Product quality of parenteral vancomycin products in the United States.

In response to concerns raised about the quality of parenteral vancomycin products, the U.S. Food and Drug Administration (FDA) is investigating the product quality of all FDA-approved parenteral vancomycin products available in the United States. Product quality was evaluated independently at two FDA Office of Testing and Research (FDA-OTR) sites. In the next phase of the investigation, being done in collaboration with the National Institute of Allergy and Infectious Diseases, the in vivo activity of these products will be evaluated in an appropriate animal model. This paper summarizes results of the FDA investigation completed thus far. One site used a validated ultrahigh-pressure liquid chromatography method (OTR-UPLC), and the second site used the high-performance liquid chromatography (HPLC) method for related substances provided in the British Pharmacopeia (BP) monograph for vancomycin intravenous infusion. Similar results were obtained by the two FDA-OTR laboratories using two different analytical methods. The products tested had 90 to 95% vancomycin B (active component of vancomycin) by the BP-HPLC method and 89 to 94% vancomycin by OTR-UPLC methods. Total impurities were 5 to 10% by BP-HPLC and 6 to 11% by OTR-UPLC methods. No single impurity was >2.0%, and the CDP-1 level was ≤ 2.0% across all products. Some variability in impurity profiles of the various products was observed. No adverse product quality issues were identified with the six U.S. vancomycin parenteral products. The quality parameters of all parenteral vancomycin products tested surpassed the United States Pharmacopeia acceptance criteria. Additional testing will characterize in vivo performance characteristics of these products.

SeiVis: An Interactive Visual Subsurface Modeling Application.

The most important resources to fulfill today's energy demands are fossil fuels, such as oil and natural gas. When exploiting hydrocarbon reservoirs, a detailed and credible model of the subsurface structures is crucial in order to minimize economic and ecological risks. Creating such a model is an inverse problem: reconstructing structures from measured reflection seismics. The major challenge here is twofold: First, the structures in highly ambiguous seismic data are interpreted in the time domain. Second, a velocity model has to be built from this interpretation to match the model to depth measurements from wells. If it is not possible to obtain a match at all positions, the interpretation has to be updated, going back to the first step. This results in a lengthy back and forth between the different steps, or in an unphysical velocity model in many cases. This paper presents a novel, integrated approach to interactively creating subsurface models from reflection seismics. It integrates the interpretation of the seismic data using an interactive horizon extraction technique based on piecewise global optimization with velocity modeling. Computing and visualizing the effects of changes to the interpretation and velocity model on the depth-converted model on the fly enables an integrated feedback loop that enables a completely new connection of the seismic data in time domain and well data in depth domain. Using a novel joint time/depth visualization, depicting side-by-side views of the original and the resulting depth-converted data, domain experts can directly fit their interpretation in time domain to spatial ground truth data. We have conducted a domain expert evaluation, which illustrates that the presented workflow enables the creation of exact subsurface models much more rapidly than previous approaches.

Interactive Volume Exploration of Petascale Microscopy Data Streams Using a Visualization-Driven Virtual Memory Approach.

This paper presents the first volume visualization system that scales to petascale volumes imaged as a continuous stream of high-resolution electron microscopy images. Our architecture scales to dense, anisotropic petascale volumes because it: (1) decouples construction of the 3D multi-resolution representation required for visualization from data acquisition, and (2) decouples sample access time during ray-casting from the size of the multi-resolution hierarchy. Our system is designed around a scalable multi-resolution virtual memory architecture that handles missing data naturally, does not pre-compute any 3D multi-resolution representation such as an octree, and can accept a constant stream of 2D image tiles from the microscopes. A novelty of our system design is that it is visualization-driven: we restrict most computations to the visible volume data. Leveraging the virtual memory architecture, missing data are detected during volume ray-casting as cache misses, which are propagated backwards for on-demand out-of-core processing. 3D blocks of volume data are only constructed from 2D microscope image tiles when they have actually been accessed during ray-casting. We extensively evaluate our system design choices with respect to scalability and performance, compare to previous best-of-breed systems, and illustrate the effectiveness of our system for real microscopy data from neuroscience.

Interactive diffusion-based smoothing and segmentation of volumetric datasets on graphics hardware.

