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PubMed1992

Approach to the sterilization with gamma rays of a drug. Note I: Treatment technique and effects at zero time.

Authors, considering a possible use of the sterilizing treatment with gamma rays for the productive process of a drug, performed a series of practical treatment tests. To this purpose, they used a single molecule, stable in time and with an easy analytical approach. The examined active principle is the injectable salt of acetylcarnitine chloride. For tests, they used irradiating doses by 2.5-5.0-7.5 Mrads in order to point out the process possible effects. The treatment, even at highest dosages, did not show damages to the molecule that could prevent from going on with the investigation.

Acetylcarnitine↗
PubMed2001

Numerical modelling of mass resolution in a scanning atom probe.

We have recently suggested a novel method for improving mass resolution in the scanning atom probe (SAP), based on a post-deceleration scheme. A two-conductor counter electrode is used, and the high voltage pulse is applied to the front conductor, with the rear conductor being held at ground. For a separation between the two conductors of 100 microm or less, ions travel between the two while the pulse is essentially constant, so that the ion leaves the counter electrode with an energy equivalent to the applied d.c. potential. In this paper, we have used a numerical model for the electric fields in the SAP to verify the results of the simpler analytical approach used earlier. In particular, the ion acceleration in the vicinity of the tip, previously assumed to be instantaneous, was modelled using a hyperboloidal field approximation. The numerical model was used to calculate the flight time for ions having a range of masses and evaporating over a range of times at the peak of a high voltage pulse. Modelled mass resolutions, calculated in this way, were then compared with analytical expressions, and were found to agree very well. This shows that the earlier assumption of an instantaneous acceleration did not seriously affect the validity of the approach.

Journal Article↗
PubMed2006

Strategies for the investigation and control of process-related impurities in drug substances.

The understanding, identification, quantification and control of impurities in drug substances are essential as new molecular entities are evaluated in clinical development. As chemical processes used to produce drug substances mature from the early phases of development through registration, a concomitant maturing of process-related impurity understanding and control is required. This paper outlines strategies available to pharmaceutical scientists to aid in that understanding. Methodology aspects for impurity investigations are discussed along with an emphasis on understanding the origin and fate of impurities to guide decisions on process controls and specifications. Orthogonal analytical approaches for impurity investigations to provide a complete understanding of a drug substance impurity profile and to aid chemical process development are described. Special considerations necessary for stereochemical impurity investigations are also discussed. Considerations for control of toxic impurities include sensitive and selective analytical methodology and determination of the process capability for removing the impurity. A case study is given where routine analytical testing for a toxic impurity was not required because a high impurity rejection efficiency of the synthetic process was demonstrated. Quality assessment of starting materials from multiple sources and the impact of starting material impurities on the impurity profile of the drug substance are discussed with illustrative examples. Knowledge gained from these investigations provides a sound basis for setting specifications for impurities in key starting materials.

Chemistry, Pharmaceutical↗
PubMed2006

Critical appraisal of DNA microarrays in psychiatric genomics.

Transcriptome profiling using DNA microarrays are data-driven approaches with the potential to uncover unanticipated relationships between gene expression alterations and psychiatric disorders. Studies to date have yielded both convergent and divergent findings. Differences may be explained, at least in part, by the use of a variety of microarray platforms and analytical approaches. Consistent findings across studies suggest, however, that important relationships may exist between altered gene expression and genetic susceptibility to psychiatric disorders. For example, GAD67, RGS4, DTNBP1, NRG1, and GABRAB2 show expression alterations in the postmortem brain of subjects with schizophrenia, and these genes have been also implicated as putative, heritable schizophrenia susceptibility genes. Thus, we propose that for some genes, altered expression in the postmortem human brain may have a dual origin: polymorphisms in the candidate genes themselves or upstream genetic-environmental factors that converge to alter their expression level. We hypothesize that certain gene products, which function as "molecular hubs," commonly show altered expression in psychiatric disorders and confer genetic susceptibility for one or more diseases. Microarray gene expression studies are ideally suited to reveal these putative disease-associated molecular hubs and to identify promising candidates for genetic association studies.

