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PubMed2005

Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification.

Replacement of the N-butyl side-chain of lead 5-HT4 receptor antagonist 2 with propanesulfonylpiperidinyl, morpholinyl, and piperazinyl groups led to higher affinity analogs 4-6. In vitro drug metabolism screens and cassette pharmacokinetic studies in the dog led to identification of the N-methylpiperazinyl analog (6b), which displayed pharmacokinetic, selectivity, and safety parameters sufficient for advancement to the clinic for the treatment of urinary incontinence.

Animals↗
PubMed2006

The effect of water solubility of solutes on their flux through human skin in vitro.

The Flynn database (n=97) for determining the effect of the physicochemical properties of solutes on their skin absorption has been edited to give a database for which the solubilities of the solutes in water, S(AQ), and their maximum fluxes from water through human skin in vitro, J(MAQ), are known or can be calculated (n=76). Data from the six major contributors to the original Flynn database have been included. Data for solutes, which were significantly ionized or for experiments using different thicknesses of skin were not excluded so that the edited database is as diverse as the original. The edited database was fit to five equations where the independent variables were solubility in octanol (S(OCT)) in water (S(AQ)) or molecular weight (MW), and combinations of those three variables; and the dependent variable was J(MAQ). The best fit was obtained from the Roberts-Sloan (RS) equation: logJ(MAQ)=x+ylogS(OCT)+(1-y)logS(AQ)-zMW, x=-3.00, y=0.73, z=0.0048, r(2)=0.934, S.D.=0.37 and F=274. This result is important because J (amount/area time) is the more clinically useful descriptor of permeation compared to P (distance/time); and because the identification of S(AQ) as a significant variable in predicting flux changes the design parameters for optimizing topical delivery of drugs from solubility in lipids (or partition coefficients between OCT and AQ, K(OCT:AQ)) and MW, to solubility in lipids, S(OCT), and in water, S(AQ), as well as MW.

Analgesics↗
PubMed2001

Identification of the factors that influence the reproducibility of chromatographic retention data.

Principal component analysis was used to identify the parameters that influence the column-to-column and batch-to-batch reproducibility of retention times and retention factors measured on Symmetry C18, Kromasil C18, Luna C18 (2) and Vydac RP C18, all reversed-phase silica columns. We devised a procedure that allows the determination of the differences in column volume and packing density between two columns, provided that these columns are packed with identical stationary phases (i.e., phases that originate from the same batch). Principal component analysis of the retention times confirmed that the column-to-column variations of the column volume and the total porosity of the bed are the factors that influence the reproducibility of the retention times, the column volume being the major factor. For the fluctuations of the retention factors, the column phase ratios (or the bed porosities) and some specific, secondary retention mechanisms are responsible. All the C18 columns investigated proved to behave in a very similar fashion. Two principal components were always sufficient to characterize the variations of either the retention times or the retention factors.

Chromatography, Liquid↗
PubMed2000

Oxidation of xenobiotics by plant microsomes, a reconstituted cytochrome P450 system and peroxidase: a comparative study.

The microsomal fraction from tulip bulbs (Tulipa fosteriana, L.) contains cytochrome P450 (CYP3, EC 1.14.14.1) and peroxidase (EC 1.11.1.7.) enzymes catalyzing the NADPH--and hydrogen peroxide--dependent oxidation of the xenobiotic substrates, N-nitrosodimethylamine (NDMA), N-nitrosomethylaniline (NMA), aminopyrine and 1-phenylazo 2-hydroxynaphthalene (Sudan I), respectively. Oxidation of these model xenobiotics has also been assessed in a reconstituted electron-transport chain with a partially purified CYP fraction, phospholipid and isolated tulip NADPH:CYP reductase (EC 1.6.2.4.). Peroxidase isolated from tulip bulbs (isoenzyme C) oxidizes these xenobiotics, too. Values of kinetic parameters (Km, Vmax), requirements for cofactors (NADPH, hydrogen peroxide), the effect of inhibitors and identification of products formed from the xenobiotics by the microsomal fraction, partially purified CYP and peroxidase C were determined. These data were used to estimate the participation of the CYP preparation and peroxidase C in oxidation of two out of the four studied xenobiotics (NMA, Sudan I) in tulip microsomes. Using such detailed study, we found that the CYP-dependent enzyme system is responsible for the oxidation of these xenobiotics in the microsomal fraction of tulip bulbs. The results demonstrate the progress in resolving the role of plant CYP and peroxidase enzymes in oxidation of xenobiotics.

