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PubMed2005

Further comparison of primary hit identification by different assay technologies and effects of assay measurement variability.

High-throughput screening (HTS) has grown rapidly in the past decade, with many advances in new assay formats, detection technologies, and laboratory automation. Recently, several studies have shown that the choice of assay technology used for the screening process is particularly important and can yield quite different primary screening outcomes. However, because the screening assays in these previous studies were performed in a single-point determination, it is not clear to what extent the difference observed in the screening results between different assay technologies is attributable to inherent assay variability and day-to-day measurement variation. To address this question, a nuclear receptor coactivator recruitment assay was carried out in 2 different assay formats, namely, AlphaScreen and time-resolved fluorescence resonance energy transfer, which probed the same biochemical binding events but with different detection technologies. For each assay format, 4 independent screening runs in a typical HTS setting were completed to evaluate the run-to-run screening variability. These multiple tests with 2 assay formats allow an unambiguous comparison between the discrepancies of different assay formats and the effects of the variability of assay and screening measurements on the screening outcomes. The results provide further support that the choice of assay format or technology is a critical factor in HTS assay development.

Animals↗
PubMed2000

Near-infrared reflectance spectroscopy for noninvasive monitoring of metabolites.

An important class of substances in clinical chemistry are metabolites in body fluids, which are accessible by near-infrared spectroscopy without sample treatment using reagentless, fast and readily automated in vitro assays. Furthermore, noninvasive sensing systems are under development for the determination of blood glucose, especially for diabetic patients or for monitoring in intensive care and surgery. Near-infrared diffuse reflectance spectrometry of skin was employed allowing a certain tissue volume to be integrally probed. For calibration, the partial least-squares (PLS) algorithm was used either based on wide spectral intervals or using special spectral variable selection. Capillary blood glucose reference concentrations were obtained by finger pricking and an automated laboratory method (hexokinase/G6P-DH). Clear evidence is provided for the physical effect, as manifested by the spectral glucose absorptivities, underlying the individual single-person calibration models, which still require improvements in the methodology in the normo- and hypoglycemic concentration range. In extending the potential of noninvasive blood assays by infrared spectroscopy, a novel technique is presented for probing the intravascular fluid space by using fast spectral near-infrared measurements of skin tissue. The pulsatile blood spectrum can be derived from reflectance spectra of oral mucosa by Fourier analysis (near-infrared plethysmography). Future applications and prospects for noninvasive blood assays are discussed.

Algorithms↗
PubMed2001

Cambridge Healthtech Institute's Third Annual Conference on human genetic variation. 16-18 October 2000, Philadelphia, Pennsylvania, USA.

A major goal of pharmacogenomics is to identify the human genetic variation that influences susceptibility to complex diseases. Recently, theoretical statistical analyses have suggested that genes for complex diseases may be found by linkage disequilibrium (i.e., association). Single nucleotide polymorphism (SNP) susceptibility alleles for common diseases can occur at high frequencies in various populations and, thus, have a major impact on morbidity and mortality. To be successful, SNP mapping studies require successful teamwork, integrating clinicians, epidemiologists, molecular genetics experts, laboratory automation engineers, bioinformatics and database experts. New statistical methods are also developing rapidly and promise to further increase the power of these studies. A recent conference on human genetic variation provided an opportunity for experts in all of these disciplines to exchange ideas. At present, great technological challenges need to be overcome in order to increase the throughput greatly while lowering cost and still maintaining high accuracy for SNP genotyping. Although this approach is relatively new (at least on the scale now being contemplated), the large payoffs anticipated to accrue from the successful mapping of SNPs in disease genes has led the area to be very strongly supported by both public and private funding sources. The potential payoff for improving disease diagnosis and therapeutic efficacy, with better avoidance of adverse events based on SNP associations, is providing a tremendous incentive to move this effort forward at an ever-accelerating pace.

Genetic Predisposition to Disease↗
PubMed2006

Molecular methods for the detection and characterization of Neisseria meningitidis.