DNA↗
PubMed2001

Responding to uncertainty in nursing practice.

Uncertainty is a fact of life for practising clinicians and cannot be avoided. This paper outlines the model of uncertainty presented by Katz (1988, Cambridge University Press, Cambridge, UK. pp. 544-565) and examines the descriptive and normative power of three broad theoretical and strategic approaches to dealing with uncertainty: rationality, bounded rationality and intuition. It concludes that nursing research and development (R&D) must acknowledge uncertainty more fully in its R&D agenda and that good-quality evaluation studies which directly compare intuitive with rational-analytical approaches for given clinical problems should be a dominant feature of future R&D.

Adaptation, Psychological↗
PubMed2004

Exact decoupling of the Dirac Hamiltonian. II. The generalized Douglas-Kroll-Hess transformation up to arbitrary order.

In order to achieve exact decoupling of the Dirac Hamiltonian within a unitary transformation scheme, we have discussed in part I of this series that either a purely numerical iterative technique (the Barysz-Sadlej-Snijders method) or a stepwise analytic approach (the Douglas-Kroll-Hess method) are possible. For the evaluation of Douglas-Kroll-Hess Hamiltonians up to a pre-defined order it was shown that a symbolic scheme has to be employed. In this work, an algorithm for this analytic derivation of Douglas-Kroll-Hess Hamiltonians up to any arbitrary order in the external potential is presented. We discuss how an estimate for the necessary order for exact decoupling (within machine precision) for a given system can be determined from the convergence behavior of the Douglas-Kroll-Hess expansion prior to a quantum chemical calculation. Once this maximum order has been accomplished, the spectrum of the positive-energy part of the decoupled Hamiltonian, e.g., for electronic bound states, cannot be distinguished from the corresponding part of the spectrum of the Dirac operator. An efficient scalar-relativistic implementation of the symbolic operations for the evaluation of the positive-energy part of the block-diagonal Hamiltonian is presented, and its accuracy is tested for ground-state energies of one-electron ions over the whole periodic table. Furthermore, the first many-electron calculations employing sixth up to fourteenth order DKH Hamiltonians are presented.

Journal Article↗
PubMed1997

[Prolonged hospitalization for security reasons of narcissistic borderline adolescents: from a psychodynamic to a cognitive approach].

The notion of "mediation" has profoundly transformed clinical approaches aiming at a change either in knowledge, in the way of being or of behaving. The way to treat narcissistic-borderline adolescents in the long-term in a secure hospital does not escape this notion. Until now, the psychodynamic-analytical approach has been the only one presenting interventions in such context, and this, since many decades. The present article attempts to witness the evolution of the clinical approaches within the Quebec security-hospital milieu, and to translate in E.J. Young's cognitive language part of the clinical work currently done. The active and mediation role of the clinical intervenor (including the psychotherapist) constitutes the guiding line of the gradual transformation of approaches.

Adolescent↗
PubMed2001

Approach to patients with acid-base disorders.

Disorders of acid-base balance are commonly encountered in clinical practice and can have a substantial impact on the prognosis of the patient. Moreover, identification of a particular acid-base disturbance can provide a clue to an underlying disorder. Proper evaluation and treatment of acid-base disorders requires a systematic and analytic approach including: (1) assess the accuracy of the acid-base values using the Henderson equation or Henderson-Hasselbalch equation, (2) obtain a complete history and physical examination, (3) calculate the serum anion gap, (4) identify the primary acid-base disturbance and determine whether a simple or mixed disturbance is present, (5) examine serum electrolytes and additional laboratory data, and (6) measure urine pH and urine electrolytes and calculate the urine anion and osmolal gaps. Strict adherence to these principles will enable the clinician to diagnose the acid-base disturbance in the majority of cases. To illustrate these principles, 5 cases of patients with acid-base disturbances are analyzed.

