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Results for “Analytical Approach”

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PubMed1993

Differential effects of diclofenac and aspirin on serum glutamic oxaloacetic transaminase elevations in patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVE: To examine elevations in levels of serum glutamic oxaloacetic transaminase (SGOT) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) taking placebo, aspirin, or diclofenac, and to seek possible explanations for the occurrence of these elevations. METHODS: We conducted a meta-analysis of individual case reports from 3 RA protocols and 5 OA protocols, encompassing 814 diclofenac-treated patients, 443 aspirin-treated patients, and 359 placebo-treated patients. All of the RA protocols had nearly identical inclusion and exclusion criteria, as well as safety studies and followup; the same was true for the OA protocols. Analysis included correlation analysis and multiple linear and logistic regression, accounting for numerous potential confounding variables, with the SGOT as the dependent variable. F tests were used for hypothesis testing. RESULTS: By several analytic approaches, the principal determinants of SGOT concentrations were found to be baseline SGOT value, the use of aspirin in RA patients, and the use of diclofenac in OA patients. Other significant factors contributing to an increase in SGOT concentrations were duration of therapy and, perhaps, daily dosage (mg/lb). Hypothesis testing supported these results. Given a statistically average patient, we predicted a 1-2% chance of a mildly elevated SGOT level occurring among placebo-treated patients, a 6-7% chance among diclofenac- or aspirin-treated patients with RA, a 12% chance among diclofenac-treated patients with OA, and a 2% chance among aspirin-treated patients with OA. CONCLUSION: This study demonstrates a powerful method for performing meta-analysis, using available individual patient data to examine numerous factors that may affect an outcome of interest. In this case, mild elevations of SGOT were examined and found to be related to baseline SGOT levels, diclofenac use (in OA), and aspirin use (in RA). Of numerous other potential factors examined, including age, sex, alcohol use, concomitant medications, and concomitant diagnoses, only duration of therapy and, to a small extent, daily dosage, were also consistent determinants of SGOT elevation. The SGOT elevations were minimal and were not related to the occurrence of clinical hepatitis: No clinical hepatitis occurred.

Arthritis, Rheumatoid↗

PubMed2004

Application of kinetic polymerase chain reaction and molecular beacon assays to pooled analyses and high-throughput genotyping for candidate genes.

BACKGROUND: The addition of DNA analysis to epidemiologic studies that have traditionally incorporated demographic and interview data can provide additional power and open new avenues for investigation. DNA can be obtained from a variety of tissues, but each has attendant variation in sample quantity, quality, and cost of acquisition. Analytic approaches for DNA genotyping are under constant development, but current applications allow small amounts (less than 2 ng per assay) of DNA to be used for genotyping. METHODS: In this report, we designed effective assays for a spectrum of genes using either kinetic polymerase chain reaction (PCR) or molecular beacon applications. We also investigated the extent to which DNA use and reagent cost could be minimized. Kinetic PCR assays were also applied to investigate the potential of pooled sample analysis. RESULTS: Our results show that small amounts of DNA can be successfully amplified in a high-throughput fashion using both kinetic PCR and molecular beacon methods. Greater than 97% of the genotype results from these two methods are consistent. In addition, error rates in allele frequency measurements using DNA pools of 100 or more samples were often less than 1% and usually less than 3%, which provides another option for substantially minimizing the costs of genotyping in studies involving large numbers of individuals. CONCLUSIONS: Effective assays have been designed for a spectrum of genes widely studied in birth defects, including: MTHFR, NAT1, TGFA, RFC1, PAX9, EPHX1, and SKI. An efficient assay has been designed for the detection of the presence of X and Y chromosomes, which can be applied to the studies of sex chromosome abnormalities or sample quality control.

Carrier Proteins↗

PubMed2005

Maternal diabetes and congenital anomalies in South Australia 1986-2000: a population-based cohort study.