Cytochrome P-450 Enzyme System↗
PubMed2003

Supramolecular assembly of dendritic polymers elucidated by 1H and 13C solid-state MAS NMR spectroscopy.

Advanced solid-state NMR methods under fast magic-angle spinning (MAS) are used to study the structure and dynamics of large supramolecular systems, which consist of a polymer backbone with dendritic side groups and self-assemble into a columnar structure. The NMR experiments are performed on as-synthesized samples, i.e., no isotopic enrichment is required. The analysis of (1)H NMR chemical-shift effects as well as dipolar (1)H-(1)H or (1)H-(13)C couplings provide site-specific insight into the local structure and the segmental dynamics, in particular, of phenyl rings and -CH(2)O- linking units within the dendrons. Relative changes of (1)H chemical shifts (of up to -3 ppm) serve as distance constraints and allow protons to be positioned relative to aromatic rings. Together with dipolar spinning sideband patterns, pi-pi packing phenomena and local order parameters (showing variations between 30% and 100%) are selectively and precisely determined, enabling the identification of the dendron cores as the structure-directing moieties within the supramolecular architecture. The study is carried out over a representative selection of systems which reflect characteristic differences, such as different polymer backbones, sizes of dendritic side groups, or length and flexibility of linking units. While the polymer backbone is found to have virtually no effect on the overall structure and properties, the systems are sensitively affected by changing the generation or the linkage of the dendrons. The results help to understand the self-assembly process of dendritic moieties and aid the chemical design of self-organizing molecular structures.

Journal Article↗
PubMed2003

A numerical-experimental method to characterize the non-linear mechanical behaviour of human skin.

BACKGROUND/AIMS: Human skin is a complex tissue consisting of several distinct layers. Each layer consists of various components with a specific structure. To gain a better insight into the overall mechanical behaviour of the skin, we wish to study the mechanical properties of the different layers. A numerical-experimental method was developed to characterize the non-linear mechanical behaviour of human dermis. METHODS: Suction measurements at varying pressures were performed on the volar forearm skin of 10 subjects aged 19-24 years old. Deformation of dermis and fat during suction was measured using ultrasound. The experiment was simulated by a finite element model exhibiting extended Mooney material behaviour to account for the non-linear stress-strain relationship. An identification method is used to compare the experimental and numerical results to identify the parameters of the material model. RESULTS: C10, dermis was found to be 9.4 +/- 3.6 kPa and C11, dermis to be 82 +/- 60 kPa. A first rough estimate of C10, fat was 0.02 kPa. CONCLUSIONS: The resulting finite element model demonstrated its ability to describe the response of the skin to suction at various pressures. In the future, this method can be used to characterize the mechanical behaviour of different skin layers using various aperture sizes and to characterize the skin behaviour under various loading conditions.

Adipose Tissue↗
PubMed2002

The sustained impact of an evidenced-based clinical pathway for acute appendicitis.

Appendicitis is a frequent pediatric surgical condition for which there is great variability among practitioners regarding diagnosis and postoperative management. With this in mind, the authors designed and implemented an evidence-based appendicitis clinical pathway at their institution. Establishment of the pathway resulted in decreased hospital cost, reduced hospital stay, and fewer unnecessary laboratory tests. The purpose of the current study was to determine the sustainability of the pathway beyond its initial implementation phase. The authors showed that several, but not all, favorable outcomes of the pathway were sustained. These data suggest that a clinical pathway for appendicitis at the authors' institution results in sustained beneficial effects in some but not all outcome parameters. Ongoing monitoring of pathway compliance, continued education of practitioners and nursing personnel, and identification of key pathway team member(s) responsible for the pathway system might result in a greater long-term impact of these guidelines.

