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PubMed2005

The psychological outcome of constitutional delay of growth and puberty.

Does being of short stature (SS) matter? Growth studies are important because endocrinologists need to be able to give not only diagnostic but also prognostic indication to those of SS, and give advice for or against treatment. Studies on body height may give significant insight into the behavioural-hypothalamic-pituitary axis underlying the surface effect on social behaviour. This research presents adult follow-up studies of 49 males who attended at a growth clinic as children and who were diagnosed as having the condition of maturational delay short stature (MDSS). From the psychological perspective, the elements of diagnosis and prognosis, attitudinal influences both social and individual, treatment, and psychological issues which could have bearing on SS are drawn together. Where there is a poor psychosocial outcome finding, the MDSS patients seem to be more like those with growth hormone (GH) deficiency. With GH deficiency (GHD), a poor psychosocial outcome of SS has been demonstrated with greater certainty. The current situation is that there remains divergence between previous SS outcome studies. Differing research SS psychosocial outcomes are analysed and a methodological explanation of past divergent outcomes is presented, being: (1) differences in sensitivity between psychological assessment tools; (2) Invalidation by confounding the psychological with sociological outcomes, and (3) confounding of results by failure to control for psychological states. An innovative new approach of changing the methodology of past SS research from the biological to the psychological perspective is employed: previous SS research has appointed height status as the independent variable, with psychosocial outcome as the dependent variable. The innovative approach in this research is to reverse that order and psychological status has been made the independent variable for both the MDSS and for a predetermined psychologically and physically healthy (PPH) comparison group of males. The results of the follow-up studies in this research indicate that there is an association between psychological distress and attained height which supports other studies where the findings indicate a poor psychological outcome associated with SS. It can therefore be concluded that the psychological status of children should be determined when they attend a growth clinic with concerns of SS.

Adult↗

PubMed1986

Deferred consent. A new approach for resuscitation research on comatose patients.

Methodological constraints inherent in the rapidly growing field of resuscitation research have created an apparent conflict with newly promulgated federal regulations, especially those concerning informed consent requirements. We propose that two new concepts be applied to resuscitation research to satisfy the current federal regulations governing biomedical research. The first of these concepts is "minimal differential risk," ie, in resuscitation medicine, the difference between the risk of an undesirable outcome when standard, commonly accepted therapy may be used and the risk of an undesirable outcome with experimental therapy is minimal. The second concept is "deferred consent," ie, obtaining consent to continue with an experimental therapy after administration of that therapy has already begun. We believe that the emergency exception to informed consent applies to resuscitation research. Recognition of the applicability of these concepts to resuscitation research should allow compliance with federal and state regulations that otherwise might inhibit or preclude such research endeavors.

Brain Diseases↗

PubMed2002

Assessment of cognitive load in multimedia learning using dual-task methodology.

In two pilot experiments, a new approach for the direct assessment of cognitive load during multimedia learning was tested that uses dual-task methodology. Using this approach, we obtained the same pattern of cognitive load as predicted by cognitive load theory when applied to multimedia learning: The audiovisual presentation of text-based and picture-based learning materials induced less cognitive load than the visual-only presentation of the same material. The findings confirm the utility of dual-task methodology as a promising approach for the assessment of cognitive load induced by complex multimedia learning systems.

Adult↗

PubMed2001

Optimizing analytical methods using sequential response surface methodology. Application to the pararosaniline determination of formaldehyde.

Sequential response surface methodology is a general procedure to re-optimize common analytical methods on the basis of the application of the response surface methodology and of a new approach to the steepest ascent method. This procedure, which is easy to apply, consists of estimating an analytical function relating the response with the experimental parameters by means of a second-degree polynomial. Thus, a 2nd order design covering the total experimental domain is used and when a maximum is obtained, the characteristics of the response surface are confirmed using a new design, which is obtained contracting the first one. In the proposed methodology, Box-Behnken designs are used because they offer advantages in comparison with second order designs more frequently used in the steepest ascent method (central composite designs), i.e. fewer experiments are needed, they are more efficient, they can be moved through the experimental domain and they can even be easily contracted or expanded.