Acid-Base Equilibrium↗
PubMed1998

The hope and the hazards of using compliance data in randomized controlled trials.

This paper aims to elucidate both the advantages and limitations of using compliance data in the reporting of treatment differences in clinical trials, illustrating the issues with some recent examples. While analysis by intention-to-treat should remain the principal reporting approach for most major clinical trials, arguments are put forward as to why supplementary analyses taking account of compliance can be of value. However, continued recognition of the potential biases inherent in all such selective analysis is of key importance. Some of the possible analytical approaches are presented along with suggestions on interpretation. Particular emphasis is on one case study, a large European trial in obesity incorporating repeated measures of weight loss, drug plasma level and pill count data. In working on compliance data in clinical trials, the statistician's main responsibilities may be to undertake a cohesive analysis strategy not influenced by data dredging, to achieve clarity of exposition without undue complexity or oversimplification, and to provide appropriately cautious interpretations which take account of selection biases and data limitations.

Appetite Depressants↗
PubMed2004

Getting a GR(i)P on oligodendrocyte development.

One of the most extensively studied of mammalian cells is the oligodendrocyte, the myelin-forming cell of the central nervous system. The ancestry and development of this cell have been studied with every approach utilized by developmental biologists. Such detailed efforts have the potential of providing paradigms of relevance to those interested in analyzing the ancestry and development of any cell type. One of the striking features of studies on the development of oligodendrocytes is that different analytical approaches have led to strikingly different theoretical views regarding the ancestry of these cells. On one extreme is the hypothesis that the steps leading to the generation of oligodendrocytes begin with the generation of a glial-restricted precursor (GRP) cell from neuroepithelial stem cells. GRP cells are thought to be capable of giving rise to all glial cells (including oligodendrocytes and multiple astrocyte populations), but not to neurons, a process that appears to require progression through further stages of greater lineage restriction. On the other extreme is the hypothesis that oligodendrocytes are derived from a precursor cell that generates only motor neurons and oligodendrocytes, with astrocytes being generated through a separate lineage. In this review, we critically consider the various contributions to understanding the ancestry of oligodendrocytes, with particular attention to the respective merits of the GRP cell vs. the motor neuron-oligodendrocyte precursor (MNOP) cell hypothesis. We draw the conclusion that, at present, the strengths of the GRP cell hypothesis outweigh those of the MNOP hypothesis and other hypotheses suggesting oligodendrocytes are developmentally more related to motor neurons than to astrocytes. Moreover, it is clear from existing data that, following the period of motor neuron generation, the major glial precursor cell in the embryonic spinal cord is the GRP cell, and that multiple previous studies on the earliest stages of oligodendrocyte generation in the developing spinal cord have been focused on a differentiation stage of GRP cells.

Animals↗
PubMed2006

Analysis of variance of microarray data.

Analysis of variance (ANOVA) is an approach used to identify differentially expressed genes in complex experimental designs. It is based on testing for the significance of the magnitude of effect of two or more treatments taking into account the variance within and between treatment classes. ANOVA is a highly flexible analytical approach that allows investigators to simultaneously assess the contributions of multiple factors to gene expression variation, including technical (dye, batch) effects and biological (sex, genotype, drug, time) ones, as well as interactions between factors. This chapter provides an overview of the theory of linear mixture modeling and the sequence of steps involved in fitting gene-specific models and discusses essential features of experimental design. Commercial and open-source software for performing ANOVA is widely available.

Analysis of Variance↗
PubMed2000

Manakov solitons and polarization mode dispersion.

The effect of polarization mode dispersion (PMD) on Manakov solitons and dispersion managed solitons is treated analytically and by numerical simulation. In the analytic approach the internal motion of the Manakov soliton is represented as a damped harmonic oscillator. The PMD functions as a white noise source driving the oscillations. It is shown that the solitons can withstand PMD up to a certain instability threshold for which an analytic expression is obtained. This threshold is also evaluated for dispersion managed solitons. (c) 2000 American Institute of Physics.

