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At least 199 records · Page 11Linked to original sources

PubMed1999

Prenatal origin of acute lymphoblastic leukaemia in children.

BACKGROUND: There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally. METHODS: We identified, by reverse-transcriptase PCR screening of blood or bone marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AML1 fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AML1 genomic fusion sequences in neonatal blood spots from each child. FINDINGS: We initially identified TEL-AML1 fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AML1 sequence that suggested prenatal origin in one twin. Three children were excluded because control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative. INTERPRETATION: Our findings showed that childhood acute lymphoblastic leukaemia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also required.

Burkitt Lymphoma↗

PubMed2004

Development and validation of enzyme-linked immunosorbent assays for quantification of anti-methotrexate IgG and Fab in mouse and rat plasma.

This laboratory is investigating the use of anti-methotrexate IgG (AMI) and anti-methotrexate Fab fragments (AMF) within an inverse targeting strategy that is designed to enhance the pharmacokinetic selectivity of intraperitoneal (i.p.) chemotherapy. The goal of this study was to develop enzyme-linked immunosorbent assays (ELISAs) to determine concentrations of AMI and AMF in mouse and rat plasma. An antigen-specific ELISA was developed for AMI and AMF in mouse and rat plasma. The assay was validated with respect to precision and accuracy by evaluating the recovery of AMI and AMF from mouse and rat plasma samples. Preliminary pharmacokinetic studies of AMI and AMF were performed in Sprague-Dawley rats and Swiss Webster mice. The animals were instrumented with a jugular vein cannula and administered AMI or AMF, 15 mg kg(-1) via the cannula. Plasma samples were taken at various time points and analyzed using the ELISA, and the observed concentration vs. time profiles were subjected to non-compartmental pharmacokinetic analyses. Standard curves for the ELISAs were found to be linear over concentration ranges of 0-250 and 0-350 ng mL(-1) for AMI and AMF, respectively. Intra-assay and inter-assay recovery of AMI and AMF from plasma samples were found to be within 15% of theoretical values. Preliminary pharmacokinetic investigations of AMI allowed estimation of AMI clearance to be 0.017 mL kg(-1) min(-1) in the rat and 0.043 mL kg(-1) min(-1) in the mouse. AMF clearance was estimated to be 0.038 and 1.93 mL kg(-1) min(-1) in the mouse and rat, respectively. In conclusion, ELISAs have been developed and validated for quantitation of AMI and AMF in rat and mouse plasma. The assays will allow further investigations of AMI and AMF pharmacokinetics.

Animals↗

PubMed1986

Single dose pharmacokinetics of 5 formulations of lithium: a controlled comparison in healthy subjects.

The single dose pharmacokinetics of 4 lithium preparations (Camcolit-400, Priadel, Liskonum, Litarex) and a new micro-encapsulated formulation were compared in normal volunteers using a balanced cross-over design. The data show an inverse relationship between rate of release and bioavailability. The pharmacokinetic characteristics of Camcolit-400 and Priadel were similar; both showed earlier and greater peak serum concentrations than the other 3. The new formulation, which accounted for most of the significant variance, had the slowest rate of release and the lowest bioavailability. Statistical analysis showed significant differences between the 5 preparations for C-max, T-max, 12-h serum levels, AUC and urinary excretion, but not for the 24-h serum levels. No serious untoward side-effects were noted.

Adult↗

PubMed2001

Polymorphisms flanking the mariner integration sites in the rice gall midge (Orseolia oryzae Wood-Mason) genome are biotype-specific.

In an effort to study genome diversity within and between the Indian biotypes of the Asian rice gall midge, Orseolia oryzae, a major insect pest of rice, we made use of mariner transposable element integration site polymorphisms. Using degenerate primers, the design of which is based on mariner sequences, we amplified a ca. 450 bp mariner sequence from the rice gall midge. The mariner sequence showed homology with that of a mariner element isolated from the Hessian fly, Mayetiola destructor, a major dipteran pest of wheat. Southern hybridization, using this mariner fragment as a probe, revealed that the mariner elements are moderately to highly repetitive in the rice gall midge genome. Based on the sequence information of this 450-bp PCR-amplified fragment, outward-directed primers were designed and used in an inverse PCR (iPCR) to amplify the DNA flanking the conserved regions. To study the regions flanking the mariner integration sites, we employed a novel PCR-based approach: a combination of sequence specific amplification polymorphism (SSAP) and amplified fragment length polymorphism (AFLP). The outward-directed mariner-specific primer was used in combination with adapter-specific primers with 1-3 selective nucleotides at their 3' ends. The amplification products were resolved on an agarose gel, Southern-transferred onto nylon membranes, and probed with the iPCR fragment. Results revealed biotype-specific polymorphisms in the regions flanking the mariner integration sites, suggesting that mariner elements in the rice gall midge may be fixed in a biotype-specific manner. The implications of these results are discussed in the context of biotype differentiation.

