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Significant Resistance (significant + resistance)
Selected AbstractsFusion protein consisting of the first immunoglobulin-like domain of porcine nectin-1 and Fc portion of human IgG1 provides a marked resistance against pseudorabies virus infection to transgenic miceMICROBIOLOGY AND IMMUNOLOGY, Issue 1 2009Yukiko Tomioka ABSTRACT Nectin-1 is a Ca2+ -independent Ig-like cell,cell adhesion molecule and an alphaherpesvirus receptor that binds to virion glycoprotein D by the first Ig-like domain. We have investigated the antiviral potentials of soluble forms of porcine nectin-1 to PRV infection by generating transgenic mice expressing different types of fusion protein. Previously, we reported that mice transgenic for a chimera that carried the entire ectodomain of porcine nectin-1 fused to the Fc portion of porcine IgG1 were more resistant than those transgenic for a chimera that carried the first Ig-like domain fused to the Fc portion. Recently, we generated transgenic mice expressing a fusion protein made of the first Ig-like domain fused to the Fc portion of human IgG1, and reported that they showed a microphthalmia. Here, two transgenic mouse lines expressing the fusion protein were challenged with PRV for comparing their resistances with those of transgenic mice expressing different types of fusion protein. Surprisingly, both transgenic mouse lines showed a high resistance to the viral infection, especially via the i.n. route. Significant resistance of the embryonic fibroblasts was also observed. Altogether, these findings indicated that the fusion protein consisting of the first Ig-like domain fused to the human Fc portion provided a marked resistance against PRV infection to the transgenic mice. [source] Novel DNA repair alkyltransferase from Caenorhabditis elegansENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2001Sreenivas Kanugula Abstract O6 -Alkylguanine DNA-alkyltransferase (AGT) is a widely distributed DNA repair protein that protects living organisms from endogenous and exogenous alkylation damage to DNA at the O6 -position of guanine. The search of the C. elegans genome database for an AGT protein revealed the presence of a protein (cAGT-2) with some similarity to known AGTs in addition to the easily recognized cAGT-1 protein. The predicted protein sequence of cAGT-2 contains the amino acid sequence ,ProCysHisPro, at the presumed active site of the protein, whereas all other known AGTs have ,ProCysHisArg,. A truncated version of the cAGT-2 protein was expressed in E. coli. This purified recombinant protein was able to repair O6 -methylguanine and O4 -methylthymine adducts in DNA in vitro and also reacted with the bulky benzyl adduct in O6 -benzylguanine. This fragment of cAGT-2 (104 amino acids) is the smallest protein possessing AGT activity yet described. The full-length cAGT-2 protein (274 amino acids) totally lacks the N-terminal domain present in all other known AGTs but has a long C-terminal extension that has significant homology to histone 1C. Expression of cAGT-2 in an E. coli strain lacking endogenous AGT activity provided modest but statistically significant resistance to the toxicity of N -methyl- N,-nitro- N -nitrosoguanidine, confirming that cAGT-2 is an alkyltransferase. Environ. Mol. Mutagen. 38:235,243, 2001. © 2001 Wiley-Liss, Inc. [source] Pyroglutamate-modified amyloid ,-peptides , A,N3(pE) , strongly affect cultured neuron and astrocyte survivalJOURNAL OF NEUROCHEMISTRY, Issue 6 2002Claudio Russo Abstract N-terminally truncated amyloid-, (A,) peptides are present in early and diffuse plaques of individuals with Alzheimer's disease (AD), are overproduced in early onset familial AD and their amount seems to be directly correlated to the severity and the progression of the disease in AD and Down's syndrome (DS). The pyroglutamate-containing isoforms at position 3 [A,N3(pE),40/42] represent the prominent form among the N-truncated species, and may account for more than 50% of A, accumulated in plaques. In this study, we compared the toxic properties, fibrillogenic capabilities, and in vitro degradation profile of A,1,40, A,1,42, A,N3(pE),40 and A,N3(pE),42. Our data show that fibre morphology of A, peptides is greatly influenced by the C-terminus while toxicity, interaction with cell membranes and degradation are influenced