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Results for “double robustness”

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At least 73 records · Page 4Linked to original sources
PubMed1999

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS: Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the study's end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS: In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.

Adult↗
PubMed2000

Laser Ray Tracing versus Hartmann-Shack sensor for measuring optical aberrations in the human eye.

A comparison and validation study of Laser Ray Tracing (LRT) and Hartmann-Shack wave-front-sensor (to be referred to as H-S) methods was carried out on both artificial and human eyes. The aim of this work was double. First, we wanted to verify experimentally the equivalence of single- and double-pass measurements for both H-S and LRT. This interest is due to the impossibility of making single-pass measurements in human eyes. In addition, we wanted to validate the LRT technique by comparing it with the H-S wave-front sensor, currently used in many physiological optics laboratories. Comparison of the different methods and configurations carried out in the artificial eye yielded basically the same results in all cases, which means a reciprocal validation of both LRT and H-S, in either single- or double-pass configurations. Other aspects, such as robustness against speckle noise or the influence of the size of the entrance (H-S) or exit (LRT) pupil were studied as well. As a global reference, the point-spread function (PSF) of the artificial eye was recorded directly on a CCD camera and compared with simulated PSF's computed from the experimental aberration data. We also applied these two methods to real eyes (double pass), finding again a close match between the resulting aberration coefficients and also between the standard errors for two normal subjects. However, for one myopic eye with an especially low optical quality (RMS wave-front error >2 microm) and asymmetric aberrations, the array of spots recorded with the H-S sensor was highly distorted and too difficult to analyze.

Adult↗
PubMed2006

The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses.

The IgE-facilitated allergen binding (IgE-FAB) assay represents an in vitro model of facilitated allergen presentation. Allergen-IgE complexes are incubated with an EBV-transformed B cell line and complexes bound to CD23 on the surface of cells are detected by flow cytometry. The addition of serum from patients who have received allergen-specific immunotherapy has been shown previously to inhibit allergen-IgE complex binding to CD23 on B cells. In this study, we describe the characterisation and analytical validation of the grass pollen-specific IgE-FAB assay according to guidelines from the International Conference on Harmonisation. We established the intra- and inter-assay variability of IgE-FAB and have defined the detection limits of this assay. We have also demonstrated assay linearity and robustness. Using the results from a randomised double-blind placebo-controlled trial of grass pollen immunotherapy (n=33), we have defined the clinical sensitivity and specificity of the IgE-FAB assay using ROC curve analysis. In conclusion, the IgE-FAB assay is reproducible, robust, sensitive and a specific method suitable as a tool for monitoring inhibitory antibody function from patients receiving allergen immunotherapy.

Allergens↗
PubMed2006

Long-term prevention of diabetes and marked suppression of insulin autoantibodies and insulitis in mice lacking native insulin B9-23 sequence.

We analyzed double native insulin gene knockout NOD mice with a mutated (B16:alanine) proinsulin transgene at multiple ages for the development of insulin autoantibodies, insulitis, and diabetes. In contrast to mice with at least one copy of a native insulin gene that expressed insulin antibodies, only 2 out of 21 (10%) double native insulin gene knockout mice with a mutated insulin transgene developed insulin autoantibodies. Of 21 double insulin knockout mice sacrificed between 10 to 48 weeks of age, only 5 showed minimal insulitis versus 100% of wild-type NOD and more than 90% of insulin 1 knockout mice. Consistent with robust suppression of insulin autoantibodies and insulitis, no double insulin knockout mice developed diabetes. In that the B9-23 peptide with B16A is an altered peptide ligand inducing Th2 responses, we analyzed transfer of splenocytes into NOD.SCID mice. There was no evidence for regulatory T cells able to inhibit transfer of diabetes by diabetogenic NOD splenocytes. Insulin peptide B9-23 is likely a crucial target for initiation of islet autoimmunity and further mutation of the sequence will be tested to attempt to eliminate all anti-islet autoimmunity.

Alanine↗
PubMed2004

Treatment of cervical dystonia with botulinum toxin.

Cervical dystonia (CD) is the most common form of dystonia encountered in a movement disorders clinic. The treatment of this focal dystonia has improved markedly with the advent on botulinum toxin (BTX) injections, which has now become the treatment of choice. Initial studies, even double-blind controlled trials, failed to show robust effect, largely as a result of poor design, often using fixed dosage and site of administration. When the BTX treatment is customized to the needs of the individual patients and the most involved muscles are targeted, the effects can be quite dramatic and the improvement usually lasts 3 to 4 months. Experience and improved skills can largely prevent the adverse effects such as dysphagia and neck weakness. Although there is no evidence that BTX slows the progression of the disease, as a result of early intervention with BTX, many of the long-term complications of CD, such as contractures and radiculopathy, have been largely eliminated.