Amino Acid Sequence↗

PubMed1998

Nucleotide sequence of the gene encoding the precursor protein of pepstatin insensitive acid protease B, scytalidopepsin B, from Scytalidium lignicolum.

A chromosomal DNA of Scytalidium lignicolum was digested with Sau3AI. The digest was self-ligated and amplified by inverse PCR procedure using primers designed based on the nucleotide sequences of up- and down-stream regions of an intron present in the scytalidopepsin B gene. Analysis of the nucleotide sequence of PCR product (700 bp) showed that the enzyme is synthesized as a precursor protein consisting of the prepro- and mature enzyme regions. The deduced amino acid sequence was highly similar to those of aspergillopepsin A and recently reported endothiapepsins B and C, but quite different from those of pepstatin-insensitive bacterial acid proteases and the pepstatin-sensitive aspartic protease family.

Amino Acid Sequence↗

PubMed2003

Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway.

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.

Adenoma↗

PubMed2006

Education and diabetes in a racially and ethnically diverse population.

OBJECTIVES: We used data from the National Health Interview Survey (1997-2002) to examine the association between education and the prevalence of diabetes in US adults and whether this relation differs by race/ethnicity. METHODS: The analyses were limited to non-Hispanic Blacks, non-Hispanic Whites, and Hispanics. SUDAAN was used to account for the complex sampling design. RESULTS: Educational attainment was inversely associated with the prevalence of diabetes. Individuals with less than a high-school diploma were 1.6 (95% confidence interval [CI]=1.4, 1.8) times more likely to have diabetes than those with at least a bachelor's degree. Whites and Hispanics exhibited a significant relation between diabetes and having less than a high-school education (odds ratio [OR]=1.7; 95% CI=1.5, 2.0; and OR=1.6; 95% CI=1.1, 2.3, respectively). In addition, the odds of having diabetes was stronger for women (OR=1.9; 95% CI=1.6, 2.4) than for men (OR=1.4; 95% CI=1.1, 1.6) CONCLUSIONS: Educational attainment was inversely associated with diabetes prevalence among Whites, Hispanics, and women but not among Blacks. Education may have a different effect on diabetes health among different racial/ethnic groups.

Adult↗

PubMed2005

[Construction of a trans-splicing ribozyme for restoring EGFP truncation mutation].

Special designed group I intron ribozymes can specifically splice objective RNA, repair the mutant gene in RNA level. The specificity of ribozyme is determined by nucleotides specific internal guide sequence (IGS) introduced to the enzyme. In this study, fragment sequence containing Tetrahymena thermophilia intron I of 26S rRNA gene was cloned and cis-splicing activity of this ribozyme was confirmed by in vitro transcription. For evaluating the trans-splicing activity of this ribozyme, a truncated mutant Green Fluorescence Protein (GFP) vector, XYQ5/XYQ10- pEGFP-C2, was constructed. This vector deleted the 3' end 564bp fragment of EGFP coding sequence, led to the lost the activity of emitting green fluorescence. Trans-splicing ribozyme plasmids ptrans-rib-CMV2 for remedy of the truncated mutant EGFP was constructed by PCR and molecular cloning techniques. This vector utilizing cloned 26S rRNA intron 1 as core enzyme; selecting T-G site at 194bp of EGFP coding sequence as splicing receptor, designed an IGS which is inversely complement to the 188-193nt of EGFP mRNA; the 195-890bp fragment of EGFP coding sequence was ligated to the 3'-end of ribozyme core. The fragment containing these components was inserted to a eukayotic expression vector pRC-CMV2. Using linearized XYQ5/XYQ10- pEGFP-C2 and ptrans-rib-CMV2 as templates, truncated EGFP mRNA and the constructed ribozyme vector were transcribed and mixed to evaluate the trans-splicing activity. Analysis of in vitro transcription products mix by RT-PCR verified the existence of wild type EGFP mRNA molecule. Co-transfection of XYQ5/XYQ10- pEGFP-C2 with ptrans-rib-CMV2 to Hela cells proved this ribozyme restored green fluorescence within cell, but the efficiency was low.