BACKGROUND: This study examined the risk of congenital anomalies in infants born in South Australia to women with maternal diabetes in a population-based cohort study of births over a 15-year period, 1986-2000. Differences in the reporting, recording, and diagnosis of pre-existing diabetes mellitus, gestational diabetes mellitus, and impaired glucose tolerance make comparisons between studies difficult. In order to compare published research, details of research methods and analytic approaches are required to understand the potential confounding, bias, and effect modification that may occur. METHODS: Data on congenital anomalies from the South Australian Birth Defects Register were linked to birth data from the Pregnancy Outcome Statistics Unit of the South Australian Department of Health. This enabled information on congenital anomalies to be linked to pregnancy details, including diabetes status. RESULTS: Between 1986 and 2000, the prevalence of congenital anomalies in the infants of mothers with pre-existing diabetes mellitus, gestational diabetes mellitus, or impaired glucose tolerance was significantly higher than in the total population; relative risk = 2.01 (1.66-2.43) and 1.19 (1.08-1.31), respectively. This increased prevalence was not modified by adjustments for maternal age, ethnicity, or other demographic factors, nor did the rate change over the 15 years of the study period. CONCLUSIONS: The prevalence of congenital anomalies was found to be significantly higher in the infants of mothers with maternal diabetes. Larger population-based studies are needed to determine which anomalies are involved and how their occurrence can be reduced.

Chi-Square Distribution↗

PubMed2005

Analysis of seasonal variation of birth defects in Atlanta.

BACKGROUND: Compared with analyses of temporal trends, analyses of seasonal variations in the prevalence of birth defects have been more limited and have provided less consistent information. Possible reasons for this lack of consistency in findings include differences in populations, underlying factors, seasons or climates, and methods of ascertainment and analysis between studies. This study examines possible seasonal variation in the prevalence of selected birth defects in a defined study population using graphical displays and three statistical methods. METHODS: Cases were infants and fetal deaths in nine birth defect groups born to residents of mothers in five counties of metropolitan Atlanta during the period of 1978-2001 and ascertained by the Metropolitan Atlanta Congenital Defects Program. These birth defect groups were anencephaly, spina bifida, total neural tube defects, cleft palate, cleft lip with or without cleft palate, anomalies of the pulmonary valve, anomalies of the aortic valve, hypoplastic left heart syndrome, and congenital dislocation of the hip. We pooled monthly case counts and calculated monthly rates for each of these birth defect groups for five different birth periods: 1978-2001, 1978-1989, 1990-2001, 1990-1994, and 1995-2001. We applied the Cochran-Armitage test for trend to rule out homogeneity in pooled monthly rates. Data for each defect group were examined for possible seasonal (i.e., cyclical) variation overall and within the cited birth periods using the Hewitt-Rogerson test and the Walter-Elwood test. RESULTS: Graphical analyses of the pooled monthly rates showed no apparent seasonal patterns for any of the nine defect groups examined. Statistical tests for seasonality suggested possible seasonality for three defect groups: the Hewitt-Rogerson test was statistically significant for anencephaly (peak March-August, p = 0.048),while the Walter-Elwood test was significant for anomalies of the pulmonary valve (peak September, p = 0.02), and anomalies of the aortic valve (peak July, p = 0.039). With both methods, the results appeared to be influenced by the choice of time (i.e., birth) period. Results for anomalies of the pulmonary valve were statistically significant and more consistent with all tests in most of the time periods examined. CONCLUSIONS: Graphical analyses and basic statistical tests for seasonality showed no consistent evidence of seasonality for any of the nine defect groups examined, except for anomalies of the pulmonary valve. The two basic statistical methods coupled by a trend test for exploring seasonal patterns of the prevalence of birth defects can be useful for preliminary analyses of possible seasonal patterns. However, these methods have some limitations: (1) an assumption of no strong temporal trend over the study years, and (2) the results can vary by time period chosen. For specific hypotheses regarding seasonality, a more robust analytical approach such as time-series analysis might be more appropriate.

Anencephaly↗

PubMed2005

Hierarchical phylogenetics as a quantitative analytical framework for evolutionary developmental biology.

Phylogenetics has inherent utility in evolutionary developmental biology (EDB) as it is an established methodology for estimating evolutionary relationships and for making comparisons between levels of biological organization. However, explicit phylogenetic methods generally have been limited to two levels of organization in EDB-the species and the gene. We demonstrate that phylogenetic methods can be applied broadly to other organizational levels, such as morphological structures or cell types, to identify evolutionary patterns. We present examples at and between different hierarchical levels of organization to address questions central to EDB. We argue that this application of "hierarchical phylogenetics" can be a unifying analytical approach to the field of EDB.

