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The application of various mathematical models for the identification of binding parameters in steroid receptor studies is discussed. In contrast to the usual statistical error considerations a deterministic error analysis based on the Euclidian norm and condition numbers is included. The predicted sensitivity behaviour with respect to data scattering is in good agreement with the experimental results.
This paper presents a brief description and the advantages of the singular spectrum analysis (SSA). SSA has recently been recommended for analysis of short, noisy time series. The method was applied to single trials of EEG activity at Cz, Fz, C4, Pz and C3, recorded 3.6 s prior to and 1.2 s after the onset of a voluntary motor act. This specific activity is known in its averaged form as readiness potential (RP) and is considered to reflect the preparation of the voluntary movement. However, some physiological investigations require identification of the parameters of single-trial RPs-their onset and successive phases. SSA is based on analysis of the principal components in vector space of delay coordinates of time series. As a result, SSA algorithm decomposes real data records to components reflecting the trend, alpha and beta frequency bands, respectively, whose oscillations appear or disappear in different time instants. The latter were interpreted to distinguish different dynamical stages of the movement preparatory process.
A panel of different B-cell malignancies representing various stages of B-cell differentiation were analyzed for the expression of an antigen labeled by the monoclonal antibody FMC7 and of tartrate-resistant acid phosphatase (TracP) activity. The FMC7 antigen and TracP were not found on early immature pre B-cell proliferations, appeared at early and intermediate B-cell stages, reached their peak of expression in terms of both incidence of positivity and staining intensity at the late B cell stage (as represented by hairy cell leukemia) and were lost at the B-cell/plasma cell transition. Although detected at similar stages of B-cell differentiation, FMC7 and TracP appear to be independently expressed and were not related to a particular Ig class. The simultaneous detection of FMC7 and TracP represents a distinguishing parameter for the identification of hairy cell leukemia.
We tested categorical perception and speech-in-noise perception in a group of five-year-old preschool children genetically at risk for dyslexia, compared to a group of well-matched control children and a group of adults. Both groups of children differed significantly from the adults on all speech measures. Comparing both child groups, the risk group presented a slight but significant deficit in speech-in-noise perception, particularly in the most difficult listening condition. For categorical perception a marginally significant deficit was observed on the discrimination task but not on the identification task. Speech parameters were significantly related to phonological awareness and low-level auditory measures. Results are discussed within the framework of a causal model where low-level auditory problems are hypothesized to result in subtle speech perception problems that might interfere with the development of phonology and reading and spelling ability.
The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.
We developed an efficient and convenient strategy for protein identification and glycosylation analysis of a small amount of unknown glycoprotein in a biological sample. The procedure involves isolation of proteins by electrophoresis and mass spectrometric peptide/glycopeptide mapping by LC/ion trap mass spectrometer. For the complete glycosylation analysis, proteins were extracted in intact form from the gel, and proteinase-digested glycoproteins were then subjected to LC/multistage tandem MS (MSn) incorporating a full mass scan, in-source collision-induced dissociation (CID), and data-dependent MSn. The glycopeptides were localized in the peptide/glycopeptide map by using oxonium ions such as HexNAc+ and NeuAc+, generated by in-source CID, and neutral loss by CID-MS/MS. We conducted the search analysis for the glycopeptide identification using search parameters containing a possible glycosylation at the Asn residue with N-acetylglucosamine (203 Da). We were able to identify the glycopeptides resulting from predictable digestion with proteinase. The glycopeptides caused by irregular cleavages were not identified by the database search analysis, but their elution positions were localized using oxonium ions produced by in-source CID, and neutral loss by the data-dependent MSn. Then, all glycopeptides could be identified based on the product ion spectra which were sorted from data-dependent CID-MSn spectra acquired around localized positions. Using this strategy, we successfully elucidated site-specific glycosylation of Thy-1, glycosylphosphatidylinositol (GPI)-anchored proteins glycosylated at Asn23, 74, and 98, and at Cys111. High-mannose-type, complex-type, and hybrid-type oligosaccharides were all found to be attached to Asn23, 74 and 98, and four GPI structures could be characterized. Our method is simple, rapid and useful for the characterization of unknown glycoproteins in a complex mixture of proteins.