Appendicitis↗
PubMed1989

[Ultrasonic diagnosis of acute appendicitis].

The ranking of sonography in the diagnosis of acute appendicitis and its complications was examined in 208 patients in a prospective study. With a prevalence of the disease of 31.25% the sensitivity of sonography was 91.5, and the specificity more than 96% with a low negative laparotomy rate of 12.9%. Since due to increasing experience in the techniques of examination and also due to technological improvements the normal appendix or concomitant appendicitis in enteritic disease patterns become visualisable, the sonographically determined appendix pattern is an important parameter. Sonography contributes to a reduction of the negative laparotomy rate due to the identification of differential diagnostically important diseases including lymphadenitis mesenterialis and Crohn's disease of the terminal ileum. At the same time, this method safely identifies perityphlitic abscesses and perforations of the appendix.

Abscess↗
PubMed1989

Comparative 13C and 31P NMR assessment of altered metabolism during graded reductions in coronary flow in intact rat hearts.

13C NMR spectroscopy may offer a unique ability to characterize the metabolic response to graded reduction in coronary flow since it allows repeated, nondestructive identification of products of intermediary metabolism in the same heart. The sensitivity of 13C parameters of glucose metabolism was compared with changes in levels of phosphocreatine, ATP, and pH as determined by 31P NMR in the intact, beating rat heart model during graded reductions in coronary flow. Experiments were performed during 60 min of perfusion with [1-13C]glucose (5 mM) at normal flow (15 ml/min) and at the reduced flow rates of 5 and 2 ml/min. During flow at 5 ml/min, isovolumic developed pressure fell to 51 +/- 4% of control. Although phosphocreatine, ATP, and pH were not changed, [3-13C]lactate was increased (1.46 +/- 0.12 mumol/g of wet weight vs. 0.63 +/- 0.08 during normal flow). In addition, the time to 50% maximum enrichment of [2-13C]glutamate was prolonged (17 +/- 1 min vs. 9 +/- 1 min during normal flow), indicating that glucose-supported flux through the tricarboxylic acid (TCA) cycle was decreased. The relative anaplerotic contribution to citrate synthase-supported TCA flux was increased from 6% to 35%. These 13C metabolic changes could not be reproduced by reduced [1-13C]glucose delivery in the absence of ischemia, although similar reduced TCA flux indices were reproduced in additional hearts when workload was reduced by low calcium (0.7 mM) perfusion. Therefore, the information provided by 13C NMR spectroscopy can be a more sensitive indicator of flow-induced alterations in cardiac metabolism than that provided by the much more commonly used 31P NMR technique.

Adenosine Triphosphate↗
PubMed2003

The most useful findings for diagnosing acute appendicitis on contrast-enhanced helical CT.

PURPOSE: To evaluate the most useful findings to look for in diagnosing acute appendicitis on contrast-enhanced helical CT. MATERIAL AND METHODS: Appendiceal helical CT scans with intravenous contrast administration (abdomen, 7-mm collimation; abdominopelvic junction, 5-mm collimation) of 71 patients with surgically proven acute appendicitis and 167 patients with alternative diagnoses were reviewed retrospectively. Three radiologists analyzed the following parameters: enlarged appendix (>6 mm in diameter), appendiceal wall thickening, appendiceal wall enhancement, no identification of the appendix, appendicolith(s), appendiceal intraluminal air, intramural air, extraluminal air, periappendiceal fat stranding, extraluminal fluid, phlegmon, abscess, lymphadenopathy, segmental terminal ileal wall thickening, focal cecal apical thickening, focal colonic wall thickening, and segmental colonic wall thickening. The features that best distinguished appendicitis from alternative diagnoses were selected with stepwise logistic regression analysis. RESULTS: Nine CT findings distinguished acute appendicitis from alternative diagnoses (P < 0.05): enlarged appendix (R = 0.739), appendiceal wall thickening (R = 0.525), periappendiceal fat stranding (R = 0.414), appendiceal wall enhancement (R = 0.404), focal cecal apical thickening (R = 0.171), appendicolith(s) (R = 0.157), extraluminal air (R = 0.050), intramural air (R = 0.043), and phlegmon (R = 0.030). Enlarged appendix (sensitivity, 93%; specificity, 92%), appendiceal wall thickening (sensitivity, 66%; specificity, 96%), periappendiceal fat stranding (sensitivity, 87%; specificity, 74%), and appendiceal wall enhancement (sensitivity, 75%; specificity, 85%) showed the statistically most significant association with acute appendicitis. CONCLUSION: On 5-mm-section contrast-enhanced helical CT examinations, enlarged appendix, appendiceal wall thickening, periappendiceal fat stranding, and appendiceal wall enhancement were the most useful findings for diagnosing acute appendicitis.

