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Selected AbstractsProtein kinase C , phosphorylates keratin 8 at Ser8 and Ser23 in GH4C1 cells stimulated by thyrotropin-releasing hormoneFEBS JOURNAL, Issue 13 2007Yoshiko Akita Protein kinase C , (PKC,) is activated by thyrotropin-releasing hormone (TRH), a regulator of pituitary function in rat pituitary GH4C1 cells. We analyzed the downstream mechanism after PKC, activation. Exposure of GH4C1 cells to TRH or a phorbol ester increased the phosphorylation of three p52 proteins (p52a, p52b and p52c) and decreased the phosphorylation of destrin and cofilin. GF109203X, an inhibitor of protein kinases including PKC, inhibited phosphorylation of the p52 proteins by TRH stimulation. Peptide mapping, amino-acid sequencing, and immunochemical studies indicated that p52a, p52b, and p52c are the differentially phosphorylated isoforms of keratin 8 (K8), an intermediate filament protein. The unphosphorylated K8 (p52n) localized exclusively to the cytoskeleton, whereas the phosphorylated forms (especially p52c), which are increased in TRH-stimulated cells, localized mainly to the cytosol. K8 phosphorylation was enhanced in PKC,-overexpressing clones, and purified recombinant PKC, directly phosphorylated K8 with a profile similar to that observed in TRH-stimulated cells. PKC, and K8 colocalized near the nucleus under basal conditions and were concentrated in the cell periphery and cell,cell contact area after TRH stimulation. MS analyses of phospho-K8 and K8-synthesized peptide (amino acids 1,53) showed that PKC, phosphorylates Ser8 and Ser23 of K8. Phosphorylation of these sites is enhanced in TRH-stimulated cells and PKC,-overexpressing cells, as assessed by immunoblotting using antibodies to phospho-K8. These results suggest that K8 is a physiological substrate for PKC,, and the phosphorylation at Ser8 and Ser23 transduces, at least in part, TRH,PKC, signaling in pituitary cells. [source] Murid herpesvirus-4 induces chronic inflammation of intrahepatic bile ducts in mice deficient in gamma-interferon signallingHEPATOLOGY RESEARCH, Issue 2 2009Babunilayam Gangadharan Aim:, Infection of gamma interferon receptor defective mice with murid herpesvirus-4 also known as murine gammaherpesvirus-68 results in multi-organ fibrosis. In this paper we characterise the pathological changes occurring in the liver in this model. Methods:, Standard immunohistochemistry and in situ hybridisation techniques were used to identify the cellular changes and the presence of virus at different times post infection. Results:, In liver sections from infected gamma interferon receptor defective mice sampled on day 16 to at least day 120, 79% showed proliferating intrahepatic bile ducts associated with a chronic mononuclear cell inflammation. Only 8% of wild type mice showed similar lesions. Coincident with the inflammatory response bile duct epithelial cells were positive for arginase 1. Around day 50 post infection onwards focal fibrotic lesions appeared in approximately 30% of gamma interferon receptor defective mice resulting in destruction of intrahepatic bile ducts. In contrast to the chronic persisting inflammatory response the presence of virus infected cells were only observed between day 12,20 post-infection. Conclusion:, Infection of gamma interferon receptor defective mice with a murine gammaherpesvirus initiates a chronic persisting inflammatory response with a pathological profile similar to the human fibrotic liver disorder Primary Sclerosing Cholangitis. [source] Degradation of naphthenic acids by sediment micro-organismsJOURNAL OF APPLIED MICROBIOLOGY, Issue 5 2006L.F. Del Rio Abstract Aims:, Naphthenic acids (NAs) are naturally occurring, linear and cyclic carboxylic surfactants associated with the acidic fraction of petroleum. NAs account for most of the acute aquatic toxicity of oil sands process-affected water (OSPW). The toxicity of OSPW can be reduced by microbial degradation. The aim of this research was to determine the extent of NA degradation by sediment microbial communities exposed to varying amounts of OSPW. Methods and Results:, Eleven wetlands, both natural and process-affected, and one tailings settling pond in Northern Alberta were studied. The natural wetlands and process-affected sites fell into two distinct groups based on their water chemistry. The extent of degradation of a 14C-labelled monocyclic NA surrogate [14C-cyclohexane carboxylic acid (CCA)] was relatively uniform in all sediments (approximately 30%) after 14 days. In contrast, degradation of a bicyclic NA surrogate [14C-decahydronaphthoic acid (DHNA)]was significantly lower in non process-affected sediments. Enrichment cultures, obtained from an active tailings settling pond, using commercially available NAs as the sole carbon source, resulted in the isolation of a co-culture containing Pseudomonas putida and Pseudomonas fluorescens. Quantitative GC,MS analysis showed that the co-culture removed >95% of the commercial NAs, and partially degraded the process NAs from OSPW with a resulting NA profile similar to that from ,aged wetlands'. Conclusions:, Exposure to NAs induced and/or selected micro-organisms capable