Journal Article↗
PubMed2004

Micro parallel liquid chromatography: enabling technology for discovery analytical chemistry.

Since the introduction of combinatorial chemistry, compound libraries have undergone a significant increase in size and diversity. The ensuing expansion and diversification of compound libraries have resulted in increased demand for analytical throughput. Following the evolution of new technologies for generating lead compounds and targets and the desire to increase research and development productivity, analytical chemistry is now gaining attention as a bottleneck that would benefit from advances in instrumentation for increased analytical throughput. The commercial introduction of the Veloce trade mark micro parallel liquid chromatography system from Nanostream offers discovery analytical chemists the capability to analyze 24 samples in parallel with as little as 0.5 microl of sample. The system offers a scalable analytical approach to address bottlenecks in historically underserved areas, such as compound library purity screening, as well as higher value-added applications, such as log P determination and aqueous solubility assessment. This article describes the Veloce system and presents representative data from several discovery analytical applications.

Chemistry Techniques, Analytical↗
PubMed1991

Measuring potential doubling times of murine tumors using flow cytometry.

Flow cytometric analysis of bromodeoxyuridine (BrdUrd) labeled cells has led to the description of various methods for determining population potential doubling times (Tpot) from samples obtained at a single time point. There have been several reports of results from human tumor samples using these various methods of analysis, but little documentation of the validity of these approaches in experimental tumor models. Recently, we reported results using in vitro cell cultures and determined the most reliable method for these. In this paper we report the results of this methodology when applied to two in vivo murine tumor models (MCaK and FSA). The analytic approach tested is summarized as follows: The relative movement (RMlu(t], a measure of the mean DNA fluorescence of BrdUrd-labeled cells that have not undergone division at the time of sampling, and a quantity v, a function of the fractions of BrdUrd-labeled divided and undivided cells, were measured for a series of time points following labeling. From each value of RMlu(t) an estimate of the length of S-phase (TS) was computed and from each v and TS a value for Tpot was found. These results were compared to the values of TS and Tpot obtained by fitting all the values simultaneously. Tumor MCaK values of TS and Tpot of 9.6 and 28.0 h were obtained from fitting all of the data. Tumor FSA gave values of 16.8 and 42.3 h for TS and Tpot, respectively. The results of this analysis show that single time point measurements can give reliable estimates of TS and Tpot.

Animals↗
PubMed2005

Gas chromatography/mass spectrometry determination of amphetamine-related drugs and ephedrines in plasma, urine and hair samples after derivatization with 2,2,2-trichloroethyl chloroformate.

A new analytical approach, based on derivatization with 2,2,2-trichloroethyl chloroformate and gas chromatography/mass spectrometry (GC/MS), was investigated for qualitative and quantitative analyses of a large range of amphetamine-related drugs and ephedrines in plasma, urine and hair samples. Sample preparation involved alkaline extraction of analytes from biological samples using Extrelut columns, after addition of the internal standard 3,4-methylenedioxypropylamphetamine (MDPA), and subsequent derivatization to produce 2,2,2-trichloroethylcarbamates. GC/MS analyses, in splitless mode using a slightly polar 30-m capillary column, were performed with quadrupole or ion trap instruments. MS acquisition modes were electron ionization (EI) in full-scan or selected ion monitoring (SIM) modes (quadrupole), and full-scan MS or MS/MS modes with chemical ionization (CI) conditions (ion trap). EI spectra of 2,2,2-trichloroethylcarbamates showed variably abundant molecular ions as well as abundant diagnostic fragment ions, both characterized by ion clusters reflecting the isotope distribution of three chlorine atoms in the derivatized molecules. CI spectra showed abundant protonated molecules. Quantitative studies using EI SIM conditions gave recoveries in the range 74-89%, linear response over ranges of 10-2000 ng/mL (plasma and urine) and 0.20-20 ng/mg (hair), with corresponding limits of detection in the ranges 2-5 ng/mL and 0.1-0.2 ng/mg. Potential applications (following full method validation) include clinical and forensic toxicology, as well as doping control.