Anti-Dyskinesia Agents↗
PubMed2005

Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection.

Human rhinovirus (HRV) infections trigger exacerbations of asthma and chronic obstructive pulmonary disease (COPD) and are associated with lymphocytic infiltration of the airways. We demonstrate that infection of primary cultures of human airway epithelial cells, or of the BEAS-2B human bronchial epithelial cell line, with human rhinovirus type 16 (HRV-16) induces expression of CXCL10 [IFN-gamma-inducible protein 10 (IP-10)], a ligand for the CXCR3 receptor found on activated type 1 T lymphocytes and natural killer cells. IP-10 mRNA reached maximal levels 24 h after HRV-16 infection then declined, whereas protein levels peaked 48 h after infection with no subsequent new synthesis. Cytosolic levels of AU-rich factor 1, a protein associated with mRNA destabilization, increased beginning 24 h after HRV-16 infection. Generation of IP-10 required virus capable of replication but was not dependent on prior induction of type 1 interferons. Transfection of synthetic double-stranded RNA into epithelial cells induced robust production of IP-10, whereas transfection of single-stranded RNA had no effect. Induction of IP-10 gene expression by HRV-16 depended upon activation of NF-kappaB, as well as other transcription factor recognition sequences further upstream in the IP-10 promoter. In vivo infection of human volunteers with HRV-16 strikingly increased IP-10 protein in nasal lavages during symptomatic colds. Levels of IP-10 correlated with symptom severity, viral titer, and numbers of lymphocytes in airway secretions. Thus IP-10 may play a role in the pathogenesis of HRV-induced colds and in HRV-induced exacerbations of COPD and asthma.

Asthma↗
PubMed1994

The topography of visual evoked response properties across the visual field.

Visual evoked potentials (VEPs) to luminance and pattern reversal stimulation were derived for a large number of small areas throughout the central visual field. In one study, the field was tested with a stimulus array consisting of 64 equal-area patches. Local response components were extracted by independent m-sequence modulation of the patches. Field topographies were compared between and within subjects using different electrode placements. The subject-dependent local variability observed in response characteristics is attributed to contributions from two or more cortical representations of the visual field and to inter-subject variations in gross cortical anatomy. The second study used luminance modulation of 56 patches across a 15 degrees field, scaled to activate approximately equal cortical areas in area V1. This produced many robust signals at all eccentricities. Bipolar and double differential ("1-dimensional Laplacian") signals were compared. The double differencing reduced contributions from distant or distributed sources, enhancing nearby current source activity, and greatly improved S/N for many stimulus locations. The high-resolution visual field maps demonstrated that clinical field testing using the VEP is not feasible because of effects of cortical convolutions on responses. However, the vast improvement in data quality and quantity make it a useful tool for VEP source localization and identification.

Brain↗
PubMed2004

Transient and reversible deoxyribonucleic acid damage in human left ventricle under controlled ischemia and reperfusion.

OBJECTIVES: We sought to describe the sequence of molecular events during ischemia and reperfusion of the human heart and to determine the activation of stress kinases and deoxyribonucleic acid (DNA) damage response elements on apoptosis in ischemia or reperfusion of the human heart. BACKGROUND: Brief ischemia is tolerated by cardiac myocytes, but it determines immediate metabolic changes and block of contraction. Prompt restoration of coronary blood flow is inexorably associated with a slow recovery of myocardial contractile function. The prolonged, postischemic contractile dysfunction in the viable tissue is called myocardial stunning. The molecular mechanisms underlying myocardial stunning and ischemia-reperfusion injury are still poorly understood. Their elucidation would be valuable in order to identify novel therapeutic strategies. METHODS: We examined human left ventricular samples taken from 20 patients undergoing elective valve surgery before aortic cross-clamping, 20 +/- 2 min (brief ischemia), 58 +/- 5 min after the cross-clamping period (prolonged ischemia), and 21 +/- 4 min after reconstitution of coronary blood flow (reperfusion). Stress kinases and DNA damage sensor proteins (ATM, H2AX, p53) were determined by immunoblotting with specific antibodies. Electron microscopy analysis was carried out on ischemic and reperfused samples. ATP content, reactive oxygen species (ROS) levels, and cytochrome oxidase activity were determined by biochemical assays. RESULTS: Ischemia caused accumulation of ROS, reduction of cytochrome C oxidase and ATP, and activation of stress kinases p38 and Jun terminal kinase. Electron microscopy showed significant mitochondrial swelling in the majority of cells, but no appreciable apoptosis of cardiomyocytes. During ischemia, myocytes were intensely stained by TUNEL, and many cells showed proliferative cell nuclear antigen-positive nuclei. Finally, we found in ischemic tissues increased p53/p21(WAF) levels and phosphorylation of histone H2AX, a substrate of ATM kinase, which marks double-strand DNA breaks. Reperfusion caused a robust extracellular signal-regulated kinase-1/2 activation, a marked reduction of TUNEL staining, and persistent activation of ATM checkpoint. CONCLUSIONS: These data indicate that ischemia induces extensive DNA damage and activation of ATM checkpoint. Reperfusion allows the repair of the DNA lesions and salvage of ischemic cells.