by the N-terminus. A,N3(pE),40 induced significantly more cell loss than the other species both in neuronal and glial cell cultures. Aggregated A,N3(pE) peptides were heavily distributed on plasma membrane and within the cytoplasm of treated cells. A,N3(pE),40/42 peptides showed a significant resistance to degradation by cultured astrocytes, while full-length peptides resulted partially degraded. These findings suggest that formation of N-terminally modified peptides may enhance ,-amyloid aggregation and toxicity, likely worsening the onset and progression of the disease. [source] Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic studyJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2007Jhi-Joung Wang Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K,). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and ,75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, ,-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation. [source] Educating doctors in France and Canada: are the differences based on evidence or history?MEDICAL EDUCATION, Issue 12 2005Christophe Segouin Background, Despite many economic and political similarities between France and Canada, particularly in their health care systems, there are very significant differences in their systems of medical education. Aim, This work aims to highlight the sociohistorical values of each country that explain these differences by comparing the medical education systems of the 2 countries, including medical schools (teachers, funding), key processes (curriculum, student selection) and quality assurance methods. Discussion, In France, means and processes are standardised and defined at a national level. France has almost no national system of assessment of medical schools nor of students. By contrast, Canada leaves medical schools free to design their medical curricula, select students and appoint teachers using their own criteria. In order to guarantee the homogeneity and quality of graduates, the medical profession in Canada has created independent national organisations that are responsible for accreditation and certification processes. Each country has a set of founding values that partly explain the choices that have been made. In France these include equality and the right to receive free education. In Canada, these include equity, affirmative action and market-driven tuition. Conclusion, Many of the differences are more easily explained by history and national values than by a robust base of evidence. There is a constant tension between a vision of education promoted by medical educators, based on contextually non-specific ideas such as those found in the medical education literature, and the sociopolitical foundations and forces that are unique to each country. If we fail to consider such variables, we are likely to encounter significant resistance when implementing reforms. [source] Enhanced fungal resistance in transgenic cotton expressing an endochitinase gene from Trichoderma virensPLANT BIOTECHNOLOGY JOURNAL, Issue 5 2003Chandrakanth Emani Summary Mycoparasitic fungi are proving to be rich sources of antifungal genes that can be utilized to genetically engineer important crops for resistance against fungal pathogens. We have transformed cotton and tobacco plants with a cDNA clone encoding a 42 kDa endochitinase from the mycoparasitic fungus, Trichoderma virens. Plants from 82 independently transformed callus lines of cotton were regenerated and analysed for transgene expression. Several primary transformants were identified with endochitinase activities that were significantly higher than the control values. Transgene integration and expression was confirmed by Southern and Northern blot analyses, respectively. The transgenic endochitinase activities were examined in the leaves of transgenic tobacco as well as in the leaves, roots, hypocotyls and seeds of transgenic cotton. Transgenic plants with elevated endochitinase activities also showed the expected 42 kDa endochitinase band in fluorescence, gel-based assays performed with the leaf extracts in both species. Homozygous T2 plants of the high endochitinase-expressing cotton lines were tested for disease resistance against a soil-borne pathogen, Rhizoctonia solani and a foliar pathogen, Alternaria alternata. Transgenic cotton plants showed significant resistance to both