OBJECTIVE: Volume segmentation with concurrent visualization is becoming an increasingly important part of medical diagnostics. This is due to the fact that the immediate visual feedback speeds up evaluation of the segmentation process, hence enhances segmentation quality. Therefore, our aim was to develop a method for volume segmentation and smoothing which achieves interactive performance on standard PCs and is useful in clinical practice (i.e. fast and of high quality). METHODS: Our application is based on seeded region growing and nonlinear isotropic as well as anisotropic diffusion. We use current GPUs (graphics processing units) to speed up the computation of the diffusion process and use hardware-accelerated interactive volume rendering. RESULTS: Using our approach the user can observe the diffusion process in real-time, change parameters interactively and view the result in a high-quality 3D direct volume rendering (DVR). CONCLUSION: The interactive nature of our algorithm and simultaneous visualization improved the usability of our segmentation and smoothing algorithm and proved useful in the clinical workflow. Using our application we were able to speed up the (an)isotropic diffusion process to achieve interactive performance.

Simultaneous determination of the elimination profiles of the individual enantiomers of racemic isoproterenol using capillary electrophoresis and microdialysis sampling.

Microdialysis sampling and capillary electrophoresis with electrochemical detection (CE-EC) were used in combination to simultaneously define the elimination profile of each enantiomer of isoproterenol (ISP) administered as a racemic mixture to Sprague-Dawley rats. Resolution of the enantiomers of ISP was accomplished using a running buffer containing methyl-O-beta-cyclodextrin as a chiral recognition reagent. The CE-EC system provided a concentration limit of detection of 0.63 ng ml-1, allowing monitoring of the elimination of ISP for up to six half-lives. Microdialysis sampling was capable of continuously monitoring the concentration of ISP with 60 s resolution. The concentration versus time data for the elimination of (+) and (-) ISP were fit to a biphasic first order elimination model yielding average apparent distribution half-lives of 0.52 +/- 0.07 min and 0.55 +/- 0.08 min and average apparent elimination half-lives of 9.8 +/- 2.2 and 8.8 +/- 2.0 min for (-) and (+) ISP, respectively (n = 3 rats). No statistically significant difference in the average half-lives was found. However, because each enantiomer was simultaneously determined in each animal a paired two-sample t-Test could also be done. This statistical analysis demonstrated that a difference in the elimination half-lives of the enantiomers of ISP does exist.

Optimization of the separation and detection of the enantiomers of isoproterenol in microdialysis samples by cyclodextrin-modified capillary electrophoresis using electrochemical detection.

Isoproterenol is a chiral catecholamine with a half-life of elimination of less than 10 min. In order to study the pharmacokinetics of this compound using microdialysis sampling, an analytical method was needed which could resolve the individual enantiomers of isoproterenol and required less than 1 microliter of sample. A capillary electrophoretic method using a run buffer containing methyl-O-beta-cyclodextrin as a chiral recognition agent was developed which could resolve the enantiomers of isoproterenol. The detection limits using UV absorbance detection were found to be too high to determine the concentration of isoproterenol in plasma for a sufficient time following administration to establish the pharmacokinetics. The detection limits were decreased three orders of magnitude to 3 ng/ml by using an amperometric detector. The detection limits were decreased to 0.6 ng/ml using an on-column concentration technique in which peak stacking was accomplished by following the sample injection with a plug of acid.

Families of protein with similar total structure identified using statistical geometry.

Two quantities, herein defined as the displacement and the uniqueness, describe quantitatively the total structural difference between two proteins. All possible pairs of protein chains in the Brookhaven database are characterized in terms of these quantities. Pairs of proteins with small values of both displacement and uniqueness, in secondary and super-secondary configuration spaces, have similar total structure. Proteins related in this fashion are grouped into 158 families of similar total structure. The radial displacement function is herein defined to characterize the relative displacement of a residue from the center of the mass of its protein. In addition, the residue backbone structure function is also defined to characterize the local configuration of the protein main chain in the vicinity of the residue. The values of polynomial convolutions of these two functions are characteristic of a particular tertiary structure type. These polynomial convolutions, together with other structural parameters, are used to verify the structural similarity of proteins belonging to the families indicated above. Variations in these polynomial convolutions illustrate the amount and sequence location of structural deviations between proteins of the same family.

Liquid chromatographic determination of tacrine and its metabolites in rat bile microdialysates.