Journal Article↗

PubMed2003

Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity.

The identification and characterization of genes that influence the risk of common, complex multifactorial diseases, primarily through interactions with other genes and other environmental factors, remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions with other genes and environmental exposures. We previously introduced multifactor dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus genotype information to improve the identification of polymorphism combinations associated with disease risk. The MDR approach is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., assumes no particular inheritance model), and is directly applicable to case-control and discordant sib-pair study designs. Both empirical and theoretical studies suggest that MDR has excellent power for identifying high-order gene-gene interactions. However, the power of MDR for identifying gene-gene interactions in the presence of common sources of noise is not currently known. The goal of this study was to evaluate the power of MDR for identifying gene-gene interactions in the presence of noise due to genotyping error, missing data, phenocopy, and genetic or locus heterogeneity. Using simulated data, we show that MDR has high power to identify gene-gene interactions in the presence of 5% genotyping error, 5% missing data, or a combination of both. However, MDR has reduced power for some models in the presence of 50% phenocopy, and very limited power in the presence of 50% genetic heterogeneity. Extending MDR to address genetic heterogeneity should be a priority for the continued methodological development of this new approach.

Algorithms↗

PubMed1992

Iron and oxygen radicals in brain.

The brain has been shown to contain regions with high concentrations of non-heme iron, and some of this iron can be chelated, which suggests that it is in a low molecular mass form. The chelatable iron appears to be responsible for the in vitro peroxidation of homogenized brain tissue lipids. It has been suggested that low molecular mass iron is essential for normal brain functions, and that iron is present in the reduced ferrous state. Recent studies have shown that chelatable iron is often present in micromolar concentrations in apparently normal cerebrospinal fluids (CSF), and that this iron is often increased in certain neurological diseases. Using a molecular recognition assay, based on the in vitro degradation of DNA by bleomycin and chelated ferrous ions, it has been possible to conclude that the low molecular mass iron present in CSF is also in the reduced ferrous state. Ferrous ions are able to transfer electrons to molecular oxygen to form reactive and damaging intermediates of oxygen, some of which are free radicals. Increased levels of iron in brain tissue or CSF, however, are not necessarily synonymous with increased activation of oxygen. Detailed studies of brain iron deposits in neurological diseases are long overdue, and require new and pioneering methodologies to approach the problem.

Animals↗

PubMed1991

Contextual analysis and intermediate cell markers enhance high-resolution cell image analysis for automated cervical smear diagnosis.

Until now, efforts to automate cervical smear diagnosis have focused on analyzing features of individual cells. In a complex specimen such as that obtained from a cervical scrape, diagnostically significant cells may not be adequately represented or may elude detection by the automated technology. An approach is needed that extracts additional quantitative information from cervical smears beyond what the cell-by-cell approach can provide. A new methodology, contextual analysis, was developed to extract global quantitative information about cells, cell clusters, and background debris. This pilot study was designed to compare the efficacy of contextual analysis with high-resolution, single cell analysis and the analysis of intermediate cell markers. Thirty-four samples prepared as monolayers and stained with the Feulgen-Thionin/Congo Red stain were measured. Contextual analysis alone was able to classify 91% of the smears correctly; single cell analysis classified 94% of the cells correctly; and the intermediate cell analysis correctly identified the smear diagnosis for 84% of the cells. When all three analysis methods were combined into a simple smear level classifier, the overall smear classification accuracy was improved over those obtained using the three methodologies alone.

Biomarkers↗

PubMed1993

Activation of an apomorphine behavior pattern by cocaine: a new behavioral test for drug substitution.