Adenosine Triphosphate↗
PubMed2006

Carcinogen-induced DNA double strand break repair in sporadic breast cancer.

BACKGROUND: Induction of DNA double strand breaks and alterations in the repair of these breaks is implicated in breast carcinogenesis. Prior studies have demonstrated that peripheral blood mononuclear cells (PBMC) from breast cancer patients exhibit increased numbers of DNA strand breaks after exposure to ionizing radiation, but these studies did not specifically measure DNA double strand breaks and it is not known whether chemical carcinogens produce similar effects. MATERIALS AND METHODS: PBMC from 32 women undergoing breast surgery were genotyped at nine loci of seven DNA repair genes. DNA double strand break repair was measured using the neutral comet assay after exposure to ionizing radiation (0.5 Gy) or bioactivated benzo[a]pyrene (B[a]P, 5 microM. RESULTS: PBMC from breast cancer patients showed higher levels of residual DNA double strand breaks 30 min after exposure to radiation than PBMC from patients with benign breast disease (1.40 times baseline [95% confidence intervals [CI] 1.29-1.51] versus 1.24 times baseline [95% CI 1.15-1.33], respectively, P = 0.04). The response to B[a]P trended in the same direction, but did not reach statistical significance. The MGMT K178R variant genotype was associated with improved DNA double strand break repair in PBMC exposed to B[a]P. CONCLUSIONS: Reduced repair of radiation-induced DNA double strand breaks in PBMC is a robust biomarker of breast cancer risk. Reduced DNA repair capacity may have a genetic component even in sporadic breast cancer.

BRCA2 Protein↗
PubMed2006

Continuing controversy over monitoring men with localized prostate cancer: a systematic review of programs in the prostate specific antigen era.

PURPOSE: There is continuing controversy over the most appropriate treatment for screen detected and clinically localized prostate cancer, and increasing interest in monitoring such men initially with radical treatment targeted at cancers showing signs of progressive potential but while they are still curable. Current evidence on monitoring protocols and biomarkers used to predict disease progression was systematically reviewed. MATERIALS AND METHODS: The MEDLINE and Excerpta Medica (EMBASE) bibliographic databases were searched from 1988 to October 2004, supplemented by manual searches of reference lists, focusing on studies reporting monitoring of men with localized prostate cancer. RESULTS: A total of 48 potentially eligible articles were found but only 5 studies, in which there was a total of 451 participants, restricted entry criteria to men with clinically localized (T1-T2) prostate cancer. Monitoring protocols varied with little consensus, although the majority used prostate specific antigen and digital rectal examination, while some added re-biopsy to assess progression. Actuarial probabilities of freedom from disease progression at 4 to 5 years of followup were 67% to 72%. However, up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to increasing prostate specific antigen rather than objective evidence of disease progression. There was no robust evidence to support prostate specific antigen doubling times or velocity to identify men in whom disease may progress. Studies were characterized by small sample size, short-term followup, observer bias and uncertain validity around variable definitions of progression. CONCLUSIONS: Current evidence suggests that some form of monitoring would be a suitable treatment option in men with localized prostate cancer but there is little consensus over what markers should be used in such a program or how progression should be properly defined. The search for a method that safely identifies men with prostate cancer who could avoid radical intervention must continue.

Disease Progression↗
PubMed2002

Does the proportion of associatively related pairs modulate the associative priming effect at very brief stimulus-onset asynchronies?