pathogens. [source] Over-expression of TGA5, which encodes a bZIP transcription factor that interacts with NIM1/NPR1, confers SAR-independent resistance in Arabidopsis thaliana to Peronospora parasiticaTHE PLANT JOURNAL, Issue 2 2002Han Suk Kim Summary The Arabidopsis thaliana NIM1/NPR1 gene product is required for induction of systemic acquired resistance (SAR) by pathogens, salicylic acid (SA) or synthetic SA analogs. We identified, in a yeast two-hybrid screen, two NIM1/NPR1 interacting proteins, TGA2 and TGA5, which belong to the basic region, leucine zipper (bZIP) family of transcription factors. Both TGA2 and TGA5 strongly interact with NIM1/NPR1 in yeast and in vitro, and recognize the as-1 cis element found within the promoter of several pathogenesis-related genes, such as PR-1. To determine the role TGA2 and TGA5 may play in NIM1/NPR1-mediated disease resistance, we introduced sense and antisense versions of both genes into transgenic Arabidopsis plants. Characterization of TGA2 transgenic plants revealed that inhibition or overexpression of TGA2 does not significantly affect PR-1 expression or induction of SAR after pathogen infection or INA treatment. Surprisingly, all TGA5 -antisense transgenic plants produced showed increased accumulation of TGA5 transcripts compared with untransformed control plants, while the TGA5 -sense lines showed no significant increase in TGA5 mRNA levels. Interestingly, the high level of TGA5 mRNA in the antisense lines was accompanied by significant resistance to a highly virulent isolate of the oomycete pathogen Peronospora parasitica. Further, resistance was not coupled to accumulation of products from the SAR-linked PR-1 gene following inoculation with P. parasitica or treatment with INA, indicating that these plants express a robust, PR-1 -independent resistance mechanism. Resistance was retained when a TGA5 -accumulating line was combined genetically with a nim1-1 mutation or nahG (salicylate hydroxylase) transgene, indicating that resistance in these plants is due to an SA and SAR-independent mechanism. [source] Oral ciprofloxacin plus colistin: prophylaxis against bacterial infection in neutropenic patients.BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2001A strategy for the prevention of emergence of antimicrobial resistance Following a 2-year study, the combination of oral ciprofloxacin and colistin has been used continuously for 10 years without the emergence of resistance. During a 2-year period (1987,1989), we compared ciprofloxacin + colistin (CIP + COL) with neomycin + colistin (NEO + COL) in a randomized trial , combinations chosen because of the potential for prophylaxis of Gram-negative infection by ciprofloxacin, with colistin given to reduce the risk of emergence of resistance. Sixty-four patients with similar demographics in each arm were evaluable for efficacy analysis. Patients on CIP + COL had a significantly lower proportion of neutropenic days with fever (P < 0·001) and neutropenic days on intravenous antibiotics (P < 0·001) than patients on NEO + COL. A total of 54 (15 bacteriologically documented) pyrexial episodes occurred in patients on CIP + COL and 77 (41 bacteriologically documented) in patients on NEO + COL. Only two Gram-negative bacterial infections occurred in the CIP + COL arm compared with 16 in the NEO + COL arm. No Staphylococcus aureus infections occurred in the CIP + COL group compared with 10 in the other patients. Two CIP-resistant Gram-negative bacilli were isolated from patients on CIP + COL compared with 13 NEO-resistant Gram-negative bacilli from patients on NEO + COL. Following a subsequent decade of unchanged use of this prophylactic strategy in neutropenic patients, a 2-year follow-up study between 1 January 1998 and 31 December 1999 showed 66 significant infections during 350,400 neutropenic episodes. Eight of the 111 (7·2%) isolates were with ciprofloxacin-resistant organisms, involving 2% of the neutropenic episodes, indicating that the strategy of combining colistin with ciprofloxacin has been effective in the prevention of Gram-negative sepsis in neutropenic patients without the emergence of significant resistance despite widespread concurrent hospital and community use of the quinolones. [source] PARTICIPATION OF VASOPRESSIN IN THE DEVELOPMENT OF CEREBRAL VASOSPASM IN A RAT MODEL OF SUBARACHNOID HAEMORRHAGECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2004Cristina C Trandafir SUMMARY 1.,Previous studies have suggested the involvement of arginine vasopressin (AVP) and inflammation in the development of cerebral vasospasm after subarachnoid haemorrhage (SAH). The aim of the present study was to clarify the role of AVP in the arterial narrowing following cerebral haemorrhage by examining the effect of SR 49059 (a V1 receptor antagonist) on the diameter of rat basilar artery exposed to SAH. The effect of the 5-lipoxygenase inhibitor ZM 230487 on AVP-induced contraction of rat basilar arteries was also investigated. 