of more effectively degrading bicyclic NAs. Native Pseudomonas spp. extensively degraded fresh, commercial NA. The recalcitrant NAs resembled those found in process-affected wetlands. Significance and Impact of the Study:, These results suggest that it may be possible to manipulate the existing environmental conditions to select for a microbial community exhibiting higher rates of NA degradation. This will have significant impact on the design of artificial wetlands for water treatment. [source] Analysis of the role of bacterial endospore cortex structure in resistance properties and demonstration of its conservation amongst speciesJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2001A. Atrih Aims: The aim of this work was to compare the chemical structure of the spore cortex of a range of species, and to determine any correlation between cortex structure and spore resistance properties. Methods and Results: The fine chemical structure of the cortex of Bacillus subtilis, Bacillus megaterium, Bacillus cereus and Clostridium botulinum was examined by muropeptide analysis using reverse phase HPLC. There is a conserved basic structure between peptidoglycan of these species, with the only difference being the level of de -N -acetylation of an amino sugar. In order to determine if an alteration in cortex structure correlates with heat resistance properties, the peptidoglycan structure and properties of B. subtilis spores prepared under different conditions were compared. Peptidoglycan from spores prepared in Nutrient Broth (NB) showed reduction in single L -alanine substituted muramic acid to only 13·9% compared with 20·6% in CCY-grown spores. NB-prepared spores are also unstable, with 161-fold less heat resistance (60 min, 85°C) and 43 times less Mn2+ content than CCY-grown spores. Addition of MnCl2 to NB led to a peptidoglycan profile similar to CCY-grown spores, sevenfold more heat resistance (60 min, 85°C) and an 86-fold increase in Mn2+ content. Addition of CCY salts to NB led all parameters to be comparable with CCY-grown spore levels. Conclusions: It has been shown that peptidoglycan structure is conserved in four spore-forming bacteria. Also, spore heat resistance is multifactorial and cannot be accounted for by any single parameter. Significance and Impact of the Study: Endospores made by diverse species most likely have common mechanisms of heat resistance. However, the molecular basis for their resistance remains elusive. [source] EQUISWEET MILK CHOCOLATES WITH INTENSE SWEETENERS USING TIME-INTENSITY METHODJOURNAL OF FOOD QUALITY, Issue 6 2007LAURO LUÍS MARTINS MEDEIROS DE MELO ABSTRACT Five conventional chocolates were produced with different sucrose concentrations (from 40 to 52%) in order to determine ideal sweetness by acceptance test, and it was found that 43% sucrose milk chocolate has the ideal sweetness. Sucrose was replaced by bulking agents and sucralose or stevioside in order to prepare diabetic chocolates and 11 selected and trained judges determined the temporal characteristic of sweetness of these milk chocolates. Sucralose is 700 times sweeter than sucrose in this product, and stevioside, 200 times. Considering these potencies, they presented a time-intensity profile similar to chocolate with sucrose (i.e., conventional chocolate) and ideal sweetness. There is no significant difference between diabetic and conventional chocolates concerning the following physicochemical analyses: moisture content, medium particle size and Casson yield value. PRACTICAL APPLICATIONS The time-intensity method is becoming a useful tool because it makes it possible to compare perception over time of sucrose sweetness with that of other sweeteners. The key point of this study is to consider temporal sweetness characteristics to produce equisweet diabetic milk chocolates. The sensory analysis time-intensity method probably is a tool to obtain diabetic (i.e., with no sugar) chocolates that present a sweetness temporal profile as near as possible to conventional milk chocolate. This is a first step to produce diabetic chocolate with the same acceptance as conventional chocolate. [source] Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemiaJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006C. I. BRANDON The aim of the current study was to clone the equine adenosine A2A receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA2A -R expression construct was generated by ligation of the eA2A cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA2A -R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (KD), and receptor densities (Bmax) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p -sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A2A -R agonists revealed that the eA2A -R functionally coupled to G,s as indicated by an increase in intracellular [3H]cAMP upon receptor activation. Finally, NF- ,B reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF- ,B activity. These results indicate that the heterologously expressed eA2A -R has a pharmacological profile similar to that of other mammalian A2A receptors and thus can be utilized for further characterization of the eA2A -R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease. [source] NS5A mutations predict biochemical but not virological response to interferon-, treatment of sporadic hepatitis C virus infection in European patientsJOURNAL OF VIRAL HEPATITIS, Issue 4 2001I. Stratidaki The NS5A region of the hepatitis C virus (HCV) genome has been reported by Japanese but not European investigators to be a significant factor in predicting interferon (IFN) response patients with HCV of genotype 1. We correlated the NS5A region with treatment outcome in patients with sporadic HCV infection. Twenty-eight patients (10 men, 18 women, mean age 60 ± 2 years) with histologically proven HCV chronic hepatitis, genotype 1b, were treated with 6 MU IFN-, for 6 months. The 6954,7073 area of the NS5A region was directly sequenced for nucleotide and amino acids mutations and the results were related to biochemical and virological response. None of the patients had a strain with nucleotide sequence identical to the Japanese HCV-J. However, in five strains the nucleotide mutations led to synonymous amino acids and the amino acid sequences were identical to the prototype Japanese strain. Only 2/28 patients had four or more amino acid mutations (mutant strains) while 21 demonstrated an intermediate type and five belonged to the wild-type. The most frequent non-synonymous substitution was at position 6982 (A,G) corresponding to an amino acid change at codon 2218 (His,Arg). All patients with the wild-type were biochemical nonresponders while the two patients with the mutant strains had a sustained biochemical response. Twenty-three percent of the intermediate type had a sustained biochemical response. NS5A mutations predict the biochemical but not the virological response of patients. Virological response was poor and unrelated to the type of HCV strain. Biochemical responders had significantly lower amino acid mutations (1.14 ± 0.19) compared with nonresponders (2.57 ± 1.4, P < 0.003) as well as lower aminotransferase values (P < 0.01). Hence, mutational analysis of the NS5A region showed that our patients have a mutational profile similar to the European studies with a wild-type that is slightly different from the Japanese HCV-J sequence. The biochemical, but not the virological response to IFN-, is similar to the Japanese studies, with no response of the patients with wild-type sequence, a good response in the limited number of patients with mutant strains and 23% response rate in the patients with intermediate type sequences. [source] Cytokeratins in epithelia of odontogenic neoplasmsORAL DISEASES, Issue 1 2003MM Crivelini Neoplasms and tumours related to the odontogenic apparatus may be composed only of epithelial tissue or epithelial tissue associated with odontogenic ectomesenchyme. The immunohistochemical detection of different cytokeratins (CKs) polypeptides and vimentin has made it easier to explain the histogenesis of many epithelial diseases. The present study aimed to describe the immunohistochemical expression of cytokeratins 7, 8, 10, 13, 14, 18, 19 and vimentin in the epithelial components of the dental germ and of five types of odontogenic tumours. The results were compared and histogenesis discussed. All cells of the dental germ were positive for CK14, except for the preameloblasts and secreting ameloblasts, in which CK14 was gradually replaced by CK19. CK7 was especially expressed in the cells of the Hertwig root sheath and the stellate reticulum. The dental lamina was the only structure to express CK13. The reduced epithelium of the enamel organ contained CK14 and occasionally CK13. Cells similar to the stellate reticulum, present in the ameloblastoma and in the ameloblastic fibroma, were positive for CK13, which indicates a nature other than that of the stellate reticulum of the normal dental germ. The expression of CK14 and the ultrastructural aspects of the adenomatoid odontogenic tumour probably indicated its origin in the reduced dental epithelium. Calcifying odontogenic epithelial tumour is thought to be composed of primordial cells due to the expression of vimentin. Odontomas exhibited an immunohistochemical profile similar to that of the dental germ. In conclusion, the typical IF of odontogenic epithelium was CK14, while CK8, 10 and 18 were absent. Cytokeratins 13 and 19 labelled squamous differentiation or epithelial cells near the surface epithelium, and CK7 had variable expression. [source] Primary sensitization to inhalant allergensPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 2000Claudia Macaubas The neonatal T-cell system is capable of responding to allergens at birth, indicating the occurrence of prenatal sensitization, and the cytokine profile of these responses is skewed towards the Th-2 type. This response is further modified by postnatal exposure to different types of allergens. In relation to inhalant allergen (employed by HDM) the low level fetal Th-2 responses in non-atopics appear to be down-regulated rapidly after birth, parallel to an increase in allergen-specific IFN-, production. In contrast, atopics appear to consolidate their initial Th-2 responses, and around the age of 6 exhibit a cytokine response profile similar to the adult