In current tests for drug substitution using the 2-choice operant bar press paradigm, an animal can be trained to respond differentially between an interoceptive drug state stimulus vs. saline. Despite the long history and extensive number of investigations, the interpretation of such test results, nevertheless, is limited by number of potential sources of stimulus drug effects which can occur with repeated drug administration but which cannot be distinguished by this paradigm: (1) local effects at the injection site; (2) peripheral effects; (3) central activity effects; and/or (4) sensory-motor dysfunctional effects. By using a video-image analysis of behavior in an intact animal model and a pavlovian drug treatment protocol, new, spontaneous but environmentally contingent and stable behavior patterns emerge selectively in the paired treatment group with repeated drug administration which can be used as a behavioral marker to assess dose-response effects and drug substitution test results with a novel drug. A study with repeated administration of the DA agonist apomorphine and with a drug substitution assessment by a cocaine drug test is presented as a reference example to illustrate the new response-based methodological approach to the study of central mechanisms mediating the stimulus and response effects of drugs. Additionally, the observed efficacy of cocaine to activate a complex acquired behavioral pattern unique to repeated apomorphine treatment supports a critical role for dopaminergic mechanisms in the mediation of cocaine induced stereotypy.

Animals↗

PubMed2005

Nano-probing of the membrane dynamics of rat pheochromocytoma by near-field optics.

High-resolution analysis of activities of live cells is limited by the use of non-invasive methods. Apparatuses such as SEM, STM or AFM are not practicable because the necessary treatment or the harsh contact with system probe will disturb or destroy the cell. Optical methods are purely non-invasive, but they are usually diffraction limited and then their resolution is limited to approximately 1 microm. To overcome these restrictions, we introduce here the study of membrane activity of a live cell sample using a Scanning Near-field Optical Microscope (SNOM). A near field optical microscope is able to detect tiny vertical movement on the cell membrane in the range of only 1 nm or less, about 3 orders of magnitude better than conventional optical microscopes. It is a purely non-invasive, non-contact method, so the natural life activity of the sample is unperturbed. In this report, we demonstrated the nanometer-level resolving ability of our SNOM system analyzing cardiomyocytes samples of which membrane movement is known, and then we present new intriguing data of sharp 40 nm cell membrane sudden events on rat pheochromocytoma cell line PC12. All the measurements are carried out in culture medium with alive and unperturbed samples. We believe that this methodology will open a new approach to investigate live samples. The extreme sensitivity of SNOM allows measurements that are not possible with any other method on live biomaterial paving the way for a broad range of novel studies and applications.

Animals↗

PubMed1989

Immunologic and pharmacologic concepts of monoclonal antibodies.

While monoclonal antibodies have solved many of the difficulties of using immunologic reagents for radioimmunodiagnosis and therapy, in the 13 years since their introduction a number of persistent problems remain, most notably a low yield of antibody-producing cells from the fusion process, difficulty in obtaining high-affinity antibodies, and the potential immunogenicity of murine immunoglobulins (Igs). Several solutions are under development, including fusion techniques that enrich for cells producing desired antibodies, production of human-mouse chimeric antibodies by recombinant DNA technology, and the generation of human monoclonal antibodies by promising new approaches. Until these upcoming methodologies are established, and to better direct their development and application, a sound understanding of the pharmacology of presently available native and modified monoclonal antibodies is crucial. Although much has been already determined in this area, a great deal of further clarification remains necessary.

Animals↗

PubMed2001

Single-channel recordings of recombinant inositol trisphosphate receptors in mammalian nuclear envelope.