Acute Disease↗
PubMed2005

Internal models in sensorimotor integration: perspectives from adaptive control theory.

Internal models and adaptive controls are empirical and mathematical paradigms that have evolved separately to describe learning control processes in brain systems and engineering systems, respectively. This paper presents a comprehensive appraisal of the correlation between these paradigms with a view to forging a unified theoretical framework that may benefit both disciplines. It is suggested that the classic equilibrium-point theory of impedance control of arm movement is analogous to continuous gain-scheduling or high-gain adaptive control within or across movement trials, respectively, and that the recently proposed inverse internal model is akin to adaptive sliding control originally for robotic manipulator applications. Modular internal models' architecture for multiple motor tasks is a form of multi-model adaptive control. Stochastic methods, such as generalized predictive control, reinforcement learning, Bayesian learning and Hebbian feedback covariance learning, are reviewed and their possible relevance to motor control is discussed. Possible applicability of a Luenberger observer and an extended Kalman filter to state estimation problems-such as sensorimotor prediction or the resolution of vestibular sensory ambiguity-is also discussed. The important role played by vestibular system identification in postural control suggests an indirect adaptive control scheme whereby system states or parameters are explicitly estimated prior to the implementation of control. This interdisciplinary framework should facilitate the experimental elucidation of the mechanisms of internal models in sensorimotor systems and the reverse engineering of such neural mechanisms into novel brain-inspired adaptive control paradigms in future.

Adaptation, Physiological↗
PubMed1993

Recoveries of DNA adducts of polycyclic aromatic hydrocarbons in the 32P-postlabelling assay.

The 32P-postlabelling assay for analysis of DNA adducts of chemical carcinogens has been applied in a large number of experimental animal and human studies. Most human studies have dealt with occupational and environmental exposures to polycyclic aromatic hydrocarbons (PAHs). The postlabelling assay does not allow direct chemical identification, and most studies with this method have not been performed in a quantitative way. Very little is therefore known about the identity and absolute levels of adducts, which are important contributors to the process of risk identification and quantitation. In the present study it was, therefore, decided to test some parameters suspected to affect recoveries of adducts in the phosphorylation step of the assay. For this purpose 12 different PAHs were reacted individually and in a mixture with DNA in the presence of a rat liver S9 metabolizing system. Different concentrations of ATP, calcium chloride and polynucleotide kinase were tested using the nuclease P1 enhancement. We found that each factor contributed to adduct recovery and that optimal conditions could be defined. Diluting the modified DNA samples up to 1000 times had little influence on the recoveries of adducts. Comparing the nuclease P1 and the butanol extraction procedures for adduct purification showed that both methods gave similar patterns and levels of major adducts. The absolute recoveries in postlabelling, based on 3H-binding of radiolabelled compounds, were for most of the tested compounds relatively low. The fact that the nuclease P1 and the butanol extraction procedures gave similar recoveries points towards common factor(s) involved in the reduction of the recovered adduct levels. Based on the observed recoveries the conclusion can be drawn that when postlabelling related adducts in human samples the true total adduct levels can be considerably underestimated, even if optimal conditions are used.

Animals↗
PubMed1999

Implications for interrelationships between nuclear architecture and control of gene expression under microgravity conditions.