Animals↗

PubMed2001

Inverse adaptive cluster sampling.

Consider a population in which the variable of interest tends to be at or near zero for many of the population units but a subgroup exhibits values distinctly different from zero. Such a population can be described as rare in the sense that the proportion of elements having nonzero values is very small. Obtaining an estimate of a population parameter such as the mean or total that is nonzero is difficult under classical fixed sample-size designs since there is a reasonable probability that a fixed sample size will yield all zeroes. We consider inverse sampling designs that use stopping rules based on the number of rare units observed in the sample. We look at two stopping rules in detail and derive unbiased estimators of the population total. The estimators do not rely on knowing what proportion of the population exhibit the rare trait but instead use an estimated value. Hence, the estimators are similar to those developed for poststratification sampling designs. We also incorporate adaptive cluster sampling into the sampling design to allow for the case where the rare elements tend to cluster within the population in some manner. The formulas for the variances of the estimators do not allow direct analytic comparison of the efficiency of the various designs and stopping rules, so we provide the results of a small simulation study to obtain some insight into the differences among the stopping rules and sampling approaches. The results indicate that a modified stopping rule that incorporates an adaptive sampling component and utilizes an initial random sample of fixed size is the best in the sense of having the smallest variance.

Animals↗

PubMed1993

Recombinant chromosome 9 possibly derived from breakage and reunion of sister chromatids within a paracentric inversion loop.

Chromosomally unbalanced offspring resulting from the recombination of parental paracentric inversions are uncommon. We report on a 20-month-old boy with a partial duplication of 9p due to the recombination of a paternal paracentric inversion. The patient's recombinant chromosome was designated rec(9)(p13-->p24::p12-->p24::p12-->qter). The patient's father and paternal aunt have a paracentric inversion of chromosome 9:inv(9)(p13p24). Although several mechanisms have been proposed to explain the chromosome imbalance generated from paracentric inversions, none of the previously described mechanisms can account for the structure of the recombinant chromosome observed in the propositus. We propose an unusual mechanism of formation involving breakage and unequal reunion of sister chromatids within the inversion loop to explain the structure of the patient's recombinant chromosome.

Abnormalities, Multiple↗

PubMed2003

Broadband sound propagation in shallow water and geoacoustic inversion.

Part of an experiment to test a measurement package in a shallow water region in the Gulf of Mexico was designed to gather broadband acoustic data suitable for inversion to estimate seabed geoacoustic parameters. Continuous wave tow acoustic signals at multiple frequencies and broadband impulsive source signals were recorded on a horizontal line array in a high-noise environment. Simulated annealing with a normal mode forward propagation model is utilized to invert for a geoacoustic representation of the seabed. Several inversions are made from different data samples of two light bulb implosions, the measured sound speed profiles at the HLA and at the positions of the light bulb deployments, and for two different cost functions. The different cost functions, measured sound speed profiles, and measured time series result in different inverted geoacoustic profiles from which transmission loss is generated for comparison with measurements. On the basis of physical consistency and from the comparison of the transmission loss and time series, a best estimate geoacoustic profile is selected and compared to those obtained from previously reported inversions. Uncertainties in the sound speed profile are shown to affect the uncertainties of the estimated seabed parameters.

Journal Article↗

PubMed1992

The effects of symmetrical recombination site hixC on Hin recombinase function.