pattern. A pre-existing deficiency in IFN-, production may be one of the key factors determining the postnatal persistence of Th-2 responses in atopics. [source] Tramadol for pain relief in children undergoing tonsillectomy: a comparison with morphinePEDIATRIC ANESTHESIA, Issue 3 2003Thomas Engelhardt MD SummaryBackground: Pain control for paediatric patients undergoing tonsillectomy remains problematic. Tramadol is reported to be an effective analgesic and to have a side-effect profile similar to morphine, but is currently not licensed for paediatric use in the UK. Methods: We conducted a prospective, double-blind, randomized controlled trial in children who were scheduled for elective tonsillectomy or adenotonsillectomy at the Royal Aberdeen Children Hospital. Following local ethics committee approval and after obtaining a drug exemption certificate from the Medicines Licensing Agency for an unlicensed drug, we recruited 20 patients each into morphine (0.1 mg·kg,1), tramadol (1 mg·kg,1) and tramadol (2 mg·kg,1) groups. These drugs were given as a single injection following induction of anaesthesia. In addition, all patients received diclofenac (1 mg·kg,1) rectally. The postoperative pain scores, analgesic requirements, sedation scores, signs of respiratory depression and nausea and vomiting, as well as antiemetic requirements, were noted at 4-h intervals until discharge. Results: There were no statistically significant differences in age, weight, type of operation or induction of anaesthesia, 4-h sedation and pain scores and further analgesic requirements. There were no episodes of respiratory depression. Morphine was associated with a significantly higher incidence of vomiting following discharge to the wards (75% versus 40%, P=0.03) compared with both tramadol groups. Conclusions: Tramadol has similar analgesic properties, when compared with morphine. The various pharmaceutical presentations and the availability as a noncontrolled substance may make it a useful addition to paediatric anaesthesia if it becomes licensed for paediatric anaesthesia in the UK. [source] The genetic structure of populations from Haiti and Jamaica reflect divergent demographic historiesAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 1 2010Tanya M. Simms Abstract The West Indies represent an amalgamation of African, European and in some cases, East Asian sources, but the contributions from each ethnic group remain relatively unexplored from a genetic perspective. In the present study, we report, for the first time, allelic frequency data across the complete set of 15 autosomal STR loci for general collections from Haiti and Jamaica, which were subsequently used to examine the genetic diversity present in each island population. Our results indicate that although both Haiti and Jamaica display genetic affinities with the continental African collections, a stronger African signal is detected in Haiti than in Jamaica. Although only minimal contributions from non-African sources were observed in Haiti, Jamaica displays genetic input from both European and East Asian sources, an admixture profile similar to other New World collections of African descent analyzed in this report. The divergent genetic signatures present in these populations allude to the different migratory events of Africans, Europeans, and East Asians into the New World. Am J Phys Anthropol 2010. © 2009 Wiley-Liss, Inc. [source] Assessment of Intraoperative Safety in Transoral Robotic Surgery,THE LARYNGOSCOPE, Issue 2 2006Neil G. Hockstein MD Abstract Introduction: Robotic technology has been safely integrated into thoracic and abdominopelvic surgery, and the early experience has been very promising with very rare complications related to robotic device failure. Recently, several reports have documented the technical feasibility of transoral robotic surgery (TORS) with the daVinci Surgical System. Proposed pharyngeal and laryngeal applications include radical tonsillectomy, base-of-tongue resection, supraglottic laryngectomy, and phonomicrosurgery. The safety of transoral placement of the robotic endoscope and instruments has not been established. Potential risks specific to the transoral use of the surgical robot include facial skin laceration, tooth injury, mucosal laceration, mandible fracture, cervical spine fracture, and ocular injury. We hypothesize that these particular risks of transoral surgery are similar with robotic assistance compared with conventional transoral surgery. Methods: To test this hypothesis, we attempted to intentionally injure a human cadaver with the daVinci Surgical System by impaling the facial skin and pharyngeal and laryngeal mucosa with the robotic instruments and endoscope. We also attempted to extract or fracture teeth and fracture the cadaver's mandible and cervical spine by applying maximal pressure and torque with the robotic arms. Experiments were documented with still and video photography. Results: Impaling the cadaver's skin and mucosa resulted in only superficial lacerations. Tooth, mandible, and cervical spine fracture could not be achieved. Conclusions: Initial experiments performing TORS on a human cadaver with the daVinci Surgical