Inositol 1,4,5-trisphosphate (InsP(3)) receptors (InsP(3)Rs) are intracellular Ca(2+) channels gated by the second messenger InsP(3). Here we describe a novel approach for recording single-channel currents through recombinant InsP(3)Rs in mammalian cells that applies patch-clamp electrophysiology to nuclei isolated from COS-7 cells transiently transfected with the neuronal (SII(+)) and peripheral (SII(-)) alternatively-spliced variants of the rat type 1 InsP(3)R. Single channels that were activated by InsP(3) and inhibited by heparin were observed in 45% of patches from nuclei prepared from transfected cells overexpressing recombinant InsP(3)Rs. In contrast, nuclei from cells transfected with the vector alone had InsP(3)-dependent channel activity in only 1.5% of patches. With K(+) (140 mM) as the permeant ion, recombinant SII(+) and SII(-) channels had slope conductances of 370 pS and 390 pS, respectively. The recombinant channels were 4-fold more selective for Ca(2+) over K(+), and their open probabilities were biphasically regulated by cytoplasmic [Ca(2+)]. This approach provides a powerful new methodology to study the permeation and gating properties of recombinant mammalian InsP(3)Rs in a native mammalian membrane environment at the single-channel level.

Alternative Splicing↗

PubMed2000

The use of deuterium-labeled cortisol for in vivo evaluation of renal 11beta-HSD activity in man: urinary excretion of cortisol, cortisone and their A-ring reduced metabolites.

This study describes a new approach using stable isotope methodology in evaluating 11beta-HSD activities in vivo based on urinary excretion of cortisol, cortisone, and their A-ring reduced metabolites. The method involved the measurement of deuterium-labeled cortisol and its deuterium-labeled metabolites by GC/MS simultaneously with endogenous cortisol, cortisone, and their A-ring reduced metabolites after oral administration of deuterium-labeled cortisol to normal human subjects. This stable isotope approach offered unique advantages in assessing the appropriateness of measuring unconjugated and total (unconjugated + conjugated) cortisol, cortisone, and their A-ring reduced metabolites in urine as indices of renal 11beta-HSD2 activity in man. Our results strongly support that the measurement of urinary unconjugated cortisol and cortisone is a significant advance in assessing 11beta-HSD2 activity.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1978

A radioimmuno-chromatographic scanning method for the analysis of testosterone conjugates in urine and serum.

A method for the analysis of testosterone (and 5alpha-dihydrotestosterone) conjugates in human serum and urine samples is described. The samples were grought to pH 1 and extracted with a diethyl ether-methanol mixture. After evaporation the residues were run in a thin-layer chromatography system, individual samples' paths were cut into 1-cm long pieces and eluted with methanol. The methanol was evaporated and the residue subjected to acid hydrolysis. The released steroid was extracted by diethyl ether and measured by radioimmunoassay. The methodology described represents a new approach to the qualitative and quantitative study of steroid conjugates in serum and urine, and can easily be applied to the study of steroid conjugates in other biological mateiral.

Chromatography, Thin Layer↗

PubMedDate not supplied

2',5'-Oligoadenylate:antisense chimeras--synthesis and properties.

We have synthesized a novel bioconjugate which joins an antisense oligonucleotide to a unique and potent inhibitor of translation,pn5'A2'(p5'A2')mp5'A(2-5A). Two residues of 4-hydroxybutyl phosphate were employed as linkers to attach the 2',5'-oligoadenylate moiety through its 2'-terminus to the 5'-terminus of the chosen antisense sequence, (dT)20. The syntheses were carried on a solid support according to the phosphite triester method of DNA synthesis (Letsinger, R.L., Lunsford, W.B. (1976) J. Am. Chem. Soc. 98, 3655-3661; Beaucage, S.L., and Caruthers, M.H. (1981) Tetrahedron Lett. 22, 1859-1862). The generated 2-5A antisense chimeras retained both the ability of the 2-5A molecule to activate the 2-5A-dependent RNase as well as the ability of the oligo(dT) moiety to hybridize to the complementary poly(A). Moreover, the chimera, when annealed to its target nucleic acid sequence, was still effectively bound to the 2-5A-dependent nuclease. The methodology described represents a new approach to the selective modulation of mRNA expression.

