hospital). The participants are dripped 10 µl of a 5% or 10% shampoo dilution in water or the artificial tear in 1 eye, while in the other eye 10 µl of water is administered. The evaluation of the test substances is done both by participants and the ophthalmologist at several time points. Conclusion With the obtained results we will be able to improve the newly developed protocol and examine the predictability with reference to non- and mildly irritating formulations in humans. We hope to conclude that the SIB-procedure is a good tool to predict clinical ocular discomfort. [source] | ||||||||||||||||