System demonstrate a safety profile similar to conventional transoral surgery. Additionally, we discuss several strategies to increase patient safety in TORS. [source] Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009W. Vaudry Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ,2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 ,g * h/mL; liver 61.7 ± 29.5 ,g * h/mL; heart 58.0 ± 21.8 ,g * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults [source] Association between parasite infection and immune responses in multiple sclerosisANNALS OF NEUROLOGY, Issue 2 2007Jorge Correale MD Objective To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS). Methods A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-,, and interferon-, production by myelin basic protein,specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction. Results During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein,specific responses in peripheral blood showed a significant increase in IL-10 and TGF-, and a decrease in IL-12 and interferon-,,secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein,specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-, secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-,. Interpretation Increased production of IL-10 and TGF-,, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS. Ann Neurol 2007 [source] Predicting the optimal dietary essential amino acid profile for growth of juvenile yellow perch with whole body amino acid concentrationsAQUACULTURE NUTRITION, Issue 3 2010S.D. HART Abstract Rapid methods of estimating dietary essential amino acid (EAA) requirements might facilitate increases in aquaculture production, particularly for new or emerging industries. We conducted a 12-week feeding study to test the hypothesis that whole body EAA concentrations and the quantified methionine requirement could be used to predict the remaining dietary EAA requirements for juvenile all-female yellow perch. Six purified diets were developed and fed to triplicate groups of fish for 12 weeks. The diets contained the EAA profile of fishmeal (FM), the profile as predicted by whole body analysis, the quantified methionine requirement and resulting A/E ratios (PRED), PRED + 20% of all EAA (PRED20), PRED + 40% of all EAA (PRED40), PRED + 20% threonine, isoleucine and tryptophan (PRED320), and PRED + 40% threonine, isoleucine and typtophan (PRED340). Mean weight gain and feed consumption were significantly higher in fish fed PRED20 (35.7 ± 3.2 and 55.0 ± 5.3 g, respectively) than in fish fed FSM (25.1 ± 0.4 g wt gain, 41.0 ± 1.9 g cons), PRED (23.4 ± 2.3 g wt gain, 40.1 ± 4.2 g cons) and PRED340 (22.9 ± 3.3 g wt gain, 35.0 ± 3.8 g cons). There was no significant difference in feed efficiency among treatments. We recommend an EAA profile similar to PRED20 for feeding all-female juvenile yellow perch. [source] Optimal protein level in a semipurified diet for juvenile greenlip abalone Haliotis laevigataAQUACULTURE NUTRITION, Issue 4 2000T.A. Coote To optimize dietary protein level in relation to growth, semipurified diets with an essential amino acid profile similar to that of the soft body profile were fed for 59 days to young greenlip abalone, Haliotis laevigata (initial shell length, 15,25 mm). Animals were housed in 10-L acrylic tanks, with flow-through seawater supplied at 1 L min,1 (20 °C, salinity= 36 g L,1). Protein level of feeds ranged from 122 g kg,1 to 461 g kg,1 crude protein (CP) on an ,as is' basis. Second-order polynomial regression analysis of specific growth rate indicated that maximal growth occurs at 270 g kg,1 CP. The protein and energy components of the feed were estimated to have a digestibility of 71.7% and 55.6%, respectively. [source] High versus low dosing of oral colchicine for early acute gout flare: Twenty-four,hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study,ARTHRITIS & RHEUMATISM, Issue 4 2010Robert A. Terkeltaub Objective Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was ,50% pain reduction at 24 hours without rescue medication. Results There were 184 patients in the intent-to-treat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7,3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9,56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8,4.8]), none had severe diarrhea, and none had vomiting. Conclusion Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo. [source] MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial,ARTHRITIS & RHEUMATISM, Issue 3 2009Lorinda Chung Objective Raynaud's phenomenon (RP) affects 3,9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. Methods We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0,10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. Results The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. Conclusion MQX-503 is well tolerated and more effective than placebo for the treatment of RP. [source] Safety Pharmacology, Toxicology and Pharmacokinetic Assessment of Recombinant Human ,-Interferon Produced from CHO-SS CellsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2006Victor E. Buckwold Here we provide an overview of our preclinical safety evaluation of the fully-glycosylated human