Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin.

We compared the pharmacokinetics and the serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Fifteen healthy volunteers received 1 g of cefpirome, ceftazidime, and ceftriaxone intravenously, 500 mg of imipenem-cilastatin intravenously, and 500 mg of ciprofloxacin orally. High-performance liquid chromatographic assays were used to quantitate unchanged antibiotic in plasma and urine. Serum bactericidal activities were determined against six clinical isolates each of Staphylococcus aureus, Enterobacter cloacae, and Pseudomonas aeruginosa by using a modified microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977). Overall, cefpirome exhibited pharmacokinetics similar to those of ceftazidime: half-life (t1/2), 1.95 h; concentration at 1 h (C1h), 47 to 49 micrograms/ml for both antibiotics. Ceftriaxone displayed the longest t1/2 (7.65 h) and the highest C1h (137.8 micrograms/ml), while we observed the shortest t1/2 (1.05 h) and the lowest C1h (19.85 micrograms/ml) with imipenem. At 1 h, cefpirome and, even more so, imipenem showed significantly better serum bactericidal activities against S. aureus (1:273 and 1:80) than did the other antibiotics (P less than 0.0005; analysis of variance with randomized block design and Bonferroni correction). Against E. cloacae, we observed the highest serum bactericidal titers at 1 h with cefpirome, and this superiority vis-à-vis the other antibiotics tested was maintained for up to 8 h after dosing. Ceftazidime remained the most active agent tested against P. aeruginosa (serum bactericidal activity titers, 1:43 at 1 h) up to 8 h. In summary, the study showed that cefpirome and imipenem provide more potent serum bactericidal activities than do broad-spectrum cephalosporins against S. aureus; thus, both of these antibiotics should be adequate against serious S. aureus infections. In addition, cefpirome appears to be a promising alternative for treatment of infections caused by E. cloacae and P. aeruginosa.     

An affibody in complex with a target protein: structure and coupled folding

Combinatorial protein engineering provides powerful means for functional selection of novel binding proteins. One class of engineered binding proteins, denoted affibodies, is based on the three-helix scaffold of the Z domain derived from staphylococcal protein A. The Z(SPA-1) affibody has been selected from a phage-displayed library as a binder to protein A. Z(SPA-1) also binds with micromolar affinity to its own ancestor, the Z domain. We have characterized the Z(SPA-1) affibody in its uncomplexed state and determined the solution structure of a Z:Z(SPA-1) protein-protein complex. Uncomplexed Z(SPA-1) behaves as an aggregation-prone molten globule, but folding occurs on binding, and the original (Z) three-helix bundle scaffold is fully formed in the complex. The structural basis for selection and strong binding is a large interaction interface with tight steric and polar/nonpolar complementarity that directly involves 10 of 13 mutated amino acid residues on Z(SPA-1). We also note similarities in how the surface of the Z domain responds by induced fit to binding of Z(SPA-1) and Ig Fc, respectively, suggesting that the Z(SPA-1) affibody is capable of mimicking the morphology of the natural binding partner for the Z domain.     

Computed tomographic colonography: assessment of radiologist performance with and without computer-aided detection

BACKGROUND & AIMS: In isolation, computer-aided detection (CAD) for computed tomographic (CT) colonography is as effective as optical colonoscopy for detection of significant adenomas. However, the unavoidable interaction between CAD and the reader has not been addressed. METHODS: Ten readers trained in CT but without special expertise in colonography interpreted CT colonography images of 107 patients (60 with 142 polyps), first without CAD and then with CAD after temporal separation of 2 months. Per-patient and per-polyp detection were determined by comparing responses with known patient status. RESULTS: With CAD, 41 (68%; 95% confidence interval [CI], 55%-80%) of the 60 patients with polyps were identified more frequently by readers. Per-patient sensitivity increased significantly in 70% of readers, while specificity dropped significantly in only one. Polyp detection increased significantly with CAD; on average, 12 more polyps were detected by each reader (9.1%, 95% CI, 5.2%-12.8%). Small- (< or =5 mm) and medium-sized (6-9 mm) polyps were significantly more likely to be detected when prompted correctly by CAD. However, overall performance was relatively poor; even with CAD, on average readers detected only 10 polyps (51.0%) > or =10 mm and 24 (38.2%) > or =6 mm. Interpretation time was shortened significantly with CAD: by 1.9 minutes (95% CI, 1.4-2.4 minutes) for patients with polyps and by 2.9 minutes (95% CI, 2.5-3.3 minutes) for patients without. Overall, 9 readers (90%) benefited significantly from CAD, either by increased sensitivity and/or by reduced interpretation time. CONCLUSIONS: CAD for CT colonography significantly increases per-patient and per-polyp detection and significantly reduces interpretation times but cannot substitute for adequate training.     

Quantitative detection of respiratory Chlamydia pneumoniae infection by real-time PCR

Real-time PCR was evaluated as a quantitative diagnostic method for Chlamydia pneumoniae infection using different respiratory samples. Real-time PCR had efficiency equal to or better than that of nested touchdown PCR. This study confirmed sputum as the best sampling material to detect an ongoing C. pneumoniae infection.     

