Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “double robustness”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2004

Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice.

Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M(1) and M(3) mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M(1) and M(3) receptor single-knockout (KO) mice and newly generated M(1)/M(3) receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M(1) and M(3) receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M(1) and M(3) receptor single-KO mice, indicating that the presence of either M(1) or M(3) receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M(1) or M(3) mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M(1)/M(3) receptor double-KO mice. However, salivary glands from M(1)/M(3) receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M(1) and M(3) receptors mediates cholinergic stimulation of salivary flow.

Animals↗
PubMed2005

Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment.

OBJECTIVE: Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B. PARTICIPANTS: 288 susceptible, healthy volunteers (ages 18-45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials. INTERVENTIONS: For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100-800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50-800 mg/day. OUTCOMES: The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery. RESULTS: In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected. CONCLUSION: Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.

Acids, Carbocyclic↗
PubMed2006

RNA interference for antiviral therapy.

Silencing gene expression through a process known as RNA interference (RNAi) has been known in the plant world for many years. In recent years, knowledge of the prevalence of RNAi and the mechanism of gene silencing through RNAi has started to unfold. It is now believed that RNAi serves in part as an innate response against invading viral pathogens and, indeed, counter silencing mechanisms aimed at neutralizing RNAi have been found in various viral pathogens. During the past few years, it has been demonstrated that RNAi, induced by specifically designed double-stranded RNA (dsRNA) molecules, can silence gene expression of human viral pathogens both in acute and chronic viral infections. Furthermore, it is now apparent that in in vitro and in some in vivo models, the prospects for this technology in developing therapeutic applications are robust. However, many key questions and obstacles in the translation of RNAi into a potential therapeutic platform still remain, including the specificity and longevity of the silencing effect, and, most importantly, the delivery of the dsRNA that induces the system. It is expected that for the specific examples in which the delivery issue could be circumvented or resolved, RNAi may hold promise for the development of gene-specific therapeutics.

Animals↗
PubMed2005

Testosterone measurement by isotope-dilution liquid chromatography-tandem mass spectrometry: validation of a method for routine clinical practice.

BACKGROUND: Immunoassay is unsatisfactory for measuring the testosterone concentrations typically found in women. Bench-top tandem mass spectrometers are a viable alternative technology for measurements in the clinical laboratory. METHODS: We used stable-isotope dilution liquid chromatography-tandem mass spectrometry (ID/LC-MS/MS) to measure testosterone in plasma and serum. The sample volume was 50 muL in duplicate; preparation and analysis were carried out in a single tube, and a batch of 192 tubes was analyzed in 17.5 h. RESULTS: Intra- and interassay imprecision was <15% in the range 0.3-49 nmol/L. Recovery of testosterone added to samples at concentrations of 0.625-20 nmol/L was 96% (CV = 12%; n = 26). Six samples were serially diluted with double charcoal-stripped serum to demonstrate linearity. Correlation (r(2)) with isotope-dilution gas chromatography-mass spectrometry for 20 pools of clinical samples (range, 0.5-38.5 nmol/L) was 0.99. Correlations with our extraction RIA were 0.97 for clinical samples from men (range, 8-46.3 nmol/L) and 0.66 for samples from women (range, 0.7-3.0 nmol/L), but were 0.35 for male samples containing <3 nmol/L testosterone and 0.77 for female samples containing >8 nmol/L. Various steroids added to double charcoal-stripped serum showed no interference at the retention time of the testosterone peak. CONCLUSIONS: The ID/LC-MS/MS method has improved accuracy compared with immunoassay. The low sample volume and simplicity, rapidity, and robustness of the method make it suitable for use as a high-throughput assay in routine clinical biochemistry laboratories.

Chromatography, High Pressure Liquid↗
PubMed1986

Description of the time course of the prolactin suppressant effect of the dopamine agonist CQP201-403 by an integrated pharmacokinetic-pharmacodynamic model.

Six male volunteers (mean age 24 years) received a single oral dose of 0.025 mg CQP201-403 and placebo in a randomised double-blind crossover design. Fifteen plasma samples were collected over 48 h and were assayed by radioimmunoassay for drug substance and prolactin (PRL). Three of the samples were drawn during sleep on the first study day. The pharmacological effect (E%) of CQP201-403 was expressed as reduction in plasma PRL levels. The pharmacokinetic (PK)-pharmacodynamic (PD) model consisted of two kinetic compartments and an effect compartment linked to the central compartment. A sigmoid Emax model (Hill equation) described the relationship between the drug concentration in the effect compartment and E%. Curve-fitting of PK and PD data provided individual parameter estimates which served to generate computer-simulated PK and PD profiles after single and multiple doses in order to: investigate the in vivo concentration-effect relationship; evaluate the consequence of dosage reduction on the steady-state PD profile; and study the robustness of the response to changes in drug potency and bioavailability.

