Search

Background: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype., Methods: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12h after clarithromycin 500 mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension., Results: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 μg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4 μg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05)., Conclusion: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity., (© 2013.)

Drosophila embryonic dorsal vessel (DV) morphogenesis is a highly stereotyped process that involves the migration and morphogenesis of 52 pairs of cardioblasts (CBs) in order to form a linear tube. This process requires spatiotemporally-regulated localization of signaling and adhesive proteins in order to coordinate the formation of a central lumen while maintaining simultaneous adhesion between CBs. Previous studies have shown that the Slit/Roundabout and Netrin/Unc5 repulsive signaling pathways facilitate site-specific loss of adhesion between contralateral CBs in order to form a luminal space. However, the concomitant mechanism by which attraction initiates CB outgrowth and discrete localization of adhesive proteins remains poorly understood. Here we provide genetic evidence that Netrin signals through DCC (Deleted in Colorectal Carcinoma)/UNC-40/Frazzled (Fra) to mediate CB outgrowth and attachment and that this function occurs prior to and independently of Netrin/UNC-5 signaling. fra mRNA is expressed in the CBs prior to and during DV morphogenesis. Loss-of-fra-function results in significant defects in cell shape and alignment between contralateral CB rows. In addition, CB outgrowth and attachment is impaired in both fra loss- and gain-of-function mutants. Deletion of both Netrin genes (NetA and NetB) results in CB attachment phenotypes similar to fra mutants. Similar defects are also seen when both fra and unc5 are deleted. Finally we show that Fra accumulates at dorsal and ventral leading edges of paired CBs, and this localization is dependent upon Netrin. We propose that while repulsive guidance mechanisms contribute to lumen formation by preventing luminal domains from coming together, site-specific Netrin/Frazzled signaling mediates CB attachment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Staphylococcus aureus is a leading cause of bacteraemia. This study analysed temporal trends from 18,702 adult cases of S. aureus bacteraemia in Denmark between 1981 and 2000. After stratification for mode of acquisition, 57% of cases were hospital-acquired (HA), 28% were community-acquired (CA) and 15% were of undetermined acquisition (UA). Incidence rates increased from 18.2 to 30.5 cases/100,000 population. Annual rates increased by 6.4% for CA, by 2.2% for HA and by 3.6% for UA cases, respectively. Case-mortality associated with HA bacteraemia decreased from 36.2% to 20.7% (43% rate reduction, p 0.0001), compared with a decrease from 34.5% to 26.5% (23% rate reduction, p 0.0001) for CA bacteraemia. Following multivariate analysis, age, pneumonia, endocarditis and chronic illness were associated with increased mortality, regardless of the mode of acquisition. Overall, mortality associated with S. aureus bacteraemia declined significantly between 1981 and 2000, but incidence rates doubled, so that the total number of deaths increased. These data emphasise the public health importance of S. aureus bacteraemia and the need for further preventive measures and improved care in order to reduce incidence rates and improve outcomes.

Objective: To study the possibility of reporting results of identification and susceptibility testing of Gram-negative bacilli the same day as bacteremia is detected by using direct inoculation from positive blood cultures (Bactec 9240) into VITEK GNI+ and GNS-GA cards., Methods: All blood cultures with Gram-negative enteric bacillus-like morphology on microscopy found to be positive on workdays between 15 June 1999 and 29 February 2000 were included. Identification and susceptibility testing were done by three methods: the direct method using a suspension made by differential centrifugation of positive blood culture broth for inoculation of the VITEK cards; the standard method using an inoculum made from an overnight culture on a solid media; and the routine method (reference method) using conventional testing., Results: Of 169 isolates, the direct method resulted in 75% correct identifications, 9% misidentifications and 17% non-identifications. All misidentified isolates were Escherichia coli, of which 80% were reported as Salmonella arizonae. Five biochemical tests yielded most of the aberrant results; correcting the citrate and malonate reactions in most cases led to correct identification by the VITEK database. Despite a negative H2S reaction, 11 E. coli isolates were reported as S. arizonae. Two-thirds (69%) of identifications were reported within 6 h, and 95% of these were correct. The direct susceptibility testing method was assessable for 140 isolates. Correct results were found in 99% of isolate-antimicrobial combinations, and 85% were reported within 6 h., Conclusion: The direct VITEK method could correctly report identifications and susceptibility patterns within 6 h, making same-day reporting possible for almost two-thirds (63%) of bacteremic episodes with Gram-negative bacilli. These results could probably be improved by modification of the identification algorithms of the VITEK software.