Disrupted muscarinic M1 receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease

There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimer's disease (AD). We have previously found that attenuation of guanine nucleotide-binding (G-) protein coupling to muscarinic M(1) receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M(1)/G-protein coupling is related to alterations in signaling kinases and NMDA receptors. Postmortem frontal cortices of 22 AD subjects and 12 elderly controls were obtained to measure M(1) receptors, M(1)/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M(1)/G-protein coupling loss was correlated with reductions in PKC activity and NMDA receptor density. In contrast, Src kinase activity was neither altered nor associated with M(1)/G-protein coupling. Given the well established roles of neuronal PKC signaling and NMDA receptor function in cognitive processes, our results lend further insight into the mechanisms by which postsynaptic cholinergic dysfunction may underlie the cognitive features of AD, and suggest alternative therapeutic targets to cholinergic replacement.     

Resting posterior versus frontal delta/theta EEG activity is associated with extraversion and the COMT VALMET polymorphism

Recent studies suggest that resting posterior versus frontal EEG delta/theta activity (delta/theta Pz–Fz) is both sensitive to pharmacological manipulations of neural dopamine and associated with the agency facet of extraversion (i.e., a motivational disposition comprising enthusiasm, energy, assertiveness, achievement striving and social dominance). These observations suggest that posterior versus frontal resting EEG delta/theta activity may represent a useful marker for investigating the molecular genetic basis of extraversion. The present study aimed to test the novel hypothesis of an association between delta/theta Pz–Fz and a functional polymorphism of the enzyme catechol-O-methyltransferase (COMT VAL¹⁵⁸MET) involved in dopamine catabolism. This was conducted in a large EEG data set from the Brain Resource International Database (BRID; resting EEG from N = 1093 healthy individuals, 382 of which also genotyped for COMT VAL¹⁵⁸MET). In summary, we (1) showed for the first time that the VAL allele is associated with increased delta/theta Pz–Fz; (2) replicated the association between extraversion and delta/theta Pz–Fz in a large, heterogeneous sample including both genders; and (3) documented that the VAL allele of the COMT VAL¹⁵⁸MET is associated with increased extraversion scores, as previously reported for an overlapping BRID sample. This coherent pattern of findings adds further support to the suggestion that the posterior–anterior distribution of resting EEG slow wave activity in the delta/theta range represents a useful tool for probing the dopaminergic basis of extraversion.     

Effectiveness of Web-based Interventions on Patient Empowerment: A Systematic Review and Meta-analysis

Background

Patient empowerment is growing in popularity and application. Due to the increasing possibilities of the Internet and eHealth, many initiatives that are aimed at empowering patients are delivered online.

Objective

Our objective was to evaluate whether Web-based interventions are effective in increasing patient empowerment compared with usual care or face-to-face interventions.

Methods

We performed a systematic review by searching the MEDLINE, EMBASE, and PsycINFO databases from January 1985 to January 2009 for relevant citations. From the 7096 unique citations retrieved from the search strategy, we included 14 randomized controlled trials (RCTs) that met all inclusion criteria. Pairs of review authors assessed the methodological quality of the obtained studies using the Downs and Black checklist. A meta-analysis was performed on studies that measured comparable outcomes. The GRADE approach was used to determine the level of evidence for each outcome.

Results

In comparison with usual care or no care, Web-based interventions had a significant positive effect on empowerment measured with the Diabetes Empowerment Scale (2 studies, standardized mean difference [SMD] = 0.61, 95% confidence interval [CI] 0.29 - 0.94]), on self-efficacy measured with disease-specific self-efficacy scales (9 studies, SMD = 0.23, 95% CI 0.12 - 0.33), and on mastery measured with the Pearlin Mastery Scale (1 study, mean difference [MD] = 2.95, 95% CI 1.66 - 4.24). No effects were found for self-efficacy measured with general self-efficacy scales (3 studies, SMD = 0.05, 95% CI -0.25 to 0.35) or for self-esteem measured with the Rosenberg Self-Esteem Scale (1 study, MD = -0.38, 95% CI -2.45 to 1.69). Furthermore, when comparing Web-based interventions with face-to-face deliveries of the same interventions, no significant (beneficial or harmful) effects were found for mastery (1 study, MD = 1.20, 95% CI -1.73 to 4.13) and self-esteem (1 study, MD = -0.10, 95% CI -0.45 to 0.25).

Conclusions

Web-based interventions showed positive effects on empowerment measured with the Diabetes Empowerment Scale, disease-specific self-efficacy scales and the Pearlin Mastery Scale. Because of the low quality of evidence we found, the results should be interpreted with caution. The clinical relevance of the findings can be questioned because the significant effects we found were, in general, small.     

Distinctive alterations of the cingulum bundle during aging and Alzheimer's disease

Brain imaging studies have revealed frontal disruption during aging and parieto-temporal disruption during Alzheimer's disease (AD). The present study aims at developing a specific method based on precise anatomical landmarks for assessing the integrity all along the course of the cingulum bundle, so as to determine if it presents the classical aging and AD dissociation. Five regions of interest (ROIs) were placed on fractional anisotropy (FA) maps all along the cingulum in 15 young (Gyoung), 15 70-year-old (Gold), and 15 AD subjects (Galz). An age-related decrease of FA occurred in the anterior part of the bundle. Moreover, a specific alteration of the supero-posterior region of the cingulum during AD was observed since mean FA values as well as mean number of fibers were significantly decreased in Galz compared to Gold and Gyoung. This multiple ROIs placement allows for revealing distinctive alterations of the cingulum bundle during aging and AD, which could constitute the anatomical basis for the distinctive functional disconnection recently described in the literature using functional connectivity at rest.