Adult↗
PubMed2006

Double-strand break repair in bacteriophage T4: recombination effects of 3'-5' exonuclease mutations.

The role of 3'-5' exonucleases in double-strand break (DSB)-promoted recombination was studied in crosses of bacteriophage T4, in which DSBs were induced site specifically within the rIIB gene by SegC endonuclease in the DNA of only one of the parents. Frequency of rII+ recombinants was measured in two-factor crosses of the type i x ets1, where ets1 designates an insertion in the rIIB gene carrying the cleavage site for SegC and i's are rIIB or rIIA point mutations located at various distances (12-2040 bp) from the ets1 site. The frequency/distance relationship was obtained in crosses of the wild-type phage and dexA1 (deficiency in deoxyribonuclease A), D219A (deficiency in the proofreading exonuclease of DNA polymerase), and tsL42 (antimutator allele of DNA polymerase) mutants. In all the mutants, recombinant frequency in crosses with the i-markers located at 12 and 33 bp from ets1 was significantly enhanced, implying better preservation of 3'-terminal sequences at the ends of the broken DNA. The effects of dexA1 and D219A were additive, suggesting an independent action of the corresponding nucleases in the DSB repair pathway. The recombination enhancement in the dexA1 mutant was limited to short distances (<100 bp from ets1), whereas in the D219A mutant a significant enhancement was seen at all the tested distances. From the character of the frequency/distance relationship, it is inferred that the synthesis-dependent strand-annealing pathway may operate in the D219A mutant. The recombination-enhancing effect of the tsL42 mutation could be explained by the hypothesis that the antimutator 43Exo removes a shorter stretch of paired nucleotides than the wild-type enzyme does during hydrolysis of the unpaired terminus in the D-loop intermediate. The role of the proofreading exonuclease in the formation of a robust replicative fork is discussed.

Bacteriophage T4↗
PubMed2006

Ginkgo biloba: no robust effect on cognitive abilities or mood in healthy young or older adults.

Ginkgo biloba extracts are commonly used to prevent or treat memory problems but evidence on the efficacy of ginkgo is equivocal. In any case, the psychological locus of ginkgo's effects is unknown. A 12-week, double-blind, placebo-controlled study assessed effects of ginkgo (120 mg per day) on a wide range of cognitive abilities, executive function, attention and mood in 93 healthy older adults (55-79 years) and in 104 young adults (18-43 years). For the older adult sample, longer-term memory assessed by associational learning tasks showed improvement with ginkgo (d = 0.52, p = 0.04). There was no statistically significant difference on any other measure. For the young adult group no measure showed statistically significant effects of ginkgo enhancement. There were no side effects unequivocally attributable to treatment with ginkgo and those reported by participants in the ginkgo groups were mild and similar to those reported elsewhere.

Adolescent↗
PubMed2005

Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture.

The in vitro culture of porcine bone marrow-derived mesenchymal stem cells (MSCs) was used for the investigation of adult stem cell biology. Isolated porcine MSCs possessed the ability to proliferate extensively in an antioxidants-rich medium containing 5% fetal bovine serum (FBS). Greater than 40 serial MSC passages and 100 cell population doublings have been recorded for some MSC batches. Early and late passage MSCs were defined here as those cultures receiving less than 5 trypsin passages and more than 15 trypsin passages, respectively. Consistent with their robust ability to proliferate, both the early and late passage MSCs expressed the cell-cycle promoting enzyme p34cdc2 kinase. Late MSCs, however, exhibited certain features reminiscent of cellular aging such as actin accumulation, reduced substrate adherence, and increased activity of lysosomal acid beta-galactosidase. Early MSCs retained the multipotentiality capable of chondrogenic, osteogenic, and adipogenic differentiation upon induction in vitro. In contrast, late MSCs were only capable of adipogenic differentiation, which was greatly enhanced at the expense of the osteochondrogenic potential. Along with these changes in multipotentiality, late MSCs expressed decreased levels of the bone morphogenic protein (BMP-7) and reduced activity of alkaline phosphatase. Late MSCs also exhibited attenuated synthesis of the hematopoietic cytokines granulocyte colony-stimulating factor (G-CSF), leukemia inhibitory factor (LIF), and stem cell factor (SCF). The long-term porcine MSC culture, thus, provides a model system to study the molecular interplay between multiple MSC differentiation cascades in the context of cellular aging.

Adenoviridae↗
PubMedDate not supplied

Development of a surgical approach for telemetering guinea pigs as a model for screening QT interval effects.