An artificial recombination site hixC composed of two identical half-sites that bind the Hin recombinase served as a better operator in vivo than the wild type site hixL (Hughes, K. T., Youderian, P., and Simon, M. I (1988) Genes & Dev. 2, 937-948). In vitro binding assays such as gel retardation assay and methylation protection assay demonstrated that Hin binds to hixC as tightly as it binds to hixL, even when the sites are located in negatively supercoiled plasmids. However, hixC served as a poor recombination site when it was subjected to the standard inversion assay in vitro. hixC showed a 16-fold slower inversion rate than the wild type. A series of biochemical assays designed to probe different stages of the Hin-mediated inversion reaction, demonstrated that Hin dimers bound to hixC have difficulty in forming paired hix site intermediates. KMnO4 and S1 nuclease assays detected an anomalous structure of the center of hixC only when the site was in negatively supercoiled plasmids. Mutational analysis in the central region of hixC and assays of paired hix site formation with topoisomers of the hixC substrate plasmid suggested that Hin is not able to pair hixC sites because of the presence of the anomalous structure in the center of the site. The structure does not behave like a DNA "cruciform" since Hin dimers still bind efficiently to the site. It is thought to consist of a short denatured "bubble" encompassing 2 base pairs. During the study of mutations in the center of hixC, it was found that Hin is not able to cleave DNA if a guanine residue is one of the two central nucleotides close to the cleavage site. Furthermore, Hin acts in a concerted fashion and cannot cleave any DNA strand if one of the four strands in the inversion intermediate is not cleavable.

Base Sequence↗

PubMed2006

Planning and analyzing adaptive group sequential survival trials.

The use of adaptive methods has experienced increasing interest in the current literature on group sequential designs. Group sequential analysis in survival trials usually apply the error spending function approach due to the unpredictable amount of information available in an interim analysis. An alternative way is to apply adaptive methods where additionally the maximum amount of information and other designing parameters can be changed based on the information available at the interim stage. In this paper, it is shown how the inverse normal method can be used within a survival design using the log-rank test for comparing two survival functions. This method allows for many kinds of design modifications. In case of no modifications, the inverse normal method coincides with the commonly used analysis strategy. It is straightforward to specify effect estimates. Confidence intervals for the hazard ratio that can be calculated at each stage of the trial and intervals that can only be computed by the end of the trial are proposed. The latter also enables the calculation of median unbiased estimates. Overall p-values can be defined analogously. Properties of the analyses techniques are investigated and compared with alternative approaches. It is shown that the proposed analysis technique might help to rescue an underpowered study and opens the way to other types of changes in design. The proposed technique is implemented in the software ADDPLAN Adaptive Design, Plans and Analyses (http://www.addplan.com).

Biometry↗

PubMed2005

Monitoring event times in early phase clinical trials: some practical issues.

BACKGROUND: In many early phase clinical trials it is scientifically inappropriate or logistically infeasible to characterize patient outcome as a binary variable. In such settings, it often is more natural to construct early stopping rules based on time-to-event variables. This type of design may involve a variety of complications, however. PURPOSE: The purpose of this paper is to illustrate by example how one may deal with various complications that may arise when monitoring time-to-event outcomes in an early phase clinical trial. METHODS: We present a series of Bayesian designs for a phase II clinical trial in kidney cancer. Each design includes a procedure for monitoring the times to a severe adverse event, disease progression and death. The first design, which is the simplest, is based on the time to failure, defined as any of the three events, assuming exponentially distributed failure times with an inverse gamma prior on the mean. This design is compared by simulation to the CMAP design (Cheung and Thall, Biometrics, 2002; 58: 89-97). The model and monitoring procedure are then extended successively to accommodate several common practical complications, and we also study the method's robustness. RESULTS: Our simulations show that 1) one may apply the monitoring rule periodically, rather than continuously, without a substantive degradation of the design's reliability; 2) it is very important to account for interval censoring due to periodic evaluation of disease status; 3) it is important to account for the effect of disease progression on the subsequent death rate; 4) conducting a randomized trial presents little additional difficulty and provides unbiased comparisons; and 5) the exponential-inverse gamma model is surprisingly robust in most cases. LIMITATIONS: The methods discussed here do not account for patient heterogeneity. This is an important but complex issue that may be dealt with by extending the models and methods given here to accommodate patient covariates and treatment-covariate interaction. CONCLUSIONS: Bayesian procedures for monitoring time-to-event outcomes offer a practical way to conduct a variety of early phase trials. Considerable care must be given, however, to modeling the important aspects of the trial at hand, and to calibrating the prior and the design parameters to ensure that the design will have good operating characteristics.

Bayes Theorem↗

PubMed2002

Continuity and development in the acquisition of inversion in yes/no questions: dissociating movement and inflection.