A number of experiments have shown that the magnitude of the associative priming effect increases substantially when there is a high proportion of associatively related pairs in the list when the stimulus-onset asynchrony (SOA) between prime and target is long (more than 400 ms). In the present series of experiments we manipulated the proportion of associatively related pairs when the SOA was very brief (less than 200 ms). If processing of a target word is facilitated automatically by the prior presentation of a related prime, the occurrence of priming should be unaffected by the proportion of related pairs in the list. Experiment 1 showed a robust relatedness proportion effect obtained in a double lexical decision task. Experiments 2-4 used the masked priming technique at several very short SOAs (66, 116, and 166 ms) in lexical decision and naming. The results showed a reliable associative priming effect in the two tasks, which did not differ as a function of the proportion of related pairs. Finally, Experiment 5 used unmasked primes at an 83-ms SOA in which the primes remained in view after the target presentation. As in Experiments 2-4, the associative effect was not modulated by the proportion of associatively related pairs. The implications of these results are discussed.

Adult↗
PubMed2005

Corollary discharge and spatial updating: when the brain is split, is space still unified?

How does the brain keep track of salient locations in the visual world when the eyes move? In parietal, frontal and extrastriate cortex, and in the superior colliculus, neurons update or 'remap' stimulus representations in conjunction with eye movements. This updating reflects a transfer of visual information, from neurons that encode a salient location before the saccade, to neurons that encode the location after the saccade. Copies of the oculomotor command - corollary discharge signals - must initiate this transfer. We investigated the circuitry that supports spacial updating in the primate brain. Our central hypothesis was that the forebrain commissures provide the primary route for remapping spatial locations across visual hemifields, from one cortical hemisphere to the other. Further, we hypothesized that these commissures provide the primary route for communicating corollary discharge signals from one hemisphere to the other. We tested these hypotheses using the double-step task and subsequent physiological recording in two split-brain monkeys. In the double-step task, monkeys made sequential saccades to two briefly presented targets, T1 and T2. In the visual version of the task, the representation of T2 was updated either within the same hemifield ("visual-within"), or across hemifields ("visual-across"). In the motor version, updating of the visual stimulus was always within-hemifield. The corollary discharge signal that initiated the updating, however, was generated either within the same hemisphere ("motor-within") or in the opposite hemisphere ("motor-across"). We expected that, in the absence of the forebrain commissures, both visual-across and motor-across conditions would be impaired relative to their "within" controls. In behavioral experiments, we observed striking initial impairments in the monkeys' ability to update stimuli across visual hemifields. Surprisingly, however, both animals were ultimately capable of performing the visual-across sequences of the double-step task. In subsequent physiological experiments, we found that neurons in lateral intraparietal cortex (LIP) can remap stimuli across visual hemifields, albeit with a reduction in the strength of remapping activity. These behavioral and neural findings indicate that the transfer of visual information is compromised, but by no means abolished, in the absence of the forebrain commissures. We found minimal evidence of impairment of the motor-across condition. Both monkeys readily performed the motor-across sequences of the double-step task, and LIP neurons were robustly active when within-hemifield updating was initiated by a saccade into the opposite hemifield. These results indicate that corollary discharge signals are available bilaterally. Altogether, our findings show that both visual and corollary discharge signals from opposite hemispheres can converge to update spatial representations in the absence of the forebrain commissures. These investigations provide new evidence that a unified and stable representation of visual space is supported by a redundant circuit, comprised of cortical as well as subcortical pathways, with a remarkable capacity for reorganization.

Animals↗
PubMed2001

Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro.

Human pluripotent stem cells (hPSCs) have been derived from the inner cell mass cells of blastocysts (embryonic stem cells) and primordial germ cells of the developing gonadal ridge (embryonic germ cells). Like their mouse counterparts, hPSCs can be maintained in culture in an undifferentiated state and, upon differentiation, generate a wide variety of cell types. Embryoid body (EB) formation is a requisite step in the process of in vitro differentiation of these stem cells and has been used to derive neurons and glia, vascular endothelium, hematopoietic cells, cardiomyocytes, and glucose-responsive insulin-producing cells from mouse PSCs. EBs generated from human embryonic germ cell cultures have also been found to contain a wide variety of cell types, including neural cells, vascular endothelium, muscle cells, and endodermal derivatives. Here, we report the isolation and culture of cells from human EBs as well as a characterization of their gene expression during growth in several different culture environments. These heterogeneous cell cultures are capable of robust and long-term [>70 population doublings (PD)] proliferation in culture, have normal karyotypes, and can be cryopreserved, clonally isolated, and stably transfected. Cell cultures and clonal lines retain a broad pattern of gene expression including simultaneous expression of markers normally associated with cells of neural, vascular/hematopoietic, muscle, and endoderm lineages. The growth and expression characteristics of these EB-derived cells suggest that they are relatively uncommitted precursor or progenitor cells. EB-derived cells may be suited to studies of human cell differentiation and may play a role in future transplantation therapies.