INTRODUCTION: Identifying a compound's risk of potentially producing Torsade de Pointes (TdP)/QT interval prolongation has become a goal early within the drug development process. Our aim was to develop a surgical approach for instrumenting guinea pigs for collecting ECG data. METHODS: Male Dunkin Hartley guinea pigs (386-661 g) were surgically implanted with telemetry transducers for the measurement of lead II ECG and arterial blood pressure. Using strict aseptic techniques and isofluorane anaesthesia (0.5-5.0%), one of the three implantation procedures was used. In Phase I the animals were either implanted intraperitoneally (abdominal aorta cannulated) or subcutaneously (carotid artery cannulated). In Phase II all animals were implanted subcutaneously and the subcutaneous pocket formed either with a single incision, as in Phase I, or a double incision. RESULTS: Phase I-During intraperitoneal implantation, rupture of the aorta occurred in 50% of the animals. The remaining animals were terminated between 2 and 14 days postsurgery on human grounds. All of the animals implanted subcutaneously survived the surgical procedure and the following 28 days. Skin thinning over the implant occurred in 25% of the animals in weeks 5-6. Phase II-Following single incision subcutaneous implantation 72% of the animals were terminated within the 28-day postsurgery due to skin rupture over the implant body, with only 22% of the animals viable after 28 days. Following double incision subcutaneous implantation 86% of animals were viable after 28 days and thus the recommended method for implantation. DISCUSSION: The improvements to the surgical approach have improved survival rates and increased the potential for robust, long term use of telemetered guinea pig colonies for screening for QT prolonging potential and additional cardiovascular assessment in vivo.

Animals↗
PubMed1994

Assessment of the labeling index of cohorts of the anterior pituitary cell population in phenobarbital-treated male rats by a double immunohistochemical technique for bromodeoxyuridine and pituitary hormones.

A previous study demonstrated that administration of phenobarbital for up to 7 days to male AP Wistar rats caused alterations in labeling indices (LIs) of several different tissues as determined by immunohistochemical visualization of bromodeoxyuridine (BrdU) incorporation into S-phase nuclei. The pivotal role of the pituitary gland in the function of the endocrine system and changes in circulating hormone levels that result from administration of xenobiotics prompted our consideration of the possible changes in LIs of individual cohorts of the anterior pituitary cell population that may occur as a specific functional adaptation during phenobarbital administration. We evaluated the LIs of individual anterior pituitary cell cohorts by modifying a double immunohistochemical staining method for bromodeoxyuridine and pituitary hormones using a sequential peroxidase-anti-peroxidase (PAP)/alkaline phosphatase-anti-alkaline phosphatase (APAAP) method employing diaminobenzidine and New Fuchsin chromogens, respectively. The method was robust and reproducible. Differences were noted in individual anterior pituitary cohort LIs between control and phenobarbital-treated groups, although no statistically significant difference was evident. We conclude that no detectable effects on individual cohort LIs were induced by treatment with phenobarbital for up to 7 days and that any functional adaptation to treatment was associated with increased hormone release. We believe that the visualization, identification, and quantitation of replicating cells in specific hormone-positive cohorts of the anterior pituitary cell population provide opportunities for understanding the influence of xenobiotics and disease processes on pituitary function.

Animals↗
PubMed1995

A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder.

BACKGROUND: There are few controlled studies of methylphenidate hydrochloride in adults with attention-deficit hyperactivity disorder (ADHD), and their results have been equivocal. The discrepancies among these studies may be related to low doses, diagnostic uncertainties, and lack of attention to comorbid disorders. METHODS: We conducted a randomized, 7-week, placebo-controlled, crossover study of methylphenidate in 23 adult patients with DSM-III-R ADHD using standardized instruments for diagnosis, separate assessments of ADHD and depressive and anxiety symptoms, and a robust daily dose of methylphenidate hydrochloride, 1.0 mg/kg per day. RESULTS: We found a marked therapeutic response for methylphenidate treatment of ADHD symptoms that exceeded the placebo response (78% vs 4%, P < .0001). Response to methylphenidate was independent of gender, psychiatric comorbidity with anxiety or moderate depression, or family history of psychiatric disorders. CONCLUSION: Robust doses of methylphenidate are effective in the treatment of adult ADHD.

Adolescent↗
PubMed1994

A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives.

Although antidepressants have been found to be superior to placebo in 12 of 14 studies, the relationship between improvement in the depressive diathesis and bulimia is unclear. In this study, the efficacy of placebo, imipramine, and phenelzine is examined in patients comorbid for atypical depression and bulimia. Greater improvement was observed for both depressive and bulimic symptoms with phenelzine than with either imipramine or placebo. Consistent with its poor antidepressant effects in atypical depression, imipramine seemed to have minimal efficacy for the bulimic symptoms of atypical depressives. These data suggest that the presence of bulimia does not alter the treatment response of atypically depressed patients. Furthermore, the data may suggest a link between depression and bulimia in atypical depressives. Demonstrating a statistical difference with a small sample suggests the effect size is robust, however conclusions are limited by a small sample size.

