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Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBClog values were 32/>512 μg/ml for fosfomycin, 4/>64 μg/ml for rifampin, 1/2 μg/ml for ampicillin, 2/>256 μg/ml for linezolid, 16/32 μg/ml for gentamicin, 1/>64 μg/ml for vancomycin, and 1/5 μg/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8× and 16× MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by ≈4 log10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.  相似文献   
3.
Tobacco use is a leading cause of preventable deaths worldwide. However, current smoking cessation therapies have very limited long-term success rates. Considerable research effort is therefore focused on identification of central nervous system changes with nicotine exposure because this may lead to more successful treatment options. Although recent work suggests that α6β2* nicotinic acetylcholine receptors (nAChRs) play a dominant role in dopaminergic function in rodent nucleus accumbens, the effects of long-term nicotine exposure remain to be determined. Here, we used cyclic voltammetry to investigate α6β2* nAChR-mediated release with long-term nicotine treatment in nonhuman primate nucleus accumbens shell. Control studies showed that nAChR-mediated dopamine release occurs predominantly through the α6β2* receptor subtype. Unexpectedly, there was a complete loss of α6β2* nAChR-mediated activity after several months of nicotine treatment. This decline in function was observed with both single- and multiple-pulse-stimulated dopamine release. Paired-pulse studies showed that the facilitation of dopamine release with multiple pulsing observed in controls in the presence of nAChR antagonist was lost with long-term nicotine treatment. Nicotine-evoked [(3)H]dopamine release from nucleus accumbens synaptosomes was similar in nicotine- and vehicle-treated monkeys, indicating that long-term nicotine administration does not directly modify α6β2* nAChR-mediated dopamine release. Dopamine uptake rates, as well as dopamine transporter and α6β2* nAChRs levels, were also not changed with nicotine administration. These data indicate that nicotine exposure, as occurs with smoking, has major effects on cellular mechanisms linked to α6β2* nAChR-mediated dopamine release and that this receptor subtype may represent a novel therapeutic target for smoking cessation.  相似文献   
4.
Autoradiographic analysis of [35S]GTPγS binding was used to investigate functional activation of dopamine receptors in rat striatum. Dopamine-stimulated [35S]GTPγS binding was observed with a maximal increase of 38% over basal activity. A similar stimulatory response was obtained with the D2 agonist quinpirole, but not SKF-238393, a D1 agonist. The effect of dopamine was blocked by the D2 antagonist raclopride, but was unaffected by SCH-23990, a D1 antagonist. There appeared to be a differential distribution of dopamine-stimulated [35S]GTPγS binding, with the lowest activity obtained in the medial portion of the caudal striatum. These results demonstrate, using an autoradiographic approach, (i) that dopamine stimulated [35S]GTPγS binding in the rat striatum occurs through activation of D2 receptors, and (ii) that the effects of dopamine activation vary in different areas of the rat striatum.  相似文献   
5.
Behavioral rating scales for dyskinesia in the non-human primate are frequently used to assess the efficacy of new treatments and to provide a clinical correlative with neurochemical and neuropathological changes. Although a large variety of different scales have been used in non-human primate studies, there is no single standardized scale, and none have been evaluated for reliability and validity. We are reporting a new global non-human primate dyskinesia rating scale (GPDRS) for the squirrel monkey, developed in the context of an independent study of dyskinesia. In this report we demonstrate the reliability and validity of this scale. The GPDRS is a single-item scale with well-defined points and brevity allowing for rapid and easy application for assessing the overall degree of dyskinesia. In this study, seven MPTP-lesioned and four non-lesioned (control) non-human primates were videotaped following treatment with either levodopa or water. To test inter- and intra-rater reliability, three examiners rated the videotape independently at two different time points and these assessments were compared. The validity of the scale was tested in two phases. First, examiners rated the videotape using the GPDRS and the Abnormal Involuntary Movement Scale (AIMS), a scale commonly used to rate dyskinesia in the non-human primate, and the ratings from each scale were compared. Second, validity was tested in the context of an independent dyskinesia study, in which the scale was used to distinguish between two treatment groups. The GPDRS was shown to have high inter- and intra-rater reliability and to be valid for the assessment of dyskinesia in the squirrel monkey. In this report we also demonstrate the inter- and intra-rater reliability of the AIMS.  相似文献   
6.
This study assessed whether or not levodopa induces dyskinesias in normal (ie, unlesioned) squirrel monkeys. All six animals treated twice daily with levodopa (15 mg/kg with carbidopa by oral gavage) for two weeks developed choreoathetoid dyskinesias, whereas none of the vehicle-treated animals displayed any abnormal movements. These dyskinesias did not merely reflect a generalized motor activation as locomotion was actually suppressed. The present data demonstrate that preexisting nigrostriatal damage is not necessary for the development of levodopa-induced dyskinesias.  相似文献   
7.
Nicotine treatment has long been associated with alterations in alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of long-term nicotine treatment on the alpha6beta2(*) nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal alpha6beta2(*) nAChR function and expression. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, alpha6beta2(*) nAChR blockade with alpha-conotoxin MII (alpha-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate alpha6beta2(*) nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, alpha6beta2(*) nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the alpha6beta2(*) nAChR subtypes altered with long-term nicotine treatment, we used the novel alpha-CtxMII analog E11A in combination with alpha4 nAChR knockout mice. (125)I-alpha-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the alpha6alpha4beta2(*) subtype but increased the alpha6(nonalpha4)beta2(*) nAChR population. These data indicate that alpha6beta2(*) nAChR-evoked dopamine release in nicotine-treated rats is mediated by the alpha6(nonalpha4)beta2(*) nAChR subtype and suggest that the alpha6alpha4beta2(*) nAChR and/or alpha4beta2(*) nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, alpha6beta2(*) nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.  相似文献   
8.
Summary 1 The effect of pre-dosing with 15 mg domperidone, a relatively selective dopamine 2-receptor antagonist, on the ocular hypotensive action of a single oral dose of 25 μg pergolide, a dopamine 2-receptor agonist, was studied in 9 normal human volunteers, using a non-invasive method. 2 Compared with domperidone followed after 1 h by placebo, placebo followed after 1 h by pergolide had an ocular hypotensive effect in both eyes. Domperidone followed after 1 h by pergolide had no effect on intraocular pressure in both eyes. 2 The results of this study showed that domperidone inhibited the ocular hypotensive action of pergolide, suggesting that pergolide reduces introcular pressure by the stimulation of the peripheral dopamine 2-receptors.  相似文献   
9.
A comparison between human and porcine insulins with regard to their adsorption to administration sets was performed. A125I-mono(A14)-iodinated insulin was used to follow the adsorption phenomenon over time and the adsorption was quantified with radioimmunoassays of unlabelled insulin. The obtained data were similar for both methods. No relevant difference in adsorption was found between human and porcine insulin. Both insulins showed a significantly more pronounced initial drop in delivered insulin when polyethylene tubing was used. After 3 h a steady state was reached, resulting in the administration of a more predictable dose. Particularly in the initial phase an important reduction in the amount of both insulins actually delivered to the patient was observed when compared to the expected amount as calculated from the concentration present in the container and the infusion rate.Therefore, the mainstay in treatment of a patient with ketoacidosis remains frequent serum glucose measurement and making appropriate infusion rate adjustments on that basis.  相似文献   
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