Animals↗

PubMed2005

Analysis of flow in a cone-and-plate apparatus with respect to spatial and temporal effects on endothelial cells.

Endothelial cells, covering the inner surface of vessels and the heart, are permanently exposed to fluid flow, which affects the endothelial structure and the function. The response of endothelial cells to fluid shear stress is frequently investigated in cone-plate systems. For this type of device, we performed an analytical and numerical analysis of the steady, laminar, three-dimensional flow of a Newtonian fluid at low Reynolds numbers. Unsteady oscillating and pulsating flow was studied numerically by taking the geometry of a corresponding experimental setup into account. Our investigation provides detailed information with regard to shear-stress distribution at the plate as well as secondary flow. We show that: (i) there is a region on the plate where shear stress is almost constant and an analytical approach can be applied with high accuracy; (ii) detailed information about the flow in a real cone-plate device can only be obtained by numerical simulations; (iii) the pulsating flow is quasi-stationary; and (iv) there is a time lag on the order of 10(-3) s between cone rotation and shear stress generated on the plate.

Animals↗

PubMed2007

A comparison of direct infusion MS and GC-MS for metabolic footprinting of yeast mutants.

Recent technical advances in mass spectrometry (MS) have propelled this technology to the forefront of methods employed in metabolome analysis. Here, we compare two distinct analytical approaches based on MS for their potential in revealing specific metabolic footprints of yeast single-deletion mutants. Filtered fermentation broth samples were analyzed by GC-MS and direct infusion ESI-MS. The potential of both methods in producing specific and, therefore, discriminant metabolite profiles was evaluated using samples from several yeast deletion mutants grown in batch-culture conditions with glucose as the carbon source. The mutants evaluated were cat8, gln3, ino2, opi1, and nil1, all with deletion of genes involved in nutrient sensing and regulation. From the analysis, we found that both methods can be used to classify mutants, but the classification depends on which metabolites are measured. Thus, the GC-MS method is good for classification of mutants with altered nitrogen regulation as it primarily measures amino acids, whereas this method cannot classify mutants involved in regulation of phospholipids metabolism as well as the direct infusion MS (DI-MS) method. From the analysis, we find that it is possible to discriminate the mutants in both the exponential and stationary growth phase, but the data from the exponential growth phase provide more physiological relevant information. Based on the data, we identified metabolites that are primarily involved in discrimination of the different mutants, and hereby providing a link between high-throughput metabolome analysis, strain classification, and physiology.

Fermentation↗

PubMed2006

Propensity scores and the surgeon.

BACKGROUND: Evidence-based surgery has been established as a cornerstone of good clinical practice, promising to improve the treatment of patients and the quality of surgical education. However, evidence-based surgery requires dedicated clinicians trained to perform methodologically sound clinical investigations. Statistical knowledge is therefore invaluable. Surgical studies often cannot be randomized. Propensity scores offer a powerful alternative to multivariable analysis in the assessment of observational, non-randomized surgical studies. Unfortunately, many surgeons are unaware of this important analytical approach that has gained increasing stature in medical research. Thus, propensity score analyses are not used often in surgical studies. OBJECTIVE: The purpose of this paper is to provide a comprehensive overview of propensity score analysis, allowing the surgeon to understand the role, advantages and limitations of propensity scores, boosting their development in surgical investigations.

Confounding Factors, Epidemiologic↗

PubMed2002

Testing for nandrolone metabolites in urine samples of professional athletes and sedentary subjects by GC/MS/MS analysis.