In the last few years, novel immunosuppressive agents and new formulations, including sirolimus, mycophenolic acid (the active metabolite of mycophenolate mofetil), tacrolimus, and microemulsion cyclosporine, have significantly improved the clinical outcome of transplant recipients. However, the majority of immunosuppressive agents need a constant monitoring of drug levels to reduce the risk of graft rejection as well as drug-induced toxicities. Many factors may affect the pharmacokinetic characteristics of immunosuppressive agents, potentially reducing treatment effectiveness. Absorption and metabolism of immunosuppressive drugs are influenced by patient genotype and comedications, while comorbidities (ie, diabetes and cystic fibrosis) are responsible for altered pharmacokinetics. Dose individualization in transplant recipients is performed according to their health status, graft function, and drug therapeutic range. With respect to the last issue, therapeutic drug monitoring (TDM) plays a crucial role in achieving optimal immunosuppression, improving the efficacy of drugs, and lowering toxic effects. Pharmacokinetic analysis allowed the identification of specific parameters, such as plasma or blood levels, immediately before dosing (C(min) or trough levels) or 2 hours after administration (C(2)), which are significantly related to tissue exposure to the drug. More recently, studies have investigated treatment individualization by evaluating drug pharmacogenetics based on the expression level or mutations of their molecular targets, including calcineurin for cyclosporine and tacrolimus, and inosine monophosphate dehydrogenase for mycophenolic acid. Although no conclusive data may be drawn from these preliminary trials, further studies are underway to address the role of pharmacogenetics in clinical decision making.
Biomechanical study of car driver posture is one of the most referenced aspects for the ergonomic design process of the whole vehicle. The aim of this work is to present a multi-factor method for the analysis of sitting posture and the resulting interactions of the car driver body with the cushion and the backrest. The proposed method, based on the combined use of an optoelectronic system for motion capture and suitable matrices of pressure sensors, has allowed the measurement of a large set of car driver posture parameters and the identification of specific sitting strategies characterising the driving posture, despite the different behaviours of the analysed subjects.
Atomic force microscopy performed on single crystals of three different polymorphs of bovine insulin revealed molecularly smooth (001) layers separated by steps whose heights reflect the dimensions of a single insulin hexamer. Whereas contact mode imaging caused etching that prevented molecular-scale resolution, tapping mode imaging in solution provided molecular-scale contrast that enabled determination of lattice parameters and polymorph identification while simultaneously enabling real-time examination of growth modes and assessment of crystal quality. Crystallization proceeds layer by layer, a process in which the protein molecules assemble homoepitaxially with nearly perfect orientational and translational commensurism. Tapping mode imaging also revealed insulin aggregates attached to the (001) faces, their incorporation into growing terraces, and their role in defect formation. These observations demonstrate that tapping mode imaging is ideal for real-time in situ investigation of the crystallization of soft protein crystals of relatively small proteins such as insulin, which cannot withstand the lateral shear forces exerted by the scanning probe in conventional imaging modes.
We analyzed the parameters predictive of identification of methicillin-resistant Staphylococcus epidermidis (MRSE) in sample performed in hospitalized patients. One hundred six Staphylococcus epidermidis strains (60 MRSE and 46 MSSE) were collected. Three variables were independently linked to MRSE isolation in multivariate analysis: hospitalization during the month preceding the current admission; on-going antimicrobial therapy before sampling, and on-going infection at the time of sampling. MRSE isolation was associated with a poor vital prognosis. The air and surfaces sampling in the rooms of two patients with nasal MRSE carriage yielded the same strains as those carried by the patient, and could play a role in the epidemiological chain of hospital-acquired MRSE infections.
We describe the development of an HPLC method with diode-array detection (DAD) for the analysis and identification of 20 substances with anabolic properties, that are considered as potential growth promoters, to be used for the analysis of extracts of calf urine samples. The substances are separated on an RP-Select B column using a mobile phase consisting of a mixture of acetonitrile and water. Gradient elution from 43-76% acetonitrile in water with a concave curve was used to achieve a good separation of the compounds with an acceptable analysis time. For the identification, a retention parameter and the UV spectrum were used. The retention parameter was the retention time corrected with a reference mixture. The latter reduced the standard deviations to about 25% of their original values. The limits of detection of the HPLC system ranged from 0.5-5 ng injected amount for the androgens, progestagens, stilbenes and resorcylic acid lactones and to 5-10 ng injected amount for the oestrogens. After extraction from urine the limits of detection were increased by the presence of matrix components, but they were between 5 and 10 ng injected amount for most of the substances.