IFN-, produced from CHO-SS cells that is currently being evaluated clinically. IFN-, was not associated with any biologically-relevant adverse effects in a series of 10 safety pharmacology experiments, in the Ames mutagenicity test, in the micronucleus test, or in intraarterial, intravenous, paravenous or subcutaneous local tolerance studies. Acute, subacute, subchronic and reproductive toxicity studies performed in cynomolgus monkeys and rats showed a toxicity profile similar to that of human , interferon (IFN-,). Except for the acute (single-dose) toxicology study, all of the other toxicity studies showed evidence for the formation of anti-IFN-, antibodies over time in the animals. These antibodies were found to neutralize IFN-, antiviral activity in vitro in a dose-dependent manner. The average pharmacokinetic parameters following a single subcutaneous dose of IFN-, in rabbits, rats and monkeys were determined and found to be similar to that of human IFN-,. These findings demonstrate that IFN-, has a safety profile consistent with that required for its use in man. IFN-, might be beneficial for the treatment of patients infected with hepatitis C virus who fail to respond to IFN-, or as a first-line treatment option. [source] Stereoselective pharmacokinetics of desbutylhalofantrine, a metabolite of halofantrine, in the rat after administration of the racemic metabolite or parent drugBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2000Dion R. Brocks Abstract The main objective of this study was to determine the pharmacokinetics of the enantiomers of desbutylhalofantrine (DHF), a metabolite of halofantrine (HF), in the rat. Rats received either intravenous (2 mg/kg) or oral (7 mg/kg) (±)-DHF HCl, or (±)-HF HCl intravenously (3 mg/kg). Enantiomer concentrations in plasma were determined by a stereospecific assay. In all rats, the plasma concentrations of (+)-DHF exceeded those of (,)-DHF. After (±)-DHF, the mean (+):(,) ratios of AUC0,, after oral and intravenous dosing were 3.7 and 2.8, respectively. After intravenous doses of DHF, the (,):(+) enantiomeric ratios of Cl and Vdss were approximately 2.8. There were no significant differences between the enantiomers in t1/2 (mean 14,23 h) or tmax (mean 10,12 h) after intravenous or oral administration of DHF. Oral bioavailability estimates of DHF enantiomers (>59%) were higher than those previously estimated for HF in the rat. The stereoselectivity in HF kinetics was not as pronounced as for DHF. It was estimated that over 44% of the dose of HF is metabolized to DHF enantiomers. It was concluded that DHF possesses a pharmacokinetic profile similar to that of HF, each possessing low values of clearance and high volume of distribution. DHF differed from HF in its degree of stereoselectivity in pharmacokinetics, and in its extent of oral bioavailability. Copyright © 2000 John Wiley & Sons, Ltd. [source] Unique Reactivity of the Mukaiyama Glycosidation Catalyst (SnCl3ClO4) Toward ,-MannopyranosidesCHEMISTRY - AN ASIAN JOURNAL, Issue 2 2008Yonghui Wang Dr. Abstract Glycosidation of a mannosyl donor in the presence of the Mukaiyama catalyst was found to give exceptionally high ,/, selectivity. A systematic study was conducted to reveal that selective ,-to-, anomerization accounts for the observed high ,/, stereoselectivity. Furthermore, the Mukaiyama catalyst was shown to exhibit an unusual level of substrate and anomer selectivity for the anomerization. On the basis of the combined anomeric and ,2 effects, a mechanistic rationale was proposed, thereby suggesting the minimum structural moiety essential for the anomerization in question. With this analysis, ,-talo-, ,-altro-, and ,-idopyranosides are predicted to exhibit a reactivity profile similar to ,-mannopyranosides, but all other pyranosides should not. This prediction was verified by using ,- and ,-talopyranosides as an example. [source] Production of native and modified recombinant Der p 1 molecules in tobacco plantsCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2009D. Burtin Summary Background As a complex molecule requiring post-translational processing, it has been difficult to produce the Der p 1 major allergen from the Dermatophagoides pteronyssinus house dust mite in a recombinant form. Objective Here, we tested whether transgenic tobacco plants are suitable to express Der p 1, either as a wild-type molecule or as variants lacking N -glycosylation sites (Gly,) and/or cysteine protease activity (Enz,). Methods Using Agrobacterium tumefaciens -based transformation, pro Der p 1 molecules bearing mutations within either the N -glycosylation sites (N34Q, N150Q) and/or the cysteine protease-active site (C132V) were expressed in tobacco plants. After purification by ion exchange chromatography, allergens were characterized using immunoblotting, circular dichroism (CD), as well as basophil and T lymphocyte stimulation assays. Results Four forms of recombinant Der p 1 (i.e. wild-type Gly+/Enz+, as well as Gly,/Enz+, Gly+/Enz, or Gly,/Enz, variants) were successfully expressed in tobacco leaves as pro Der p 1 molecules. Spontaneous cleavage of the pro-peptide was observed in tobacco leaf extracts for all forms of