Amphetamines↗
PubMed2000

Twelve-month outcome of nonmelancholic depressive subjects: refinement of subgroups by examination of trajectories.

We previously studied a sample of patients with nonmelancholic depression and attempted to subtype their depression on the basis of etiological factors and current clinical features, analyzed individually and together. We now examine the validity of the three contrasting analytic approaches by examining outcome trajectories in a prospective study. At follow-up we reinterviewed 67% of our initially assessed nonmelancholic subjects, with progress over the 12-month interval assessed across a range of outcome parameters. The "anxious depressed" groups identified across all three differing analytic strategies consistently had the poorest 12-month outcome. However, varying definitions of this group influenced quite differing trajectories, with the worst outcome being for those defined on the basis of clinical features. Study results strongly suggest that patients presenting with a nonmelancholic depressive disorder and who acknowledge a significant number of concurrent anxiety symptoms are likely to have a distinctly poor medium-term outcome. Thus, clinical definition does have predictive utility in such a group.

Affect↗
PubMed2000

Extending the method of mathematically controlled comparison to include numerical comparisons.

MOTIVATION: The method of mathematically controlled comparison has been used for some time to determine which of two alternative regulatory designs is better according to specific quantitative criteria for functional effectiveness. In some cases, the results obtained using this technique are general and independent of parameter values and the answers are clear-cut. In others, the result might be general, but the demonstration is difficult and numerical results with specific parameter values can help to clarify the situation. In either case, numerical results with specific parameter values can also provide an answer to the question of how much larger the values might be. In contrast, a more ambiguous result is obtained when either of the alternatives can have the larger value for a given systemic property, depending on the specific values of the parameters. In any case, introduction of specific values for the parameters reduces the generality of the results. Therefore, we have been motivated to develop and apply statistical methods that would permit the use of numerical values for the parameters and yet retain some of the generality that makes mathematically controlled comparison so attractive. RESULTS: We illustrate this new numerical method in a step-by-step application using a very simple didactic example. We also validate the results by comparison with the corresponding results obtained using the previously developed analytical method. The analytical approach is briefly present for reference purposes, since some of the same key concepts are needed to understand the numerical method and the results are needed for comparison. The numerical method confirms the qualitative differences between the systemic behavior of alternative designs obtained from the analytical method. In addition, the numerical method allows for quantification of the differences and it provides results that are general in a statistical sense. For example, the older analytical method showed that overall feedback inhibition in an unbranched pathway makes the system more robust whereas it decreases the stability margin of the steady state. The numerical method shows that the magnitudes of these differences are not comparable. The differences in stability margins (1-2% on average) are small when compared to the differences in robustness (50-100% on average). Furthermore, the numerical method shows that the system with overall feedback responds more quickly to change than the otherwise equivalent system without overall feedback. These results suggest reasons why overall feedback inhibition is such a prevalent regulatory pattern in unbranched biosynthetic pathways.

Computational Biology↗
PubMed1994

Utilization review for Medicaid diagnosis-related group systems: practice, innovation, and lessons of experience.

Utilization review practices, innovations and trends for the 21 states using diagnosis-related groups for Medicaid during 1992 are described. According to this descriptive survey, Medicaid inpatient utilization review programs vary widely in authority, approach and focus, reflecting state payment system incentives, health and hospital system characteristics, and provider practice norms. More than half of the states with Medicaid diagnosis-related group systems contract with a Medicare Peer Review Organization. State programs are developing complementary clinical and data analytic approaches, advised by multidisciplinary utilization review committees, and are moving from random review to strategies that focus on specific types of admissions/procedures, and shift as provider practices and utilization patterns change. Utilization review strategies also support payment incentives and system features, e.g., by targeting outliers, readmissions and transfers, and short stays. Overall, programs are becoming more flexible, targeted, and interactive. Trends and suggestions for refining utilization review programs for diagnosis-related group systems are presented.

Data Collection↗