Adult↗
PubMedDate not supplied

Robust feeding following central administration of neuropeptide Y or peptide YY in chicks, Gallus domesticus.

Neuropeptide Y (NPY) and peptide YY (PYY) were injected intracerebroventricularly (ICV) in broiler chicks. Both NPY and PYY markedly increased food intake during the first hour post-injection compared to saline (SAL) controls. Food intake doubled in chicks given 5 micrograms NPY. A response surface analysis suggested that following ICV injection of NPY, maximum food intake occurred, using a dose of 9 micrograms. In contrast, an estimated dose between one and 5 micrograms PYY resulted in maximum food intake, giving the latter a slightly higher potency. Time spent drinking was not significantly different among NPY, PYY and SAL groups. Chicks given NPY or PYY also spent significantly less time standing while those given PYY spent significantly less time preening compared to controls.

Animals↗
PubMed2005

Robust two-qubit quantum registers.

We carry out a systematic analysis of a pair of coupled qubits, each of which is subject to its own dissipative environment, and argue that a combination of the interqubit couplings which provides for the lowest possible decoherence rates corresponds to the incidence of a double spectral degeneracy in the two-qubit system. We support this general argument by the results of an evolutionary genetic algorithm which can also be used for optimizing time-dependent processes (gates) and their sequences that implement various quantum computing protocols.

Journal Article↗
PubMed2004

Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).

OBJECTIVE: To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness. DESIGN: Prospective, double blind, randomised, placebo controlled trial. SETTING: Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002. PARTICIPANTS: 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent. MAIN OUTCOME MEASURES: Incidence measured by Lake Louise acute mountain sickness score > or = 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores > or = 5), incidence of headache, and severity of headache. RESULTS: Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70). CONCLUSIONS: When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.

Acetazolamide↗
PubMed1995

Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety.

OBJECTIVE: To examine the effects of methylphenidate (MPH) on working memory and behavior in anxious and nonanxious children with attention-deficit hyperactivity disorder (ADHD). METHOD: A total of 40 ADHD children (22 nonanxious, 18 anxious) completed a randomized, double-blind, placebo-controlled, crossover trial with three doses (0.3, 0.6, 0.9 mg/kg) of MPH. A serial addition task was used to assess working memory; direct observation of motor activity indexed behavior. RESULTS: MPH improved working memory in the nonanxious ADHD group but not in the comorbidity anxious group. By contrast, MPH reduced activity level in both groups. The presence of concurrent learning disabilities did not influence stimulant response. CONCLUSIONS: The presence of comorbid anxiety in children with ADHD predicts a less robust response to stimulant treatment and suggests that ADHD with anxiety may constitute a distinct and clinically meaningful subtype of ADHD.

Anxiety Disorders↗
PubMedDate not supplied

[The peptide nucleic acids (PNAs): "high-tech" probes for genetic and molecular cytogenetic investigations].

The peptide nucleic acids (PNAs) constitute a remarkable new class of synthetic nucleic acids analogs, in which the sugar phosphate backbone is replaced by repeating N-(2-aminoethyl) glycine units linked by amine bonds and to which the nucleobases are fixed. This structure gives to PNAs the capacity to hybridize with high affinity and specificity to complementary RNA and DNA sequences, and a great resistance to nucleases and proteinases. Originally conceived as ligands for the study of double stranded DNA, the unique physico-chemical properties of PNAs have led to the development of a large variety of research and diagnostic assays, including antigene and antisense therapy and genome mapping. Several sensitive and robust PNA-dependent methods have been designed for modulating polymerase chain reactions, detecting genomic polymorphisms and mutations or capturing nucleic acids. Over the last few years, the use of PNAs has proven its powerful usefulness in cytogenetics for the rapid in situ identification of human chromosomes and the detection of aneuploidies. Recent studies have reported the successful use of chromosome-specific PNA probes on human lymphocytes, amniocytes, spermatozoa as well as on isolated oocytes and blastomeres. Muticolor PNA protocols have been described for the identification of several human chromosomes, indicating that PNAs could become a powerful tool for in situ chromosomal investigation.

Cytogenetics↗
PubMed2003

The relationship between blood lead, bone lead and child intelligence.

We report associations between serial measures of blood lead and intelligence in children age 10-12 years, half heavily exposed to lead from the prenatal period onward, and half relatively unexposed. For a subsample, we examine bone lead-IQ associations, comparing them with bone lead associations. Both blood and bone lead levels were associated with intelligence decrements, small relative to the contribution of social factors. For each doubling of Tib-Pb, Full Scale, Performance, and Verbal IQ decreased by an estimated 5.5, 6.2, and 4.1 points, respectively. Bone lead-IQ associations were stronger than those for blood lead, which nonetheless provide robust analogues. Current BPb, easy to obtain, provides a useful means for assessing Pb exposure/IQ associations.

Bone and Bones↗