Neisseria meningitidis remains a common global cause of morbidity and mortality. The laboratory confirmation of meningococcal disease is, therefore, very important for individual patient management and for public health management. Through surveillance schemes, it provides long-term epidemiologic data that can be used to inform vaccine policy. Traditional methods, such as latex agglutination and the enzyme-linked immunosorbent assay, are still used, but molecular methods are now also established. In this review, molecular methods for the laboratory confirmation and characterization of meningococci are described. PCR is an invaluable tool in modern biology and can be used to predict the group, type and subtype of meningococci. It is now also used in a fluorescence-based format for increased sensitivity and specificity. The method also provides the amplified DNA for other techniques, such as multilocus sequence typing. Other methods for the discrimination of meningococci have also played and continue to play an important part in epidemiology. For example, pulsed-field gel electrophoresis is highly discriminatory, whilst multilocus enzyme electrophoresis provided the basis for the description of global meningococcal clones and formed the foundation for multilocus sequence typing. Other less commonly used methods, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and pyrosequencing, may increasingly find their way into microbiology reference laboratories. Nevertheless, nucleotide sequencing and laboratory automation have aided the introduction of many methods and provide data that are digitally based and, therefore, highly accurate and portable.

Animals↗
PubMed2004

Racial and ethnic differences in microalbuminuria prevalence in a diabetes population: the pathways study.

The objective of this study was to determine whether racial or ethnic differences in prevalence of diabetic microalbuminuria were observed in a large primary care population in which comparable access to health care exists. A cross-sectional analysis of survey and automated laboratory data 2969 primary care diabetic patients of a large regional health maintenance organization was conducted. Study data were analyzed for racial/ethnic differences in microalbuminuria (30 to 300 mg albumin/g creatinine) and macroalbuminuria (>300 mg albumin/g creatinine) prevalence among diabetes registry-identified patients who completed a survey that assessed demographics, diabetes care, and depression. Computerized pharmacy, hospital, and laboratory data were linked to survey data for analysis. Racial/ethnic differences in the odds of microalbuminuria and macroalbuminuria were assessed by unconditional logistic regression, stratified by the presence of hypertension. Among those tested, the unadjusted prevalence of micro- or macroalbuminuria was 30.9%, which was similar among the various racial/ethnic groups. Among those without hypertension, microalbuminuria was twofold greater (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.14 to 3.53) and macroalbuminuria was threefold greater (OR 3.17; 95% CI 1.09 to 9.26) for Asians as compared with whites. Among those with hypertension, adjusted odds of microalbuminuria were greater for Hispanics (OR 3.82; 95% CI 1.16 to 12.57) than whites, whereas adjusted odds of macroalbuminuria were threefold greater for blacks (OR 3.32; 95% CI 1.26 to 8.76) than for whites. For most racial/ethnic minorities, hypertriglyceridemia was significantly associated with greater odds of micro- and macroalbuminuria. Among a large primary care population, racial/ethnic differences exist in the adjusted prevalence of microalbuminuria and macroalbuminuria depending on hypertension status. In this setting, racial/ethnic differences in early diabetic nephropathy were observed despite comparable access to diabetes care.

Aged↗
PubMed2005

Chromatography and computational chemical analysis for drug discovery.

Analytical chemists have increasingly turned their attention to drug discovery and drug analysis and to solve fundamental questions of biological significance in physiology and genetics. New technologies have been developed, and a variety of instruments have been redesigned for biomedical applications. The development of high-performance liquid chromatography (HPLC) opened a new era in biorelated fields and allowed faster separations of fragile macromolecules. Capillary column gas chromatography (GC)/mass spectrometry (MS) have been used to achieve more powerful separation and to perform structural analysis of molecules, and laboratory automation including robotics has become a powerful trend in both analysis and synthesis. Liquid chromatography (LC)/MS is more suitable for biomedical applications than GC/MS because almost all biomolecules are heat sensitive. Furthermore, a combination of various mass spectrometers has been used even for proteins directly. Improving the sensitivity of nuclear magnetic resonance spectrometry (NMR) has permitted a direct connection with LC. Purification of biomolecules on-line by LC has been performed since the development of chip-electrophoresis, On the other hand, computational chemical analysis is a promising technique given the advancing the hardware and software for use in chemical fields. In this review, a combination of chromatography and computational chemistry for use in drug discovery studies is described. Fast LC analysis using a column switching technique was introduced for aromatic amino acid metabolites and guanidino compounds. Recent developments in related technologies are also included from review papers.