The hippocampus plays a central role in the generation and propagation of seizures in patients with complex partial seizures. Hippocampal sclerosis (HS) is a common structural abnormality in patients with refractory epilepsy. The aim of this study was to quantify diffusion in the hippocampus in patients with epilepsy to evaluate the diffusion changes associated with HS. We scanned 20 subjects (14 patients and 6 controls) with a 1.5T magnetic resonance (MR) system using a cardiac-gated, navigated spin-echo diffusion-weighted sequence. Hippocampal ADC measurements were performed on maps of the ADC measured in three orthogonal directions labeled x, y, and z. The mean ADC (ADCav) and an anisotropy index (AI) were calculated. Hippocampi which fulfilled the MR criteria for HS had a higher ADCav (p < 0.001) and a lower AI (p=0.04) than normal appearing hippocampi in patients and hippocampi in controls. These results imply a loss of structural organization in sclerotic hippocampi and an expansion of the extracellular space. Quantitative measurements of diffusion can be used as an independent parameter for the identification and characterization of abnormal hippocampi in epilepsy.
The universal caution to consult your family doctor before beginning an exercise program creates an image of exercise as potentially harmful. Moreover, insistence on extensive screening prior to exercise is both unrealistic and often inappropriate for the older adult. Recasting the role of the physician as a physical activity advocate rather than as a gatekeeper is recommended for incorporation into guidelines for exercise screening. A geriatric assessment focusing on identification of specific parameters predictive of disablement risk can be incorporated into the exercise prescription as a guide for initiating exercise. The purpose of this article is to: (1). review the role of the primary care physician in screening and advocating exercise; (2). examine objectively the risk of exercise among older adults and place these risks in context with current screening guidelines with a particular emphasis on the exercise test; and (3). examine how key concepts derived from epidemiologic studies of disability can be distilled into practical guidelines for exercise therapy. We provide an overview of relevant literature related to screening and initiating exercise. Key challenges are highlighted and discussed. Suggestions for changes in policy are recommended. Given the apparent discordance between screening guidelines for the older adult and risk of adverse events, and between existing recommendations for physical activity and epidemiologic studies of disability, an evidence-based approach is recommended to review and revise screening and prescribing practices.
Classical adaptive and robust adaptive schemes, are unable to ensure convergence of the identification error to zero, in the case of modeling errors. Therefore, the usage of such schemes to "black-box" identification of nonlinear systems ensures-in the best case-bounded identification error. In this paper, new learning (adaptive) laws are proposed which when applied to recurrent high order neural networks (RHONN) ensure that the identification error converges to zero exponentially fast, and even more, in the case where the identification error is initially zero, it remains equal to zero during the whole identification process. The parameter convergence properties of the proposed scheme, that is, their capability of converging to the optimal neural network model, is also examined; it is shown to be similar to that of classical adaptive and parameter estimation schemes. Finally, it is mentioned that the proposed learning laws are not locally implementable, as they make use of global knowledge of signals and parameters. Copyright 1997 Elsevier Science Ltd. All Rights Reserved.