Components of nuclear architecture are functionally interrelated with control of gene expression. There is growing appreciation that multiple levels of nuclear organization integrate the regulatory cues that support activation and suppression of genes as well as the processing of gene transcripts. The linear representation of genes and promoter elements provide the potential for responsiveness to physiological regulatory signals. Parameters of chromatin structure and nucleosome organization support synergism between activities at independent regulatory sequences and render promoter elements accessible or refractory to transcription factors. Association of genes, transcription factors, and the machinery for transcript processing with the nuclear matrix facilitates fidelity of gene expression within the three-dimensional context of nuclear architecture. Mechanisms must be defined that couple nuclear morphology with enzymatic parameters of gene expression. The recent characterization of factors that mediate chromatin remodeling and identification of intranuclear targeting signals that direct transcription factors to subnuclear domains where gene expression occurs link genetic and structural components of transcriptional control. Nuclear reorganization and aberrant intranuclear trafficking of transcription factors for developmental and tissue-specific control occurs in tumor cells and in neurological disorders. Compromises in nuclear structure-function interrelationships can occur as a consequence of microgravity-mediated perturbations in cellular architecture.

Cell Nucleus↗
PubMed1997

Risk groups of myeloma patients by histologic pattern and proliferative activity.

We investigated the histologic pattern and the cell proliferative activity of myeloma cells by the analysis of the nucleolar organizer regions (AgNORs) in bone marrow biopsy specimens from 150 multiple myelomas at diagnosis. The objective was an attempt to define risk groups of myeloma patients. On univariate analysis, the percentage of bone marrow plasma cells (BMPC%), the pattern of infiltration, the degree of plasma cell (PC) atypia, the marrow fibrosis, and the number of AgNOR/PC were correlated with survival time. On multivariate analysis, only AgNOR counts and pattern of infiltration retained independent prognostic significance. At 4-year followup, all patients with BMPC% < or = 20, interstitial pattern of invasion, and well-differentiated (G1) PC plus AgNOR/cell < or = 3.32 were alive, while no patient with BMPC% >50, diffuse pattern of infiltration, and poorly differentiated (G3) PC plus AgNOR/cell >5.15 survived (p < 0.0001). In conclusion, the histologic pattern and proliferative activity of myeloma cells, evaluated by AgNOR counts, are reliable predictors of survival in myeloma. Both parameters can be easily assessed in the same biopsy specimen, are reproducible, and permit identification of a group of patients with favourable outcome at 4-year followup. Thus, bone marrow biopsy should always be included in the diagnostic procedures for myeloma patients.

Adult↗
PubMed2005

Sedation, analgesia, and neuromuscular blockade for high-frequency oscillatory ventilation.

OBJECTIVE: To provide a comprehensive review of the issue related to the administration of sedative, analgesic, and neuromuscular blocking agents (NMBA) to patients who are receiving ventilatory support for acute respiratory distress syndrome (ARDS) with high-frequency oscillatory ventilation. RESULTS: Sedative, analgesic, and NMBA are used with great frequency in patients with severe ARDS who are undergoing high-frequency oscillatory ventilation. In particular, the use of NMBA has been higher than for other ARDS populations. Important considerations for effective treatment include careful patient evaluation, patient-based medication selection, identification of treatment goals with periodic re-assessment, titration of medications to objective parameters such as sedation scales and peripheral nerve stimulation, use of intermittent therapy when feasible, implementation of drug interruption strategies, and discontinuation of medications at the earliest possible time. It is important to recognize that patients evolve from severe ARDS through phases of recovery to the resolution of respiratory failure and that ventilatory management, as well as sedative and related medication requirements, will vary markedly over the course of this process. CONCLUSIONS: A multidisciplinary, structured approach that is based on the considerations described should help achieve optimal results in this challenging patient population.

Analgesia↗
PubMed1994

Characterization of human AFLP systems apolipoprotein B, phenylalanine hydroxylase, and D1S80.