Amino Acids, Aromatic↗
PubMed2006

Exploiting high-throughput ion channel screening technologies in integrated drug discovery.

Ion channels are increasingly being implicated in disease. Although existing drugs that modulate channel function currently represent a key class of pharmaceutical agents, future ion channel drugs could help to treat an even wider variety of diseases. Despite their disease relevance, ion channels remain largely under exploited as drug targets, chiefly resulting from the absence of screening technologies that provide the throughput and quality of data required to support medicinal chemistry. Although some technical challenges still lie ahead, this historic bottleneck in drug discovery is now being bypassed by newer technologies that can be fully integrated into the early stages of drug discovery and will allow the discovery of novel therapeutic agents. Sequencing the human genome has greatly added to the number of potential drug targets but selecting suitable ion channels for drug discovery research should be based on the potential therapeutic relevance of the channel and not just the availability of suitable screens. Currently, ion channel drug discovery is focused on the need to identify compounds that can provide tractable starting points for medicinal chemistry. Advances in laboratory automation have brought significant opportunities to increase screening throughput for ion channel assays but careful assay configuration to model drug-target interactions in a physiological manner remains an essential consideration. Ion channel screening platforms are described in this review to provide some insight into the variety of technologies available for screening, together with some of their inherent advantages and limitations.

Drug Design↗
PubMed2006

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Chemistry, Pharmaceutical↗
PubMed2005

Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.

Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration.

Combinatorial Chemistry Techniques↗
PubMed1984

The Technicon Ektacytometer: automated exploration of erythrocyte function.

The Ektacytometer is a visco-diffractometric method to preferentially examine the functional properties of erythrocytes. The realization of this method in the form of an automated laboratory instrument, the Technicon Ektacytometer, is described. A suspension of RBC is submitted to a uniform shear stress. The resulting deformation of the cells is seen as an elongation of the diffraction image and expressed as the Elongation Index or EI. EI may be traced on an X-Y recorder as a function of stress, time and of suspending medium osmolality. The osmolality is varied automatically in the viscometer and automatically measured via its conductivity, resulting in an "Osmoscan". The Osmoscan is highly reproducible and requires only 150 microliter of blood and 5 minutes per sample. Its high sensitivity to small changes in erythrocyte properties permits the separation of factors affecting RBC deformability, and provides a measure of the osmotic fragility which correlates very well with the traditional test. Other applications are described, including mechanical fragility assays on whole cells, relaxation times of ghosts and the automatic variation of PO2. Possible future applications are suggested.

Anemia, Sickle Cell↗
PubMed1976

[Advantages, disadvantages and selection methods of thyroxine measurement--comparison of CPBA and RIA].

Although recent progress in radioimmunoassay (RIA) permitted direct RIA for thyroxine (T4), there appeared few reports evaluating clinical applicability of T4 RIA as routine method. The authors evaluated advantage, disadvantage of methods for T4 measurement in comparison between CPBA (competitive protein binding analysis) and RIA, and tried to discuss about selection of methods for T4 measurement. Res-O-Mat T4 was chosen as CPBA, and RIAMAT-T4(St) and T4-RIAKIT(Sp) were chosen as RIAs. Detailed descriptions about both RIA methods appeared elsewhere [2, 3]. From the basic experiments, reproducibility of CPBA, St and Sp within assay were 5.8% (C.V.), 4.0% (C.V.), and 8.5%(C.V.) respectively, and mean recovery rates were 92.2%, 100.7% and 96.1% respectively. T4 value measured by both RIAs correlated well with CPBA, and St showed slightly lower value and Sp showed slightly higher value than CPBA. The normal ranges for RIAs were 3.7-11.7 microng% (St) and 4.6-15.2 microng% (Sp). Diagnostic accuracy for hyperthyroid state were 83.3% (CPBA), 85.7%(St) and 69.2% (Sp), and for euthyroid state were 92.0% (CPBA), 98.8% (St) and 95.7% (Sp). The diagnostic accuracy for hypothyroid state in three methods were lowest. From the economical point of view, cost performance, time performance and total time for single assay were analysed and mathematical equations were obtained from actual assay by each methods. When the number of samples per single assay was less than 10, CPBA was most economic in terms of cost and time performance and total time required. In the assay of more than 20 samples, RIAs were efficient in each point of views. In the point of view of sample volumes required, RIAs were most promising. The authors concluded that guides for selection of methods in T4 assay were as follows: A) CPBA was most efficient in local use especially when less than 10 samples were frequently to be assayed. B) RIAs were efficient in batch processing more than 20 samples, especially in automated laboratories.