The concentrations of nandrolone metabolites, 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) were analysed in urine samples of professional athletes doing intense physical activity and sedentary subjects to verify if there was endogenous production of nandrolone and if there was any link between physical effort and the urinary metabolites of the steroid. We collected 18 urine samples from professional footballers age range 20-30 years, all from the same team, and 18 urine samples from males not doing any physical activity, age range 20-30 years. Neither group used nandrolone. Qualitative and quantitative analyses of urinary nandrolone metabolites were carried out by GC/MS followed by GC/MS/MS to confirm positive samples. This technique has been demonstrated to be an excellent analytical approach for the determination of anabolic steroids at very low detection limits in complex matrices such as urine. In five urine samples from professional footballers traces of 19-NA were detected. No trace of 19-NA was found in the group of sedentary subjects and no trace of 19-NE was found in any urine sample. The absence of nandrolone metabolites in sedentary subjects supports the hypothesis that the presence of 19-NA and 19-NE could be linked to physical effort even though the origin is not yet clear.

Adult↗

PubMed1981

Quantitative profiling of the metabolic cascade of arachidonic acid by capillary gas chromatography mass spectrometry.

The analytical approach described allows for the rapid screening and concurrent quantitative determination of all of the major metabolites of the cyclooxygenase pathway of arachidonic acid, including the primary prostaglandins PGE2, PGD2 and PGF2 alpha in addition to the stable end-products of short-lived prostacyclin and thromboxane A2 (6-keto-PGF1 alpha and TXB2, respectively), generated by incubating arachidonic acid with mouse peritoneal macrophage cells. After derivatization into the corresponding methyl ester-methoxime-TMS derivative, the extracted endogenous compounds were analysed by combined high efficiency glass capillary column chromatography and selected ion monitoring. Comparatively lower detection limits can be achieved with the methyl ester-butylboronate-TMS derivatives (e.g. 10 pg for 6-keto-PGF1 alpha). A brief account is also presented on a new type of mixed methyl ester-pentafluorobenzyloxime-butylboronate-TMS derivative of TXB2 and 5-keto-PGF1 alpha.

Animals↗

PubMed1983

Application of mass spectrometry in the regulatory analysis of pesticides and industrial chemicals in food and feed commodities.

During regulatory analysis of pesticides and industrial chemicals, compounds are frequently encountered which cannot be readily identified by gas chromatography alone on two or more stationary phases. Such incurred unknown analytical responses are examined by gas chromatography mass spectrometry, particularly if they have been shown to contain P, S, N or halogen via specific gas chromatography detectors. Seven case histories are presented to illustrate the analytical approach adopted to structurally elucidate such compounds at the ppm level. These examples demonstrate the potential complementary combination provided by low resolution electron impact and chemical ionization mass spectrometry in structural determinations.

Animal Feed↗

PubMed1988

Rapid sample throughput for biomedical stable isotope tracer studies.

Typical 13C or 15N tracer studies generate large numbers of samples. Instrumentation capable of rapid automated analysis is therefore of importance as a practical alternative to conventional isotope methodology. Although biomedical sample nature is diverse, experimenters often require analysis of substrates and products of particular biochemical pathways. Clearly, reaction products can contain considerably less isotope tracer than precursors. Analytical techniques thus need to accommodate samples of widely varying nature, size and isotope enrichment. In the clinical field, where stable isotopes are increasingly used to study protein, carbohydrate and fat metabolism, analysis of the isotope ratio of a substrate infused into the plasma and a product of its metabolism is often required. Conventional analytical approaches demand access to two mass spectrometers: isotope ratio mass spectrometry (IRMS) for isotope analysis of the relatively large concentrations of low-enrichment metabolic product, and gas chromatography/mass spectrometry (GC/MS) for analysis of the infused substrate often present at high enrichment but low concentration offers a practical alternative to the conventional approaches that is rapid and automatic. In addition to providing a considerably less complex and costly alternative to conventional instrumentation, a single CF-IRMS instrument can also analyse small quantities of low-enrichment metabolites with superior performance than either of the alternative approaches. CF-IRMS is illustrated using results from constant-infusion studies in human protein and fat metabolism which require measurement of the isotope enrichment in submicromolar quantities of plasma substrates together with analysis of larger quantities of their oxidation products, urinary nitrogen and breath CO2.

Ammonia↗

PubMed1992

Utility of the parent-neutral loss scan screening technique: partial characterization of urinary metabolites of U-78875 in monkey urine.

