Determination of aqueous solubility by heating and equilibration: A technical note

Summary and Conclusion  A modified shake-flask solubility method, where the equilibration time was shortened through heating, was used to determine the solubility of 48 different drugs and pharmaceutical excipients in pure water at room temperature. The heating process accelerates dissolution of the solid compound and frequently results in supersaturated solution. Seeding with the solid compound after heating and cooling to room temperature promotes precipitation of the solid compound in its original stable form. This modified shake-flask method generates reliable and reproducible solubility data. Published: January 13, 2006     

Effectiveness of quality improvement strategies for coordination of care to reduce use of health care services: a systematic review and meta-analysis

Background:

Frequent users of health care services are a relatively small group of patients who account for a disproportionately large amount of health care utilization. We conducted a meta-analysis of the effectiveness of interventions to improve the coordination of care to reduce health care utilization in this patient group.

Methods:

We searched MEDLINE, Embase and the Cochrane Library from inception until May 2014 for randomized clinical trials (RCTs) assessing quality improvement strategies for the coordination of care of frequent users of the health care system. Articles were screened, and data abstracted and appraised for quality by 2 reviewers, independently. Random effects meta-analyses were conducted.

Results:

We identified 36 RCTs and 14 companion reports (total 7494 patients). Significantly fewer patients in the intervention group than in the control group were admitted to hospital (relative risk [RR] 0.81, 95% confidence interval [CI] 0.72–0.91). In subgroup analyses, a similar effect was observed among patients with chronic medical conditions other than mental illness, but not among patients with mental illness. In addition, significantly fewer patients 65 years and older in the intervention group than in the control group visited emergency departments (RR 0.69, 95% CI 0.54–0.89).

Interpretation:

We found that quality improvement strategies for coordination of care reduced hospital admissions among patients with chronic conditions other than mental illness and reduced emergency department visits among older patients. Our results may help clinicians and policy-makers reduce utilization through the use of strategies that target the system (team changes, case management) and the patient (promotion of self-management).Frequent users of health care services represent a relatively small group of patients who account for a disproportionately large amount of health care utilization, including emergency department visits,^1,2 hospital admissions and clinic visits. These patients are often of low socioeconomic status,^3,4 have multiple medical, psychiatric and social disorders^5,6 and have a high mortality.⁷ Frequent use of the health care system contributes to longer wait times and affects the quality of care.^4,8Disproportionate use of health care services by a segment of the population has been identified as a challenge in many countries, including Canada.^9–12 To encourage less resource-intensive care for frequent users, many efforts have been implemented. Some of these interventions, for example, have been designed specifically to transition health care utilization away from the hospital to other settings, such as community-based clinics.¹³Much of the literature has focused on frequent users of emergency departments, with less focus on their use of the health care system in general. One systematic review identified a number of studies that assessed the effect of various interventions, including care coordination.¹⁴ The authors concluded that case management and multidisciplinary teams were likely effective interventions to reduce emergency department visits.Emergency department visits typically represent only a fraction of the cost burden on the health care system. There is a need to understand the impact of interventions aimed at reducing overall health care utilization, including hospital admissions. We conducted a systematic review and meta-analysis of the effectiveness of quality improvement strategies for care coordination for patients who are frequent users of the health care system.     

Bacterial Diversity of Weathered Terrestrial Icelandic Volcanic Glasses

The diversity of microbial communities inhabiting two terrestrial volcanic glasses of contrasting mineralogy and age was characterised. Basaltic glass from a <0.8 Ma hyaloclastite deposit (Valafell) harboured a more diverse Bacteria community than the younger rhyolitic glass from ～150-300 AD (D?madalshraun lava flow). Actinobacteria dominated 16S rRNA gene clone libraries from both sites, however, Proteobacteria, Acidobacteria and Cyanobacteria were also numerically abundant in each. A significant proportion (15-34%) of the sequenced clones displayed <85% sequence similarities with current database sequences, thus suggesting the presence of novel microbial diversity in each volcanic glass. The majority of clone sequences shared the greatest similarity to uncultured organisms, mainly from soil environments, among these clones from Antarctic environments and Hawaiian and Andean volcanic deposits. Additionally, a large number of clones within the Cyanobacteria and Proteobacteria were more similar to sequences from other lithic environments, included among these Icelandic clones from crystalline basalt and rhyolite, however, no similarities to sequences reported from marine volcanic glasses were observed. PhyloChip analysis detected substantially greater numbers of phylotypes at both sites than the corresponding clone libraries, but nonetheless also identified the basaltic glass community as the richer, containing approximately 29% unique phylotypes compared to rhyolitic glass.     

Automated methods for improved protein identification by peptide mass fingerprinting

In order to maximize protein identification by peptide mass fingerprinting noise peaks must be removed from spectra and recalibration is often required. The preprocessing of the spectra before database searching is essential but is time-consuming. Nevertheless, the optimal database search parameters often vary over a batch of samples. For high-throughput protein identification, these factors should be set automatically, with no or little human intervention. In the present work automated batch filtering and recalibration using a statistical filter is described. The filter is combined with multiple data searches that are performed automatically. We show that, using several hundred protein digests, protein identification rates could be more than doubled, compared to standard database searching. Furthermore, automated large-scale in-gel digestion of proteins with endoproteinase LysC, and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) analysis, followed by subsequent trypsin digestion and MALDI-TOF analysis were performed. Several proteins could be identified only after digestion with one of the enzymes, and some less significant protein identifications were confirmed after digestion with the other enzyme. The results indicate that identification of especially small and low-abundance proteins could be significantly improved after sequential digestions with two enzymes.     