Binding, Competitive↗
PubMedDate not supplied

Fat contents of cereal foods: comparison of classical with recently developed extraction techniques.

Eight cereal products ranging from a fat-free ready-to-eat (RTE) cereal (frosted flakes) to a full-fat high-ratio cake mix were subjected to analyte separation by anhydrous diethyl ether extraction (EE), acid hydrolysis/mixed ether extraction (AH), solid-phase extraction (SPE), and supercritical fluid extraction (SFE) with CO2 and with CO2 modified with 15% ethanol (SFEmod). Gravimetric analyses of extracts indicated higher (P < or = 0.05) crude fat values by AH than by EE, SFE, or SFEmod. Extractions followed by fatty acid methyl ester analysis also produced higher (P < or = 0.05) triglyceride means by AH than by other methods used for heat-treated RTE cereals and for ready-to-cook (RTC) cream of wheat. Therefore, for labeling purposes, AH seems most appropriate because in most cases it achieves higher triglyceride values than extraction with solvent(s) alone. SFE and SPE, on the other hand, yield fat values similar to those obtained by EE and offer the advantages of reduced solvent volume, short extraction times, and ease of laboratory automation.

Dietary Fats↗
PubMed2000

The use of information technology in improving medical performance. Part II. Physician-support tools.

Increasing data from a few sites demonstrate that information technologies can improve physician decision making and clinical effectiveness. For example, computer-based physician order entry systems, automated laboratory alert systems, and artificial neural networks have demonstrated significant reductions in medical errors. In addition, Internet services to disseminate new knowledge and safety alerts to physicians more rationally and effectively are rapidly developing, and telemedicine to improve rural access to specialty services is undergoing substantial growth. However, even technologies demonstrated to yield beneficial effects have not yet achieved widespread adoption, though the pace of change appears to be increasing as the Internet takes hold. Scientific evaluation of many technologies is also lacking, and the dangers of some of these technologies may be underappreciated. Research on the effects of specific technologies should be a priority. Policies should be developed to press information technology companies, such as pharmaceutical and medical device manufacturers, to recognize the importance of clinical evaluation. Research could also analyze the characteristics of effective technologies and of physicians and organizations who implement these technologies effectively.

Biomedical Technology↗
PubMed1976

The use of enzyme analysis of peritoneal blood in the clinical assessment of abdominal organ injury.

Seventy patients with blunt and penetrating abdominal trauma and hemoperitoneum were evaluated by the analysis of the enzyme content of peritoneal blood using automated laboratory methods. The enzyme levels in peritoneal blood were evaluated relative to the simultaneous levels in peripheral blood to identify enzyme differences in organ-related peritoneal and periheral blood. The findings in this study indicate that isolated liver injuries are associated with significant elevation of lactic dehydrogenase levels in peritoneal blood and glutamic-oxalacetic transaminase levels in peritoneal and peripheral blood. A multiplicity of abdominal organ injury results in elevation of lactic dehydrogenase and glutamic-oxalacetic transaminase levels in peritoneal blood. The occurrence of isolated small intestinal injury and small intestinal injury combined with other organ injury produces a significant elevation of glutamic-oxalacetic transaminase, lactic dehydrogenase and alkaline phosphatase levels in peritoneal blood. The alkaline phosphatase elevation in peritoneal blood is associated with normal mean values in peripheral blood; therefore, combined alkaline phosphatase in peritoneal and peripheral blood has potential for use in the identification of small intestinal injury in patients with hemoperitoneum of traumatic origin.