A microbore liquid chromatographic method using a phenyl stationary phase was developed for the determination of 9-amino-1,2,3,4-tetrahydroacridine (tacrine, THA) and its metabolites in microdialysis samples of bile. Analysis of microdialysis samples requires analytical methods with low detection limits and small sample volume requirements. The method uses a 1-mm I.D. phenyl column and fluorescence detection. A detection limit of 0.25 ng/ml in a 5-microliters sample was achieved for THA. This method was then used to determine THA and THA-1-ol in the bile dialysate of a rat. Because of the small sample volume requirements, a 10-min temporal resolution was achieved for the microdialysis experiment. The low detection limit allowed the THA concentration in the bile to be monitored for more than 4 h following a 1.0 mg/kg i.v. dose of THA.

Relationship of flavonoid oxidation potential and effect on rat hepatic microsomal metabolism of benzene and phenol.

The effect of several flavonoids on the benzene hydroxylase and phenol hydroxylase activity of rat hepatic microsomes was determined. The electrochemical characteristics of the flavonoids were also determined. The effect of flavonoids on microsomal phenol hydroxylase activity was found to correlate well with the oxidation potential for flavonoid aglycones. Easily oxidized flavonoids inhibited phenol hydroxylase activity with the extent of inhibition correlated to the ease of oxidation. This inhibition exhibited dose-dependent behaviour, with concentrations below 1 microM having no effect. On the other hand, flavonoids with high oxidation potentials increased phenol hydroxylase activity in a dose-independent manner. Hydroxyl substitution at C-7 was required for inhibition of phenol hydroxylase activity independently of the oxidation potential. Glycosylation at either C-7 or C-3 was found to moderate the inhibition of phenol hydroxylase activity. A linear relation was found between the degree of inhibition and the number of sugar residues for glycosylated flavonoids. There was no correlation between electrochemical properties and effect on microsomal benzene hydroxylase activity.

Explicit distance geometry: identification of all the degrees of freedom in a large RNA molecule.

An alternative approach to distance geometry ("explicit" distance geometry) is being developed for problems, such as the modeling of RNA folding in the ribosome, where relatively few distances are known. The approach explicitly identifies minimal sets of additional distances that can be added to a distance matrix in order to calculate structures that are consistent with all the known information without distorting the original input data. These additional distances are bounded to the extent possible by the known distances. These explicitly added distances can be treated as degrees of freedom and used to explore the full range of alternative foldings consistent with the original input in an organized way. The present paper establishes that it is practical to explicitly determine such degrees of freedom for even very large RNAs. To demonstrate the feasibility of the approach tRNA was represented as a simple undirected graph containing all relevant information represented in the usual cloverleaf secondary structure and nine base-base tertiary interactions. Using a three atom representation for each residue a total of 206 degrees of freedom are explicitly identified. To accomplish this a graph theoretic approach was used in which a minimal covering cycle basis was determined.

Distances as degrees of freedom.

Tertiary contact distance information of varying resolution for large biological molecules abounds in the literature. The results provided herein develop a framework by which information of this type can be used to reduce the allowable configuration space of a macromolecule. The approach combines graph theory and distance geometry. Large molecules are represented as simple, undirected graphs, with atoms, or groups, as vertices, and distances between them as edges. It is shown that determination of the exact structure of a molecule in three dimensions only requires the specification of all the distances in a single tetrahedron, and four distances to every other atom. This is 4N-10 distances which is a subset of the total N(N-1)/2 unique distances in a molecule consisting of N atoms. This requirement for only 4N-10 distances has serious implications for distance geometry implementations in which all N(N-1)/2 distances are specified by bounded random numbers. Such distance matrices represent overspecified systems which when solved lead to non-obvious distribution of any error caused by inherent contradictions in the input data. It is also shown that numerous valid subsets of 4N-10 distances can be constructed. It is thus possible to tailor a subset of distances using all known distances as degrees of freedom, and thereby reduce the configuration space of the molecule. Simple algebraic relationships are derived that relate sets of distances, and complicated rotations are avoided. These relationships are used to construct minimum, complete sets of distances necessary to specify the exact structure of the entire molecule in three dimensions from incomplete distance information, and to identify sets of inconsistent distances. The method is illustrated for the flexible structural types present in large ribosomal RNAs: 1.) A five-membered ring; 2.) a chemically bonded chain with its ends in contact (i.e., a hairpin loop); 3.) the spatial orientation of two separate molecules, and; 4.) an RNA helix that can have variation in individual base pairs, giving rise to global deviation from standardized helical forms.