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PubMed2006

Case-parent triads: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes.

Case-parent triad data are considered a robust basis for studying association between variants of a gene and a disease. Methods evaluating statistical significance of association, like the TDT-test and its extensions, are frequently used. When there are prior hypotheses of a causal effect of the gene under study, however, methods measuring penetrance of alleles or haplotypes as relative risks will be more informative. Log-linear models have been proposed as a flexible tool for such relative risk estimation. We demonstrate an extension of the log-linear model to a natural framework for also estimating effects of multiple alleles or haplotypes, incorporating both single- and double-dose effects. The model also incorporates effects of single- and double-dose maternal haplotypes on a fetus during pregnancy. Unknown phase of haplotypes as well as missing parents are accounted for by the EM algorithm. A number of numerical improvements to maximum likelihood estimation are also implemented to facilitate a larger number of haplotypes. Software for these analyses, HAPLIN, is publicly available through our web site. As an illustration we have re-analyzed data on the MSX1 homeobox-gene on chromosome 4 to show how haplotypes may influence the risk of oral clefts.

Cleft Lip↗

PubMed2001

Pasteurella multocida toxin type D serological assay as an alternative to the toxin neutralisation lethality test in mice.

The objective of this work was to develop an enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against Pasteurella multocida toxin type D, that correlated to a mouse lethality test. Currently, the mouse lethality test is one of several tests used world-wide to evaluate serological responses in animals immunised with vaccines containing toxoids. The mouse lethality test involves injecting mice with a mixture of toxin and test serum sample (from animals that have been vaccinated with a toxoid), and then determining antibody titre of the test serum from the number of mice that survive. Thus, the titre calculated is based on the neutralising activity of the test serum. The mouse lethality test requires large numbers of animals and causes severe distress to the animals. Organisations world-wide are working towards alternatives to animals in the development and control of biological products for human and veterinary use. Additionally, the mouse lethality test is labour-intensive, costly and lacks robustness and may be difficult to reproduce between different technicians. We have developed a double sandwich ELISA to measure anti- P. multocida toxoid type D antibodies in swine serum. Sera from swine immunised with vaccines containing type D toxoid showed good correlation to the mouse lethality assay (Spearman analysis=0.94 and Pearson analysis=0.84). When compared to the mouse lethality test, titres obtained using the ELISA format had higher correlation with protective immunity (i.e., lower turbinate atrophy) following challenge with virulent P. multocida. The ELISA assay is more robust, reproducible and costs less than the mouse lethality assay; and it complements efforts to reduce the use of animals in testing.

Animals↗

PubMed2004

Prediction of hospital disposition after thrombolysis for acute ischemic stroke using the National Institutes of Health Stroke Scale.

BACKGROUND: Early determination of discharge destination after acute stroke may promote earlier rehabilitation and reduce costs by shortening the duration of hospitalization. OBJECTIVE: To determine whether the National Institutes of Health Stroke Scale (NIHSS) score predicts disposition in stroke patients treated with thrombolysis. DESIGN: Cohort study. SETTING: Academic and community hospitals from 3 countries. PATIENTS: Five hundred forty-six patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rt-PA). INTERVENTIONS: Medical records were reviewed for demographic information, vascular risk factors, location of stroke, initial NIHSS score, acute hospital disposition, and complications of symptomatic or asymptomatic intracerebral hemorrhage (ICH). MAIN OUTCOME MEASURE: Discharge destination to home, acute rehabilitation, or nursing facility. RESULTS: In multinomial regression analysis, increasing NIHSS score was a robust and independent predictor of discharge to rehabilitation or nursing facilities, roughly doubling for each 5-point increment. Patients who developed symptomatic ICH were never discharged to home, but asymptomatic ICH had no significant independent effect on disposition. CONCLUSIONS: Stroke severity as determined by the admission NIHSS score is the major independent predictor of disposition after hospitalization and treatment with rt-PA for acute stroke in a broad-based population. However, symptomatic ICH after rt-PA is a catastrophic event that may preclude discharge to home.

Acute Disease↗

PubMed2003

A study of homonuclear dipolar recoupling pulse sequences in solid-state nuclear magnetic resonance.

Dipolar recoupling pulse sequences are of great importance in magic angle spinning solid-state NMR. Recoupling sequences are used for excitation of double-quantum coherence, which, in turn, is employed in experiments to estimate internuclear distances and molecular torsion angles. Much effort is spent on the design of recoupling sequences that are able to produce double-quantum coherence with high efficiency in demanding spin systems, i.e., spin systems with small dipole-dipole couplings and large chemical-shift anisotropies (CSAs). The sequence should perform robustly under a variety of experimental conditions. This paper presents experiments and computer calculations that extend the theory of double-quantum coherence preparation from the strong coupling/small CSA limit to the weak coupling limit. The performance of several popular dipole-dipole recoupling sequences-DRAWS, POST-C7, SPC-5, R1, and R2-are compared. It is found that the optimum performance for several of these sequences, in the weak coupling/large CSA limit, varies dramatically, with respect to the sample spinning speed, the magnitude and orientation of the CSAs, and the magnitude of dipole-dipole couplings. It is found that the efficiency of double-quantum coherence preparation by gamma-encoded sequences departs from the predictions of first-order theory. The discussion is supported by density-matrix calculations.

Alanine↗

PubMed2004

An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment.