OBJECTIVE: Pulmonary emphysema is frequently associated with lung cancer and, because of the impaired pulmonary function involved, it may contraindicate surgical treatment. However, improvement of pulmonary function has been observed after surgical resection in patients with advanced emphysema. The aim of this study was to evaluate whether pulmonary emphysema, as assessed by pulmonary function tests and radiological evaluation, can influence postoperative respiratory function after lobectomy for non-small cell lung cancer (NSCLC). METHODS: Respiratory function was evaluated before and after lobectomy for NSCLC. Radiological evaluation of emphysema was performed on chest X-ray and CT scan. Patients that had undergone chemo- or radiotherapy or had segmental or lobar atelectasis were excluded from the study. RESULTS: Thirty-five patients entered the study. A decrease in static lung volumes was observed after surgery. Total lung capacity (TLC) decreased from 6.58+/-0.92 to 5.46+/-0.77 l; functional residual capacity (FRC) from 3.70+/-0.88 to 2.96+/-0.73 1 and residual volume (RV) from 2.93+/-0.78 to 2.2+/-0.53 l. However, in a subgroup of 10 patients (Group 1), dynamic volumes after surgery were unchanged or slightly increased (forced vital capacity (FVC) from 3.23+/-0.65 to 3.3+/-0.68 l; forced expiratory volume in 1 s (FEV1) from 2.14+/-0.51 to 2.25+/-0.54 l), and airway resistances (sRaw) decreased from 15.58+/-5.18 to 11.42+/-5.25 cm H2O/s. Preoperative data showed that these patients had a greater obstruction, with FEV1 changing from 69+/-12.42 to 72.70+/-13.72% of predicted, as compared with a change from 87+/-12.7 to 72.08+/-13.10% in the other group of 25 patients (Group 2). Correlation analysis reached statistical significance between FEV1% variation (deltaFEV1%) and preoperative FEV1 and FVC% (r = -0.49, P = 0.002 and r = -0.5, P = 0.001, respectively) and between delta (FEV1)% and radiological scores for 3-level CT (r = 0.39, P = 0.04) and the sum of chest X-ray, single and 3-level CT scores (r = 0.49, P = 0.01). CONCLUSIONS: Pulmonary function may remain unchanged or even increase after lobectomy in patients with a pronounced emphysematous component of airway obstruction. The identification of preoperative parameters that identify this group of patients could extend the indications for the treatment of lung cancer in patients with pulmonary emphysema.
In this paper, we show that time-lags between compartments in a 2 and 3 compartment pharmacokinetic model may be taken into account but that separate identification for model parameters and for time-lags would not be suitable. Furthermore, it may happen that a time-lag model is locally identifiable while the corresponding model without delay is not. For two-compartment delayed models, with only one observation, it is not necessary to have two different inputs contrary to the case without time-lag. Both the Laplace transformation and a Jacobian matrix are used in an identifiability study. For all two-compartment models we have investigated which kind of parameters or lags are identifiable from amount (Q) or concentration (C) measures.
An important element of protein folding theory has been the identification of equilibrium parameters that might uniquely distinguish rapidly folding polypeptide sequences from those that fold slowly. One such parameter, termed sigma, is a dimensionless, equilibrium measure of the coincidence of chain compaction and folding that is predicted to be an important determinant of relative folding kinetics. To test this prediction and improve our understanding of the putative relationship between nonspecific compaction of the unfolded state and protein folding kinetics, we have used small-angle X-ray scattering and circular dichroism spectroscopy to measure the sigma of five well-characterized proteins. Consistent with theoretical predictions, we find that near-perfect coincidence of the unfolded state contraction and folding (sigma approximately 0) is associated with the rapid kinetics of these naturally occurring proteins. We do not, however, observe any significant correlation between sigma and either the relative folding rates of these proteins or the presence or absence of well-populated kinetic intermediates. Thus, while sigma approximately 0 may be a necessary condition to ensure rapid folding, differences in sigma do not account for the wide range of rates and mechanisms with which naturally occurring proteins fold.
Quantitative comparison of protein expression levels in 2D gels is complicated by the variables associated with protein separation and mass spectrometric responses. Metabolic labeling allows cells from different experiments to be mixed prior to analysis. This approach has been reported for prokaryotic cells. Here, we demonstrate that metabolic labeling can also be successfully applied to the eukaryote Saccharormyces cerevisiae. Yeast leucine auxotrophs grown on synthetic complete media containing natural abundance Leu or D10-Leu were mixed prior to 2D gel separation and MALDI analysis of the digested proteins. D10-Leu labeling provided an effective internal calibrant for peptide MS analysis, and the number of Leu residues yielded an additional parameter for peptide identification at low mass resolution (1000). Metabolic incorporation of D10-Leu into yeast proteins was found to be quantitative since the intensities of the peptide peaks corresponded to those expected on the basis of the percent label in the media. Thus, D10-Leu labeling should provide reliable data for comparing proteomes both quantitatively and qualitatively from wild-type and nonessential-gene-null-mutant strains of S. cerevisiae. Given the central role played by yeast in our understanding of eukaryotic gene and protein expression, it is anticipated that the quantitative expressional proteomic method outlined here will have widespread applications.