2.,After 1 h and 2 days from SAH induction, brains were removed and pictures of the basilar arteries were taken. The external diameter of the basilar artery was measured in the presence and absence of SR 49059 (1 mg/kg, i.v.). For in vitro experiments, the basilar arteries isolated from control and SAH rats (at 1 h and at 2 days from SAH induction) were cut into spiral preparations and the AVP (0.3 nmol/L)-induced contraction in the presence of ZM 230487 was investigated. Each group analysed (i.e. control, SAH 1 h and SAH 2 days) consisted of eight rats. 3.,The diameter of rat basilar arteries decreased by 43 and 25% at 1 h and 2 days from SAH induction, respectively, compared with control. The administration of SR 49059 significantly reduced cerebral vasospasm. After SAH induction, the diameter of the basilar artery in SR 49059-treated groups decreased by only 22% (at 1 h) and by 3% (at 2 days) compared with the control group (P < 0.01). In basilar arterial strips, ZM 230487 attenuated the vasopressin-induced contraction in both control and SAH groups. However, SAH groups showed a significant resistance of the AVP-induced contraction in the presence of ZM 230487 compared with control (P < 0.05). 4.,The results suggest that the cerebral vasospasm in SAH rats is due, at least in part, to endogenous AVP and may involve an increase in the activity of 5-lipoxygenase. SR 49059 may represent a potential therapeutic strategy for the treatment of cerebral vasospasm. [source] In vitro susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis: a European multicenter study during 2000,2001CLINICAL MICROBIOLOGY AND INFECTION, Issue 7 2003M. E. Jones Objective, To assess the current (2001) activity of respiratory fluoroquinolones and comparator agents against respiratory pathogens isolated in European countries. Methods, During 2000,2001, we prospectively collected 1995 isolates of Haemophilus influenzae, 1870 isolates of Streptococcus pneumoniae and 649 isolates of Moraxella catarrhalis from hospital laboratories in France, Germany, Greece, Italy, Spain and the UK. National Committee for Clinical Laboratory Standards (NCCLS)-approved broth microdilution antimicrobial susceptibility testing methods and interpretive criteria were used throughout. Results, Of the S. pneumoniae isolates, 99.6% were susceptible to moxifloxacin, gatifloxacin and levofloxacin; the corresponding figure for H. influenzae was 100%. All M. catarrhalis isolates had moxifloxacin MICs ,,0.12 mg/L. For all three pathogens, fluoroquinolone susceptibility remained unchanged from the previous 1997,98 study. The incidence of penicillin non-susceptibility in the S. pneumoniae isolates tested remained similar to or higher than that recorded in previous studies: France, 165/291 (56.7%); Germany, 46/506 (9.1%); Greece, 20/55 (36.4%); Italy, 45/364 (12.4%); Spain, 146/268 (54.5%); and the UK, 26/386 (6.7%). Significant levels of resistance to oral compounds (cefuroxime, cefaclor, cefdinir, clarithromycin, azithromycin, tetracycline, and trimethoprim,sulfamethoxazole) were detected among S. pneumoniae isolates. ,-Lactamase production among H. influenzae isolates ranged from 6.2% to 33.1% per country, and ampicillin, clarithromycin or trimethoprim,sulfamethoxazole resistance were the most common phenotypes detected. ,-Lactamase production among M. catarrhalis isolates ranged from 94.1% to 100% per country. Conclusions, With the exception of a few localized reports, resistance to moxifloxacin and other new fluoroquinolones in common respiratory pathogens is a rare occurrence, despite significant resistance to other compound classes. Surveillance will play a key role in tracking changes in fluoroquinolone susceptibility in European countries. [source] | |||||||||||||