Animals↗
PubMed2000

Quasiperiodicity and transition to chaos

In coupled Lorenz systems, we find that the three-frequency quasiperiodcity exists in the finite parameter range robustly. We also find the period-doubling bifurcation of the torus and the quasiperiodic windows in superchaos. Based on the separation of the dynamics, corresponding explanations are given by making use of the synchronous dynamics.

Journal Article↗
PubMed2003

The TIME FOR COFFEE gene maintains the amplitude and timing of Arabidopsis circadian clocks.

Plants synchronize developmental and metabolic processes with the earth's 24-h rotation through the integration of circadian rhythms and responses to light. We characterize the time for coffee (tic) mutant that disrupts circadian gating, photoperiodism, and multiple circadian rhythms, with differential effects among rhythms. TIC is distinct in physiological functions and genetic map position from other rhythm mutants and their homologous loci. Detailed rhythm analysis shows that the chlorophyll a/b-binding protein gene expression rhythm requires TIC function in the mid to late subjective night, when human activity may require coffee, in contrast to the function of EARLY-FLOWERING3 (ELF3) in the late day to early night. tic mutants misexpress genes that are thought to be critical for circadian timing, consistent with our functional analysis. Thus, we identify TIC as a regulator of the clock gene circuit. In contrast to tic and elf3 single mutants, tic elf3 double mutants are completely arrhythmic. Even the robust circadian clock of plants cannot function with defects at two different phases.

Arabidopsis↗
PubMed2005

Synthetic lethal analysis of Caenorhabditis elegans posterior embryonic patterning genes identifies conserved genetic interactions.

Phenotypic robustness is evidenced when single-gene mutations do not result in an obvious phenotype. It has been suggested that such phenotypic stability results from 'buffering' activities of homologous genes as well as non-homologous genes acting in parallel pathways. One approach to characterizing mechanisms of phenotypic robustness is to identify genetic interactions, specifically, double mutants where buffering is compromised. To identify interactions among genes implicated in posterior patterning of the Caenorhabditis elegans embryo, we measured synthetic lethality following RNA interference of 22 genes in 15 mutant strains. A pair of homologous T-box transcription factors (tbx-8 and tbx-9) is found to interact in both C. elegans and C. briggsae, indicating that their compensatory function is conserved. Furthermore, a muscle module is defined by transitive interactions between the MyoD homolog hlh-1, another basic helix-loop-helix transcription factor, hnd-1, and the MADS-box transcription factor unc-120. Genetic interactions within a homologous set of genes involved in vertebrate myogenesis indicate broad conservation of the muscle module and suggest that other genetic modules identified in C. elegans will be conserved.

Animals↗
PubMed2006

Laser cooling of trapped ytterbium ions with an ultraviolet diode laser.

We demonstrate an ultraviolet diode laser system for cooling of trapped ytterbium ions. The laser power and linewidth are comparable to those of previous systems based on resonant frequency doubling, but the system is simpler, more robust, and less expensive. We use the laser system to cool small numbers of ytterbium ions confined in a linear Paul trap. From the observed spectra, we deduce final temperatures of < 270 mK.

Journal Article↗
PubMed2002

Three-step priming in lexical decision.

In two experiments, we investigated mediated two-step priming (e.g., from LION to STRIPES via TIGER) and three-step priming (e.g., from MANE to STRIPES via LION and TIGER). Experiment 1 showed robust two-step priming in the double lexical decision task. In Experiment 2, we tested for three-step priming and investigated the possibility that it is not association strength based on free association, but frequency of co-occurrence, that causes three-step priming. Co-occurrence has been proposed as a measure of familiarity and semantic relatedness. Significant three-step priming was obtained. Lexical co-occurrence could not account for the effect. However, a more global measure of semantic similarity that includes the similarity of the contexts in which concepts occur revealed that the three-step pairs were semantically related. If this global measure provides a proper estimate of the semantic relatedness of our items, then three-step priming is consistent not only with spreading activation models, but also with distributed memory models and the compound cue model.

Decision Making↗