recombinant Der p 1 (r Der p 1). CD confirmed that all r Der p 1 molecules, with the exception of the Gly,/Enz, variant, exhibited secondary structures comparable to the natural protein. A cysteine protease activity was associated only with the Gly+/Enz+ form. All these molecules exhibit a profile similar to natural Der p 1 with respect to IgE immunoreactivity, basophil activation and T cell recognition. Conclusion A tobacco plant expression system allows the production of various forms of mature Der p 1, which could be used for diagnostic or immunotherapeutic purposes. [source] Aroclor 1254 alters morphology, survival, and gene expression in Xenopus laevis tadpolesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2002Anna M. Jelaso Abstract PCBs are persistent environmental contaminants that cause a variety of adverse health effects in wildlife and humans. This article describes the use of signature gene expression patterns that link increased PCB exposure with progressive, adverse biological effects. Developing Xenopus laevis tadpoles of two age classes were exposed to the PCB mixture Aroclor 1254 for 2 days. Real-time PCR was used to quantitate mRNA expression for 11 physiologically relevant, potential bioindicator genes. Younger tadpoles (5 days postfertilization) were resistant to Aroclor 1254 and showed few changes in gross morphology, swimming behavior, survival, or gene expression. Older tadpoles (11 days postfertilization) were more susceptible to Aroclor 1254. Exposure to 25 and 50 ppm Aroclor 1254 caused alterations in gross morphology and swimming behavior and statistically significant decreases in survival. These tadpoles showed statistically significant decreases in gene expression for 9 out of the 11 genes measured. Tadpoles exposed to 10 ppm showed incipient health changes but had gene expression profiles similar to the tadpoles treated with higher doses of Aroclor 1254. Tadpoles exposed to 1 ppm did not exhibit any observable adverse health effects, yet statistically significant decreases in gene expression occurred in these tadpoles (4 out of 11 genes). After prolonged exposure, tadpoles exposed to 1 and 10 ppm Aroclor 1254 exhibited health effects similar to those exposed to higher concentrations. Therefore, changes in expression of specific genes may serve not only as molecular bioindicators of Aroclor 1254 exposure but also as predictors of impending adverse health effects. Environ. Mol. Mutagen. 40:24,35, 2002. © 2002 Wiley-Liss, Inc. [source] Altered effector functions of virus-specific and virus cross-reactive CD8+ T cells in mice immunized with related flavivirusesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010Derek W. Trobaugh Abstract Memory cross-reactive CD8+ T-cell responses may induce protection or immunopathology upon secondary viral challenge. To elucidate the potential role of T cells in sequential flavivirus infection, we characterized cross-reactive CD4+ and CD8+ T-cell responses between attenuated and pathogenic Japanese encephalitis virus (JEV) and pathogenic West Nile virus (WNV). A previously reported WNV NS4b CD8+ T-cell epitope and its JEV variant elicited CD8+ T-cell responses in both JEV- and WNV-infected mice. The peptide variant homologous to the immunizing virus induced greater cytokine secretion and activated higher frequencies of epitope-specific CD8+ T cells. However, there was a virus-dependent, peptide variant-independent pattern of cytokine secretion; the IFN,+ -to-IFN,+TNF,+ CD8+ T-cell ratio was greater in JEV- than in WNV-infected mice. Despite similarities in viral burden for pathogenic WNV and JEV viruses, CD8+ T cells from pathogenic JEV-immunized mice exhibited functional and phenotypic profiles similar to those seen for the attenuated JEV strain. Patterns of killer cell lectin-like receptor G1 (KLRG1) and CD127 expression differed by virus type, with a rapid expansion and contraction of short-lived effector cells in JEV infection and persistence of high levels of short-lived effector cells in WNV infection. Such cross-reactive T-cell responses to primary infection may affect the outcomes of sequential flavivirus infections. [source] Formula Optimization of a Low-fat Food System Containing Whey Protein Isolate- Xanthan Gum Complexes as Fat ReplacerJOURNAL OF FOOD SCIENCE, Issue 8 2005Sandra I. Laneuville ABSTRACT Whey protein isolate-xanthan gum complexes (WPXC) have the potential to significantly reduce fat use in various products. However, their stability and functionality have not been extensively studied, particularly in neutral pH products. The objective of this study was to evaluate WPXC as a fat replacer in cake frostings and sandwich cookie fillings with reduced-fat content (160 or 80 g/kg fat). Response surface methodology was used to analyze the effect of WPXC on the viscosity and textural response attributes of samples and to optimize the low-fat formulations. It was found that WPXC had a positive effect (P > 0.001), providing acceptable viscosity and texture attributes to the low-fat samples. A significant moisture-WPXC interaction (P > 0.001) revealed that the optimum moisture-WPXC ratio varied, depending on the targeted texture. This ratio was