Metabolites of an antianxiety-sedative drug candidate (U-78875; 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)-imidazo[1 ,5-alpha] quinoxalin-4(5H)-one (I)) present in the urine of monkeys were detected using tandem mass spectrometry (MS/MS) by application of parent ion scans and characterized or partially characterized by performing daughter ion scans of the pseudo-molecular ions of suspected metabolites. The use of liquid secondary ion mass spectrometry ionization of crude urinary extracts in combination with tandem quadrupole MS/MS analyses using parent ion scans of m/z 69 and subsequent daughter ion scans characterized unmetabolized I and N-dealkyl I (U-85466) and partially characterized aryl hydroxyl, aryl hydroxyl-N-dealkyl, aryl O-glucuronide, aryl O-glucuronide-N-dealkyl, aryl O-sulfate and aryl O-sulfate-N-dealkyl metabolites. From these data it was concluded that some of the metabolic pathways involved in the biotransformation of U-78875 include N-dealkylation, aryl hydroxylation and conjugation of aryl hydroxides. Several other metabolites of U-78875 not detected using this analytical approach were subsequently identified by alternative mass spectrometric approaches. These data clearly demonstrated both the utility and, just as important, the limitations of the parent-neutral loss scan screening technique in detecting drug metabolites in complex biological milieux.

Animals↗

PubMed1994

Automated gas chromatography/tandem mass spectrometry assay for tebufelone and a 13C,(18)O-labeled analog in plasma: applicabilityto absolute bioavailability determination.

An automated capillary gas chromatography/tandem mass spectrometry (GC/MS/MS) assay for the simultaneous quantitation of tebufelone (TE) and 13C, (18)O-labeled TE (TE-CO) in plasma was developed. This method permits the use of stable isotope coadministration (TE and TE-CO dosed concurrently via peroral and intravenous routes, respectively) for the determination of TE absolute bioavailability. The selectivity of MS/MS conducted on a triple-quadrupole instrument allowed minimal sample preparation and rapid analysis. Electron ionization produced molecular ions (M+) for TE, TE-CO, and the 3-methyl-TE internal standard which were selected in Q1 to undergo collisionally activated dissociation in Q2. Quantitation was achieved through monitoring product ions at m/z 248, 251 and 248, respectively, in Q3. A 2-1000 ng per sample (40 pg to 20 ng injected) quantitation range provided access to an effective 1-5000 p.p.b. plasma concentration range (0.2-2 g samples) for both TE and TE-CO. The assay showed no bias and less than 8% relative standard deviation over the entire range. The method was used to determine plasma levels of TE and TE-CO in four dogs receiving 2.5:2.5 mg/kg TE:TE-CO, intravenously. The pharmacokinetics of both isotopomers proved to be identical, indicating no isotope effect and verifying the chemical stability of the (18)O-carbonyl label under these dosing conditions. In addition, the applicability of this analytical approach to the determination of TE peroral bioavailability was initially tested in dogs.

Alkynes↗

PubMed1987

Three-dimensional architecture of dendritic trees in type-identified alpha-motoneurons.

We have studied the spatial distribution of dendrites of type-identified triceps surae alpha-motoneurons, labeled intracellularly with HRP, using a variety of analytical approaches that were designed to quantify the ways in which dendrites occupy three-dimensional space. All of the methods indicated a strong tendency for motoneuron dendrites to project radially. However, regions dorsal and ventral to the somata contained fewer dendritic elements, and less membrane area, than expected for complete radial symmetry. Individual dendrites projecting into these regions tended to be smaller than those projecting rostrocaudally or mediolaterally. Nevertheless, the center of mass of membrane area for five of six fully analyzed cells was within 100 micron of the soma and, in all six cells, was located in the same dorsoventral plane as the cell soma. Maps of the projection of dendritic branches onto concentric shells at various radial distances from the soma showed that some regions have high concentrations of branches, sometimes with considerable overlap between branches arising from different stem dendrites, while other regions have relatively few branches, or none at all. Each motoneuron exhibited a different pattern of projection and there were no systematic differences between fast-twitch (type F, including both types FF and FR units) and slow-twitch (type S) motoneurons evident in the patterns of dendritic concentration. Assessment of the three-dimensional territories of individual dendrites showed that dendrites with larger numbers of terminal branches tended to have larger spatial territories. Despite considerable scatter, the results suggest that the density of branches tends to be approximately the same in large and small dendrites, and in F and S cell groups. The results are discussed in relation to the spatial location of synaptic input to motoneurons.