Why neural networks should not be used for HIV-1 protease cleavage site prediction

SUMMARY: Several papers have been published where nonlinear machine learning algorithms, e.g. artificial neural networks, support vector machines and decision trees, have been used to model the specificity of the HIV-1 protease and extract specificity rules. We show that the dataset used in these studies is linearly separable and that it is a misuse of nonlinear classifiers to apply them to this problem. The best solution on this dataset is achieved using a linear classifier like the simple perceptron or the linear support vector machine, and it is straightforward to extract rules from these linear models. We identify key residues in peptides that are efficiently cleaved by the HIV-1 protease and list the most prominent rules, relating them to experimental results for the HIV-1 protease. MOTIVATION: Understanding HIV-1 protease specificity is important when designing HIV inhibitors and several different machine learning algorithms have been applied to the problem. However, little progress has been made in understanding the specificity because nonlinear and overly complex models have been used. RESULTS: We show that the problem is much easier than what has previously been reported and that linear classifiers like the simple perceptron or linear support vector machines are at least as good predictors as nonlinear algorithms. We also show how sets of specificity rules can be generated from the resulting linear classifiers. AVAILABILITY: The datasets used are available at http://www.hh.se/staff/bioinf/     

Parenteral Delivery of HPβCD: Effects on Drug-HSA Binding

It is thought that cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin (HPβCD), will at high concentration affect pharmacokinetics of drugs through competitive binding with plasma proteins. Albumin is the major component of plasma proteins responsible for plasma protein binding. The purpose of this study was to evaluate in vitro the competitive binding of drugs between human serum albumin (HSA) and HPβCD in isotonic pH 7.4 phosphate buffer saline solution (PBS) at ambient temperature. Eight model drugs were selected based on their physicochemical properties and ability to form complexes with HSA and HPβCD. The drug/HPβCD stability constants (K _1:1) were determined by the phase-solubility method and HSA/HPβCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPβCD (i.e., have high K _1:1 value) is most likely to be affected by parenterally administered HPβCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPβCD has to be as high as 70 g to have detectable effect on their protein binding. Weakly protein bound drugs and drugs with low affinity towards HPβCD are insensitive to the cyclodextrin presence regardless their lipophilic properties.     

Cross-linked hydroxypropyl-β-cyclodextrin and γ-cyclodextrin nanogels for drug delivery: Physicochemical and loading/release properties

Due to their size and high surface-to-volume ratio, nanogels can give some unique drug delivery opportunities. A novel technique to prepare cyclodextrin (CD) nanogels, in which the cross-linking takes place simultaneously with an emulsification/solvent evaporation process, has been implemented. The aqueous phase consisted of γ-cyclodextrin (γCD) or hydroxypropyl-β-cyclodextrin (HPβCD) at a fix concentration of 20% (w/w) with or without hydroxypropyl methylcellulose (HPMC) or agar at various concentrations. The incorporation of the cross-linking agent, ethyleneglycol diglycidyl ether (EGDE), was essential for the nanogel formation. By contrast, nanogels could be formed in the absence of surfactant such as Span 80, which can be attributed to the emulsion stabilizing effect of CDs by forming inclusion complexes with the organic solvent at the interface. Gas chromatography-mass spectrometry (GC-MS) analysis of the nanogels confirmed that dichloromethane levels were below the safety limit and, therefore, that these conditions of the organic solvent evaporation (60 °C for 180 min) led to nanogels that satisfy residual solvent requirements. Infrared analysis (IR), transmission electron microscopy (TEM) and dynamic light scattering (DLS) provided information about the cross-linking degree, the size and the size distribution of the nanogels. The ability of the nanogels to host a molecule that can form inclusion complexes and to sustain its release was tested using 3-methylbenzoic acid (3-MBA) as a probe with a high affinity for both β-cyclodextrin (βCD) and γCD. Permeability tests confirmed that 3-MBA was indeed taken up by the nanogels and then slowly released.     

Rhodothermus marinus: physiology and molecular biology

Rhodothermus marinus has been the subject of many studies in recent years. It is a thermohalophilic bacterium and is the only validly described species in the genus Rhodothermus. It is not closely related to other well-known thermophiles and is the only thermophile within the family Crenotrichaceae. R. marinus has been isolated from several similar but distantly located geothermal habitats, many of which are subject to large fluctuations in environmental conditions. This presumably affects the physiology of R. marinus. Many of its enzymes show optimum activity at temperatures considerably higher than 65°C, the optimum for growth, and some are active over a broad temperature range. Studies have found distinguishing components in the R. marinus electron transport chain as well as in its pool of intracellular solutes, which accumulate during osmotic stress. The species hosts both bacteriophages and plasmids and a functional intein has been isolated from its chromosome. Despite these interesting features and its unknown genetics, interest in R. marinus has been mostly stimulated by its thermostable enzymes, particularly polysaccharide hydrolysing enzymes and enzymes of DNA synthesis which may be useful in industry and in the laboratory. R. marinus has not been amenable to genetic analysis until recently when a system for gene transfer was established. Here, we review the current literature on R. marinus.