about 8:1 for cake frostings and about 5:1 for sandwich cookie fillings. Optimal formulations were found, and samples meeting the desirability specifications presented textural and melting profiles similar to those of the control products. However, for the production of sandwich cookie fillings, the use of other ingredients (for example humectants and emulsifiers) must be considered to maintain a low water activity (Aw) and prevent moisture migration to the cookie shell. [source] A comparison of American and international prototypes of successful managersJOURNAL OF LEADERSHIP STUDIES, Issue 1 2009Melenie J. Lankau In the present study, similarities and differences between prototypes of successful managers were examined across four cultural groups: Americans, Europeans, Asians, and Latin Americans. Managers from the hospitality industry (N = 366) used an 84,item attribute inventory to rate a successful middle manager. In addition, Americans' stereotypes of ethnic managers were compared with prototypes held by managers from those ethnic cultures. Specifically, American managers' perceptions of Asian and Hispanic managers were compared against Asian and Hispanic/Latin American managers' prototypes. A high level of correspondence in prototype characteristics was found across the four cultural groups. In addition, American-defined ethnic manager stereotypes also contained profiles similar to cultural prototypes. However, important differences were also detected on many managerial characteristics. Implications of the findings for cross-cultural congruence and areas for future research are discussed. [source] Modification of polycondensation of isophthalic and terephthalic acids and bisphenols with tosyl chloride/dimethylformamide/pyridine by the presence of additivesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 7 2003Fukuji Higashi Abstract In copolycondensation with 2,2-bis(4-hydroxyphenyl)propane (BPP) and bisphenols (BPs) containing various alkylidene linkages, the associative interactions between BP moieties in the resulting oligomers most likely affected the reaction. To modify the interactions to favorably control the reaction, several additives were examined in a two-stage polycondensation of an equimolar mixture of isophthalic acid and terephthalic acid, first with BPP (50 mol %) and next with additional BPP. Of additives used, diphenylmethane of an equivalent to BPP in the preformed oligomers was most effective. The results are discussed in terms of the distributions of resulting oligomers prepared at 70% extent of reaction. Better results were obtained when the distributions showed profiles similar to the theoretical one calculated on the basis that the reactivity of the oligomers is the same independent of their chain lengths. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 970,975, 2003 [source] Implementation of three-dimensional wavelet encoding spectroscopic imaging: In vivo application and method comparisonMAGNETIC RESONANCE IN MEDICINE, Issue 1 2009Richard Young Abstract We have recently proposed a two-dimensional Wavelet Encoding-Spectroscopic Imaging (WE-SI) technique as an alternative to Chemical Shift Imaging (CSI), to reduce acquisition time and crossvoxel contamination in magnetic resonance spectroscopic imaging (MRSI). In this article we describe the extension of the WE-SI technique to three dimensions and its implementation on a clinical 1.5 T General Electric (GE) scanner. Phantom and in vivo studies are carried out to demonstrate the usefulness of this technique for further acquisition time reduction with low voxel contamination. In wavelet encoding, a set of dilated and translated prototype functions called wavelets are used to span a localized space by dividing it into a set of subspaces with predetermined sizes and locations. In spectroscopic imaging, this process is achieved using radiofrequency (RF) pulses with profiles resembling the wavelet shapes. Slice selective excitation and refocusing RF pulses, with single-band and dual-band profiles similar to Haar wavelets, are used in a modified PRESS sequence to acquire 3D WE-SI data. Wavelet dilation and translation are achieved by changing the strength of the localization gradients and frequency shift of the RF pulses, respectively. The desired spatial resolution in each direction sets the corresponding number of dilations (increases in the localization gradients), and consequently, the number of translations (frequency shift) of the Haar wavelets (RF pulses), which are used to collect magnetic resonance (MR) signals from the corresponding subspaces. Data acquisition time is reduced by using the minimum recovery time (TRmin), also called effective time, when successive MR signals from adjacent subspaces are collected. Inverse wavelet transform is performed on the acquired data to produce metabolite maps. The proposed WE-SI method is compared in terms of acquisition time, pixel bleed, and signal-to-noise ratio to the CSI technique. The study outcome shows that 3D WE-SI provides accurate results while reducing both acquisition time and voxel contamination. Magn Reson Med 61:6,15, 2009. © 2008 Wiley-Liss, Inc. [source] | |||||||||||||||||||