Animals↗

PubMed2006

Regional cerebral brain metabolism correlates of neuroticism and extraversion.

Factor-analytic approaches to human personality have consistently identified several core personality traits, such as Extraversion/Introversion, Neuroticism, Agreeableness, Consciousness, and Openness. There is an increasing recognition that certain personality traits may render individuals vulnerable to psychiatric disorders, including anxiety disorders and depression. Our purpose in this study was to explore correlates between the personality dimensions neuroticism and extraversion as assessed by the NEO Five-Factor Inventory (NEO-FFI) and resting regional cerebral glucose metabolism (rCMRglu) in healthy control subjects. Based on the anxiety and depression literatures, we predicted correlations with a network of brain structures, including ventral and medial prefrontal cortex (encompassing anterior cingulate cortex and orbitofrontal cortex), insular cortex, anterior temporal pole, ventral striatum, and the amygdala. Twenty healthy women completed an (18F)FDG (18F-fluorodeoxyglucose) positron emission tomography (PET) scan at rest and the NEO-FFI inventory. We investigated correlations between scores on NEO-FFI Neuroticism and Extraversion and rCMRglu using statistical parametric mapping (SPM99). Within a priori search territories, we found significant negative correlations between Neuroticism and rCMRglu in the insular cortex and positive correlations between Extraversion and rCMRglu in the orbitofrontal cortex. No significant correlations were found involving anterior cingulate, amygdala, or ventral striatum. Neuroticism and Extraversion are associated with activity in insular cortex and orbitofrontal cortex, respectively.

Adult↗

PubMedDate not supplied

Diabetes and mass spectrometry.

Mass spectrometry (MS) has been successfully employed to investigate non-enzymatic protein glycation, a process relevant in diabetic disease. The high sensitivity and specificity of this technique allowed the development of methods that can individuate and evaluate some glycation markers to be validly employed in monitoring diabetes. More recent mass spectrometric techniques, such as the matrix-assisted laser desorption/ionization (MALDI), are able to determine the molecular weight of intact proteins. They were first employed in studying the in vitro reaction between hexoses and different proteins. Once the validity of the results obtained by this analytical approach was confirmed, a series of investigations on plasma proteins were undertaken in healthy and diabetic subjects. The method led to the evaluation of the number of glucose molecules condensed on the protein being studied, and consequently can be validly used for an accurate follow-up of metabolic control in diabetic patients. When applied to studies on haemoglobin glycation, the method showed that both alpha- and beta-globins are glycated to a similar extent and that the simply glycated molecules are accompanied by glyco-oxidized species therefore giving information on the oxidative stress experimented on in the subject. Furthermore, in the case of immunoglobulins, MALDI/MS was able to determine not only the total glycation level of IgG, but also to establish that the fragment antigen binding (Fab) moiety is the most glycated one, thus suggesting that the possible immunological impairment sometimes invoked in diabetes is related to the inhibition of the process of molecular recognition between antibody and antigen.

Globins↗

PubMed1990

Combination of two-dimensional gel electrophoresis with microsequencing and amino acid composition analysis: improvement of speed and sensitivity in protein characterization.

High-resolution two-dimensional polyacrylamide electrophoresis (2-DE) is commonly used as an analytical approach to resolve and detect most of the numerous protein species of an organism. However, the isolation of microgram amounts of protein in a 2-DE spot in a form suitable for microsequence analysis and amino acid composition analysis is a key step in the chemical characterization of these proteins. With the development of chemically inert membranes it is now possible to retain proteins present in low quantities from the polyacrylamide matrix with high yields. The immobilized proteins are suitable for direct sequence analysis and amino acid composition analysis. The combination of protein chemical and electrophoretic techniques makes it possible to obtain chemical information from subpicomole quantities of protein, resulting in the availability of a new set of biologically important proteins for structural analysis. This paper summarizes the methods and strategies for the chemical protein analysis of 2-DE spots in our laboratory.

Amino Acid Sequence↗