This paper examines two- to five-year-old children's knowledge of inversion in English yes/no questions through a new experimental study. It challenges the view that the syntax for inversion develops slowly in child English and tests the hypothesis that grammatical competence for inversion is present from the earliest testable ages of the child's sentence production. The experimental design is based on the premise that a valid test of this hypothesis must dissociate from inversion various language-specific aspects of English grammar, including its inflectional system. An elicited imitation method was used to test parallel, lexically-matched declarative and question structures across several different verb types in a design which dissociated subject-auxiliary inversion from the English-specific realization of the inflectional/auxiliary system. Using this design, the results showed no significant difference in amount or type of children's errors between declarative (non-inverted) and question (inverted) sentences with modals or auxiliary be, but a significant difference for sentences with main verbs (requiring reconstruction of inflection through do-support) and copula be. The results from sentences with auxiliary be and those with modals indicate that knowledge of inversion is present throughout our very young sample and does not develop during this time. We argue that these results indicate that the grammar of inversion is present from the youngest ages tested. Our results also provide evidence of development relevant to the English-specific inflectional system. We conclude with a new developmental hypothesis: development in question formation occurs in integrating language-specific knowledge related to inflection with the principles of Universal Grammar which allow grammatical inversion.

Child Language↗

PubMedDate not supplied

DNA triple-helix formation at pyrimidine-purine inversion sites.

A systematic investigation of a series of triplex forming oligonucleotides (TFOs) containing alpha-, and beta-thymidine, alpha- and beta-N7-hypoxanthine, and alpha- and beta-N7 and N9 aminopurine nucleosides, designed to bind to T-A inversion sites in DNA target sequences was performed. Data obtained from gel mobility assays indicate that T-A recognition in the antiparallel triple-helical binding motif is possible if the nucleoside alpha N9-aminopurine is used opposite to the inversion site in the TFO.

Adenine↗

PubMed2004

Lateral ankle sprain: isokinetic test reliability and comparison between invertors and evertors.

OBJECTIVE: Evaluate reliability of isokinetic tests for inversion and eversion in individuals with recurrent lateral ankle sprain and compare inversion to eversion muscle performance in the same ankles. DESIGN: Reliability was evaluated by comparing the results of two ankle inversion/eversion isokinetic tests. Inversion and eversion were compared with the results presented by the tests. BACKGROUND: Previous studies showed reliable isokinetic tests for ankles with no sprain history. It is unknown if such tests can also be performed in lateral sprained ankles. It is unclear whether there is difference between invertors and evertors in these ankles. METHODS: Eleven men with recurrent ankle lateral sprain in one limb were tested using an isokinetic dynamometer. The tests consisted of 5 cycles of maximal contraction in 30 degrees /s and 120 degrees /s. Both injured and noninjured ankles were tested. Peak torque was recorded for analysis. RESULTS: The tests are reliable and intraclass coefficient correlation varied from 0.71 to 0.95. Invertors generated higher peak torques than evertors (P = 0.03) when injured ankles were tested at 120 degrees /s. CONCLUSIONS: Isokinetic inversion/eversion tests showed to be reliable. A decrease in peak torques can be seen during higher velocity tests. The only difference between invertors and evertors was seen when injured ankles were tested at 120 degrees /s. In this case invertors showed higher peak torques.

Adolescent↗

PubMed1997

The native sequence determines sidechain packing in a protein, but does optimal sidechain packing determine the native sequence?

Globular proteins have highly compact structures and the corresponding packing interactions are widely considered as the principal determinant of the native structure. It is therefore important that theoretical approaches to protein design explicitly take in account packing, which requires that a full atomic representation of the designed protein is maintained. As a first step towards this goal, we have developed in this report an inverse folding algorithm with the aim of specifically designing amino acid sequences which optimise sidechain packing for a given protein fold. The design is performed by a global Monte Carlo optimisation in sequence space, with constant amino acid composition and a full-atom representation of the various protein models. Packing is defined by a Lennard-Jones potential. The program was tested by designing stable sequence variants for the chymotrypsin inhibitor fold. The final protein models showed an increase in intramolecular atomic contacts and a decrease in the overall volume compared to the native structure. Starting from the backbone only of the target structure, the algorithm did gradually retrieve reliable though limited sequence information. Higher compatibility might be achieved by improving the potential, however our results suggest that packing interactions are an essential element of a yet-to-be-defined successful energy function for protein design.

Algorithms↗