Abdominal Injuries↗
PubMedDate not supplied

Determination of aristolochic acid in botanicals and dietary supplements by liquid chromatography with ultraviolet detection and by liquid chromatography/mass spectrometry: single laboratory validation confirmation.

The presence of aristolochic acid in some dietary supplements is a concern to regulators and consumers. A method has been developed, by initially using a reference method as a guide, during single laboratory validation (SLV) for the determination of aristolochic acid I, also known as aristolochic acid A, in botanical species and dietary supplements at concentrations of approximately 2 to 32 microg/g. Higher levels were determined by dilution to fit the standard curve. Through the SLV, the method was optimized for quantification by liquid chromatography with ultraviolet detection (LC-UV) and LC/mass spectrometry (MS) confirmation. The test samples were extracted with organic solvent and water, then injected on a reverse phase LC column. Quantification was achieved with linear regression using a laboratory automation system. The SLV study included systematically optimizing the LC-UV method with regard to test sample size, fine grinding of solids, and solvent extraction efficiency. These parameters were varied in increments (and in separate optimization studies), in order to ensure that each parameter was individually studied; the test results include corresponding tables of parameter variations. In addition, the chromatographic conditions were optimized with respect to injection volume and detection wavelength. Precision studies produced overall relative standard deviation values from 2.44 up to 8.26% for aristolochic acid I. Mean recoveries were between 100 and 103% at the 2 microg/g level, between 102 and 103% at the 10 microg/g level, and 104% at the 30 microg/g level.

Acetonitriles↗
PubMed1991

Utilizing findings from the APACHE III research to develop operational information system for the ICU--the APACHE III ICU Management System.

The APACHE III data base reflects the disease, physiologic status, and outcome data from 17,400 ICU patients at 40 hospitals, 26 of which were randomly selected from representative geographic regions, bed size, and teaching status. This provides a nationally representative standard for measuring several important aspects of ICU performance. Results from the study have now been used to develop an automated information system to provide real time information about expected ICU patient outcome, length of stay, production cost, and ICU performance. The information system provides several new capabilities to ICU clinicians, clinic, and hospital administrators. Among the system's capabilities are: the ability to compare local ICU performance against predetermined criteria; the ability to forecast nursing requirements; and, the ability to make both individual and group patient outcome predictions. The system also provides improved administrative support by tracking ICU charges at the point of origin and reduces staff workload eliminating the requirement for several manually maintained logs and patient lists. APACHE III has the capability to electronically interface with and utilize data already captured in existing hospital information systems, automated laboratory information systems, and patient monitoring systems. APACHE III will also be completely integrated with several CIS vendors' products.

Databases, Factual↗
PubMed1991

Lack of agreement of chromogenic and clotting assays for factor X and protein C in warfarinised plasma.

Coagulation serine proteases can be measured with either a chromogenic substrate assay or a clotting assay using deficient plasmas. It is a concern whether both assays give similar quantitative results, in particular in plasma obtained from patients on long term warfarin therapy. If these two assay methods were interchangeable, then the chromogenic substrate assay has the advantages of precision as well as laboratory automation. We used the intraclass correlation coefficient (rI) to assess the agreement between the two methods in measuring factor X and protein C levels in warfarinised plasma. The results indicate that the extent and pattern of agreement of the two methods for the measurement of the two variables in warfarinised plasma are poor, despite high Pearson product moment coefficients of correlation.

Blood Chemical Analysis↗
PubMed1990

Survey identifies trends in equipment acquisitions.

Automated laboratory equipment, medical imaging equipment, and patient monitors top the list of hospitals' priorities for equipment acquisition during the next year. This is according to an exclusive survey sponsored by the Linc Group, Inc., Chicago, and Hospitals magazine. The new survey also found that equipment acquisitions are most often financed with internal funds and gifts; that equipment purchasing budgets are on the rise; and that executives believe that most equipment makes money for their hospitals. Find out what your peers have to say about anticipated trends in equipment acquisition and financing during the next year.

Capital Expenditures↗