Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter

In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter.The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports.The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice.All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines.Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria.Overall, higher troughs ( >15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of >15 mg/liter.The relationship between a trough of >15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37).The relationship between troughs of >15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event.An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration.Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes.The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists.The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy

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Glucocorticoid receptor expression in human bronchial epithelial cells: effects of smoking and COPD.

Previously, we found that inflammatory mediators modulated the number and binding affinity of glucocorticoid receptors (GR) in human bronchial epithelial cell lines. In this study we investigated whether smoking and chronic obstructive pulmonary disease (COPD), both characterized by airway inflammation with increased levels of inflammatory mediators, affect GR characteristics in cultured human bronchial epithelial cells (HBEC). A statistically significant difference was found between the dissociation constant (Kd) values in HBEC from smoking (Kd = 0.98+/-0.08 nM; n = 6) and nonsmoking controls (Kd = 0.76+/-0.10 nM, P = 0.03; n = 5), but no significant difference was found between the mean number of binding sites. Our results are the first indication that cultured HBEC from smokers possess GR with a lower binding affinity. This may result from the inflammation found in the airways from smokers. Furthermore, these results provide further evidence that the bronchial epithelium may be an actual target for inhaled glucocorticoid therapy

Symmetry Breaking and Finite Size Effects in Quantum Many-Body Systems

We consider a quantum many-body system on a lattice with a continuous symmetry which exhibits a spontaneous symmetry breaking in its infinite volume ground states, but in which the order operator does not commute with the Hamiltonian. A typical example is the Heisenberg antiferromagnet with a Neel order. In the corresponding finite system, the symmetry breaking is usually "obscured" by "quantum fluctuation" and one gets a symmetric ground state with a long range order. In such a situation, we prove that there exist ever increasing numbers of low-lying eigenstates whose excitation energies are bounded by a constant times 1/N, where N denotes the number of sites. By forming linear combinations of these low-lying states and the (finite-volume) ground state, and by taking infinite volume limits, we construct infinite volume ground states with explicit symmetry breaking. Our general theorems do not only shed light on the nature ofsymmetry breaking in quantum many-body systems, but provide indispensable information for numerical approaches to these systems. We also discuss applications of our general results to a variety of examples. The present paper is intended to be accessible to the readers without background in mathematical approaches to quantum many-body systems.Comment: LaTeX, 58 pages, no figures. Notes about Bose-Einstein condenstaion are added after the publicatio

Extending the voltage window in the characterization of electrical transport of large-area molecular junctions

A large bias window is required to discriminate between different transport models in large-area molecular junctions. Under continuous DC bias, the junctions irreversibly break down at fields over 9 MV/cm. We show that, by using pulse measurements, we can reach electrical fields of 35 MV/cm before degradation. The breakdown voltage is shown to depend logarithmically on both duty cycle and pulse width. A tentative interpretation is presented based on electrolysis in the polymeric top electrode. Expanding the bias window using pulse measurements unambiguously shows that the electrical transport exhibits not an exponential but a power-law dependence on bias. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3608154

Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia

Background: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. Methods: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. Results: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score ≥ 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. Conclusions: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications

Prediction Model to Identify Patients at Risk of 30-Day Treatment Failure in Patients With Staphylococcus aureus Bacteremia

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Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a β2-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics

DISCO-SCA and Properly Applied GSVD as Swinging Methods to Find Common and Distinctive Processes

BACKGROUND: In systems biology it is common to obtain for the same set of biological entities information from multiple sources. Examples include expression data for the same set of orthologous genes screened in different organisms and data on the same set of culture samples obtained with different high-throughput techniques. A major challenge is to find the important biological processes underlying the data and to disentangle therein processes common to all data sources and processes distinctive for a specific source. Recently, two promising simultaneous data integration methods have been proposed to attain this goal, namely generalized singular value decomposition (GSVD) and simultaneous component analysis with rotation to common and distinctive components (DISCO-SCA). RESULTS: Both theoretical analyses and applications to biologically relevant data show that: (1) straightforward applications of GSVD yield unsatisfactory results, (2) DISCO-SCA performs well, (3) provided proper pre-processing and algorithmic adaptations, GSVD reaches a performance level similar to that of DISCO-SCA, and (4) DISCO-SCA is directly generalizable to more than two data sources. The biological relevance of DISCO-SCA is illustrated with two applications. First, in a setting of comparative genomics, it is shown that DISCO-SCA recovers a common theme of cell cycle progression and a yeast-specific response to pheromones. The biological annotation was obtained by applying Gene Set Enrichment Analysis in an appropriate way. Second, in an application of DISCO-SCA to metabolomics data for Escherichia coli obtained with two different chemical analysis platforms, it is illustrated that the metabolites involved in some of the biological processes underlying the data are detected by one of the two platforms only; therefore, platforms for microbial metabolomics should be tailored to the biological question. CONCLUSIONS: Both DISCO-SCA and properly applied GSVD are promising integrative methods for finding common and distinctive processes in multisource data. Open source code for both methods is provided