Adenine Nucleotides↗

PubMed2000

Synthesis of 2,3-dihydroisoxazoles from propargylic N-hydroxylamines via Zn(II)-catalyzed ring-closure reaction

A novel cyclization reaction of propargylic N-hydroxylamines to 2,3, 5-trisubstituted 2,3-dihydroisoxazoles in the presence of catalytic amounts (10 mol %) of ZnI(2) and DMAP is reported. The methodology provides a mild new approach to this useful class of substituted heterocycles that complements extant methods. The unique reactivity of the propargylic N-hydroxylamine substrates in the presence of Zn(II) and DMAP may have additional applications in other, related alkyne cyclization reactions.

Journal Article↗

PubMed1998

Malignant glioma: should chemotherapy be overthrown by experimental treatments?

Despite more than two decades of clinical research with chemotherapy, the outcome of malignant gliomas remains poor. Recent years have seen major advances in elucidation of the biology of these tumors, which in turn have led to the current development of innovative therapeutic strategies. The question confronting us at the end of the 1990s is whether we should continue to use and investigate chemotherapy or whether the time has come for experimental treatments. As a contribution to this debate, we reviewed the abundant literature on chemotherapy of malignant glioma, paying special attention to methodological features. The new treatment approaches based on current knowledge about glioma biology are then briefly summarized. Assessment of more than 20 years of chemotherapy trials is discouraging despite a few areas of modest success. Only patients with specific histology (oligodendroglioma, anaplastic astrocytoma) and good prognostic factors (young age, good performance status) may benefit from chemotherapy, with a possible reversal of neurological dysfunction. However, the real impact on survival is small (anaplastic astrocytoma) or undefined (oligodendroglioma). Furthermore, it is unfortunately obvious that the outcome of glioblastoma patients is not significantly modified by chemotherapy. We believe the time has come to explore the potential of novel biological therapies in glioblastoma patients. This could also be proposed for anaplastic astrocytoma and oligodendroglioma patients after failure of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Blood pressure analysis.

Arterial blood pressure is influenced by sleep-related breathing disorders. As cardiovascular consequences can be diagnosed by an accurate recording and analysis of blood pressure, new recording methodologies and an approach to analysis are presented here. Invasive continuous blood pressure recording is the common reference for all methodologies. As blood pressure varies rapidly in parallel with sleep-related breathing disorders it is indispensible to record blood pressure continuously. To introduce non-invasive methodology the Finapres system was used during sleep studies; a validation study showed severe limitations. This study was followed by the validation of an improved system called Portapres, which is portable, has two finger cuffs and a hydrostatic height compensation. Analysis of continuous blood pressure in patients with sleep apnoea is carried out to detect mechanisms which influence the cardiovascular risk. Spectrum analysis of systolic blood pressure showed two different major oscillations present in patients with obstructive sleep apnoea. One oscillation (<0.06 Hz) occurs in parallel with each apnoeic episode and the other oscillation (0.2-0.4 Hz) occurs in parallel with the obstructive efforts during each apnoea and in parallel with respiration during periods of snoring. These two oscillations were so specific that the use of non-invasive continuous blood pressure recording allowed an estimation of the extent of underlying breathing disorders, and assessment of cardiovascular risk in a patient with obstructive apnoea in terms of hypertension and on the basis of ambulatory monitoring.

Journal Article↗

PubMed1992

Preliminary results on speaker-dependent variation in the TIMIT database.

A set of phonetic studies based on analysis of the TIMIT speech database is presented. Using a database methodological approach, these studies detail new results in speaker-dependent variation due to sex and dialect region of the talker including effects on stop release frequency, speaking rate, vowel reduction, flapping, and the use of glottal stop. TIMIT was found to be fertile ground for gathering acoustic-phonetic knowledge having relevance to the phonetic classification and recognition goals for which TIMIT was designed, as well as to the linguist attempting to describe regularity and variability in the pronunciation of read English speech.

Databases, Factual↗