Methodology is presented for amplified fragment length polymorphism (AFLP) typing using a nonisotopic, PCR protocol. Human variable number tandem repeat (VNTR) loci used for identification in forensic and paternity testing were optimized for reaction and thermal-cycling parameters. Loci analyzed were the apolipoprotein B (APOB) 3' hypervariable region (HVR), phenylalanine hydroxylase 3' HVR (PAH), and D1S80. Coamplification of a monomorphic beta-globin fragment serves as an amplification control. Biotin is integrated into PCR amplicon through primer incorporation. AFLP products undergo agarose gel electrophoresis and Southern transfer to a nylon membrane. Amplicons were detected using a streptavidin-enzyme conjugate. Either colorimetric- or chemiluminescent-developed bands are genotyped using locus-specific allele ladders with known VNTR repeat numbers. Using this methodology, we have successfully typed > 500 individuals from three population groups for each locus during data basing and casework.

Alleles↗
PubMed2004

Influence of hydration and experimental length scale on the mechanical response of human skin in vivo, using optical coherence tomography.

BACKGROUNDS/AIMS: Human skin is a complex tissue consisting of different layers. To gain better insight into the mechanical behaviour of different skin layers, the mechanical response was studied with experiments of various length scales. Also, the influence of (superficial) hydration on the mechanical response is studied. The work is based on the hypothesis that experiments with different length scales represent the mechanical behaviour of different skin layers. For suction, this means that a large aperture diameter reflects the behaviour of mainly dermis, whereas a very small diameter reflects the behaviour of only the top layer of the skin. METHODS: Suction measurements at varying pressures and aperture sizes were performed on the volar forearm of 13 subjects aged 29-47 years. The deformation of the skin was visualized using ultrasound (US) (dermis) and optical coherence tomography (OCT) (epidermis and dermis). US measurements were performed on hydrated skin, OCT measurements on dry and hydrated skin. The experiment was simulated by a finite element model (FEM) exhibiting extended Mooney material behaviour. An identification method was used to compare the experimental and numerical results to identify the parameters of the material. RESULTS: The material parameters C(10) and C(11) were calculated for four subjects: C(10)=29.6+/-21.1 kPa and C(11)=493+/-613 kPa for 6 mm aperture diameter, C(10)=11.5+/-8.7 kPa and C(11)=18.3+/-12.6 kPa for 2 mm aperture diameter and C(10)=10.8+/-9.5 kPa and C(11)=9.3+/-7.7 kPa for 1 mm aperture diameter. Skin hydration caused ambiguous effects on the mechanical response. CONCLUSIONS: US and OCT, combined with suction, using varying apertures sizes, proved to be a valuable tool to study the mechanical behaviour of different skin layers. With increasing experimental length scale, increasing values for the parameters of the material model were found. This indicates the need of a multi-layered material layer FEM, which can be used to identify mechanical behaviour of epidermis and dermis.

Adult↗
PubMed2003

Characterization of sialidase from an influenza A (H3N2) virus strain: kinetic parameters and substrate specificity.

Neuraminidase (NA) of influenza A (H3N2) viruses was characterized after purification by gel filtration and proteolytic treatment, using the X-31 variant strain that is a reassortment between the influenza A/Victoria/3/75 (responsible for the 1975 pandemic) and the influenza A/PR/8/34 virus samples, as a model. In the purification process, NA heads, that is the spike responsible for the virus sialidase activity, were purified by filtration through a Bio-Gel polyacrylamide column. The enzyme activity was determined by periodic acid/thiobarbituric acid assay and high-performance thin-layer chromatography. The sialidase showed preference for the alpha-2,3-linkage over the alpha-2,6-linkage of sialyllactoses (K(m) of 1.8 and 5.2 x 10(-4)M, respectively) at pH 5.2. The enzyme acted on natural and synthetic substrates at different hydrolysis rates, as well as on human erythrocytes (A group, Rh+) and yeast (CANDIDA ALBICANS) cells. The active NA produced by gel filtration was characterized by different parameters of its sialidase activity, also showing to be a suitable tool for the identification of natural sialocompounds and for the screening of antisialidase drugs to treat influenza virus infections.

Chromatography, Gel↗