The present paper describe investigations which demonstrate that hyperforin is not the only phloroglucinol derivative in extracts of the medicinal plant Hypericum perforatum L., which possess a biological activity. Hyperforin was the major lipophilic constituent in two different extracts, whereas the amount of adhyperforin was approximately 10 times lower. Adhyperforin, like hyperforin, is a potent inhibitor of the uptake of dopamine, serotonin and noradrenaline. Neither hyperforin nor adhyperforin inhibited binding of the cocaine analogue, [3H]WIN 35,428 to the dopamine transporter. However, the known antidepressives imipramine, nomifensine and fluoxetine all inhibited binding of [3H]WIN 35,428, indicating that hyperforin and adhyperforin do not bind to the same site on the dopamine transporter as these compounds. Furthermore, hyperforin and adhyperforin did not prevent dopamine binding, but inhibited dopamine translocation. Our studies further support recent reports suggesting that the effect of hyperforin on uptake of monoamines is probably not caused by a direct effect of hyperforin on known sites on the transporters.

Study Objective: To compare the recovery characteristics of total intravenous anesthesia (TIVA) using midazolam-alfentanil, with or without reversal with flumazenil to a standardized neurolept anesthesia with nitrous oxide (N2O)., Design: Randomized, double-blinded clinical study., Setting: University medical center., Patients: 80 ASA physical status I and II women scheduled for major elective gynecologic surgery., Interventions: Patients were anesthetized with one of three different anesthetic techniques. Patients in the TIVA group with reversal received midazolam-alfentanil reversed with flumazenil (Group 1), the TIVA group without reversal received midazolam-alfentanil reversed with placebo (Group 2), and patients in the neurolept group received anesthesia using thiopental sodium, droperidol, fentanyl, and N2O (Group 3)., Measurements and Main Results: Recovery was assessed by an observer blinded to the treatment allocation, using a Modified Steward Recovery Score and judgment of orientation and comprehension, collaboration and degree of sedation for the first 4 hours after extubation. Arterial blood gases were measured 30 minutes after extubation. A questionnaire regarding the degree of perioperative amnesia was presented to the patients 4 and 24 hours after surgery. The recovery scores were better in the TIVA group with reversal than in the other two groups from 0 to 30 minutes postoperatively. No difference between the groups could be found thereafter, although after 30 minutes some resedation occurred in the TIVA group with reversal. The median injected amount of flumazenil in Group 1 was 0.5 mg. Respiratory depression (breathing frequency below 10 breaths/min) was reversed with naloxone in one patient in the TIVA group with reversal, five patients in the TIVA group without reversal, and no patient in the neurolept group (p < 0.001). On blood gas analysis, there was no evidence of hypoxemia or carbon dioxide retention. No difference was seen between the groups regarding consumption of analgesics, degree of amnesia, or patient rating of the quality of anesthesia. One patient in Group 2, however, recorded awareness at skin incision when questioned 4 hours after the operation, but could not recall this 20 hours later., Conclusions: TIVA with midazolam and alfentanil can be used for major gynecologic surgery. Recovery in the neurolept group was equal to recovery in the TIVA group without reversal, and flumazenil improves the recovery after midazolam anesthesia. Overall, in comparison with the neurolept technique no major advantage could be demonstrated using TIVA with midazolam-alfentanil.

The genotoxic potential of the herbicide Roundup and its active agent, glyphosate isopropylamine salt, was studied in three different assays. No clastogenic effects were found in the mouse bone marrow micronucleus test for either of the two agents. In the Salmonella assay only Roundup was tested. It showed a weak mutagenic effect for the concentrations 360 micrograms/plate in TA98 (without S9) and 720 micrograms/plate in TA100 (with S9). These concentrations are close to the toxic level. The anaphase-telophase Allium test showed no effect for the glyphosate isopropylamine salt, but a significant increase in chromosome aberrations appeared after treatment with Roundup at concentrations of 1.44 and 2.88 mg/l when calculated as glyphosate isopropylamine. The most frequent aberrations observed could be characterized as disturbances of the spindle.

We have studied the influence of clinical concentrations of propofol (2,6-diisopropyl phenol), emulsified propofol (Diprivan) and the emulsifier of propofol (Intralipid 10%) on random and chemotactic locomotion of human polymorphonuclear leucocytes in an agarose assay. Random locomotion was decreased (P < 0.001) to a similar extent by the three drugs. Concentrations of propofol 2.5 micrograms ml-1 and greater, and of Diprivan 3.33 micrograms ml-1 and greater, also reduced chemotaxis (P < 0.05) against both zymosan-activated human serum (C5a) and N-formyl-methionyl-leucylphenylalanine (FMLP), used as chemoattractants. Intralipid reduced chemotaxis towards C5a but not towards FMLP. We conclude that propofol in clinically relevant concentrations may adversely affect leucocyte locomotion in vitro.