To test potentially beneficial drugs to amyotrophic lateral sclerosis (ALS), we created an ALS mouse model with a permeable blood-brain barrier, by crossing the G93A-SOD1 transgenic mouse with a multiple drug resistance type 1a/b (mdr1a/b) gene knockout mouse. To validate the model, we administered cyclosporine A intraperitoneally to the mice. Cyclosporine A accumulated in the brain and spinal cord of this mouse model, whereas it was unable to penetrate the CNS of mdr1a/b wild-type animals. Systemic administration of cyclosporine A extended the life of the double-mutant male mice by approximately 12%. Surprisingly, the effect was more robust in male mice and only marginal in female mice. These results demonstrate the usefulness of this combined mouse model for the testing of potentially therapeutic drugs and support the role of mitochondrial-mediated apoptosis in the pathway to motor neuron death in SOD1-associated ALS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Irrelevant pictures in visual working memory.

The aim of the paper is to establish firmly the phenomenon of an irrelevant picture effect and to demonstrate that the phenomenon can be used to investigate the characteristics of the visuo-spatial sketchpad. Experiment 1 introduces the use of dynamic visual noise as an interfering technique. This technique is shown to cause interference with a word list learned under visual mnemonic mediation instructions but to cause no interference when the word list is learned under verbal mediation instructions. Experiment 2 serves both to replicate this selective interference effect and to illustrate how the dynamic visual noise technique can be used to characterize further the nature of interference in the visuo-spatial sketchpad. Experiment 3 confirms the robustness of the dynamic visual noise technique. Additionally, this experiment demonstrates a double dissociation between two types of interference, dynamic visual noise and irrelevant speech, and two types of mediation, rote and visual mnemonic.

Adult↗

PubMed1984

Personality traits influence the effects of diazepam and caffeine on CNV magnitude.

The time course of the effects of caffeine (200 mg), diazepam (8 mg) and placebo on CNV magnitude, reaction time and state of mood was investigated in normal volunteers using a double-foreperiod paradigm. CNV changes were quantified by means of a linear robust fitting technique. In general, a reduction of amplitude was found for diazepam and an enhancement followed by a suppression in the caffeine condition. Emotional lability of the subjects, as measured by the Freiburg Personality Inventory was shown to strongly influence the nature and time course of these drug effects. Differential drug responses are discussed in terms of the attention arousal model.

Adult↗

PubMed1999

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies.

Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4(+) T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.

Animals↗

PubMed2006

The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention.

Polymorphism at the serotonin transporter linked polymorphic region (5-HTTLPR) has been associated with neuroticism, increased risk for affective disorders and greater vulnerability to mood change following serotonin (5-HT) depletion. The aim of the present study was to investigate whether the cognitive effects of 5-HT depletion were differentially affected by genotype at the 5-HTTLPR polymorphism, using neuropsychological measures of memory and attention. We utilized the acute tryptophan depletion (ATD) technique to temporarily reduce 5-HT synthesis in two groups of healthy volunteers pre-selected on the basis of 5-HTTLPR genotype, 15 of the ll genotype and 15 of the ss genotype, in a double-blind, placebo-controlled crossover design. As expected, ATD resulted in a robust reduction in plasma tryptophan concentration in both genotype groups. However, the genotype groups differed in terms of the effect of ATD on cognitive performance. The ss genotype group showed impaired verbal recall following depletion, while episodic memory was unimpaired by ATD in the ll genotype group. Averaging across depletion condition, the ss genotype group outperformed the ll genotype group on tests of episodic memory and attention. Neither group was significantly affected by ATD on measures of emotional state. These data confirm previous reports that ss individuals are particularly vulnerable to 5-HT depletion, but extend these findings to the cognitive domain. The unexpected finding that ss volunteers showed improved memory and attention relative to ll volunteers suggests a possible evolutionary advantage to possession of the s allele, which may offset the disadvantage of vulnerability to depression following stressful life events.

Adult↗

PubMed2002

Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice.

Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M(2) and M(4) receptor subtypes, the two G(i)/G(o)-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M(2) and M(4) mAChRs [M(2)/M(4) double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M(2)/M(4) double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M(2) receptor single-KO mice, but retained full analgesic activity in M(4) receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M(2) and M(4) receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M(4) than for M(2) receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M(2) and M(4) mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.

Analgesia↗

PubMed2006

Low-dose atomoxetine for maintenance treatment of attention-deficit/hyperactivity disorder.

OBJECTIVE: Data from acute studies of atomoxetine in patients with attention-deficit/hyperactivity disorder suggest that a dose of approximately 1.2 mg/kg per day is required to attain a maximal symptom response. However, lower doses could be effective during maintenance treatment, which would reduce drug exposure and potential problems related to tolerability during chronic treatment. METHODS: Patients 6 to 16 years of age who had a robust response to an initial acute trial of atomoxetine were assigned randomly under double-blind conditions to continue treatment for up to 8 months with either the dose to which they had responded acutely (1.2-1.8 mg/kg per day, N = 116, continued same dose) or a lower dose (0.5 mg/kg per day, N = 113, low dose). The primary outcome measure was relapse, defined as an Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score returned to > or = 90% of the original baseline value (before acute treatment) for 2 consecutive visits. Mean change in Attention-Deficit/Hyperactivity Disorder Rating Scale total score was assessed as a secondary outcome. RESULTS: At randomization, symptom severity was low and similar in both groups. At end point, relapse rates did not differ between the groups. Mean change in Attention-Deficit/Hyperactivity Disorder Rating Scale total score from the conclusion of acute treatment to end point also was not different between groups. Reports of affective lability were higher in the patients in the low-dose group. Also, increases in heart rate (compared with when atomoxetine was started) were higher in the patients in the continued same-dose group than in the low-dose group. Finally, increases in weight over the course of the trial were greater for the low-dose group than the continued same-dose group. CONCLUSIONS: For patients who experience a robust response to atomoxetine, it may be possible to retain the response during maintenance treatment with a reduced dose of atomoxetine.

Adolescent↗

PubMed1999

Segmental genomic replacement in embryonic stem cells by double lox targeting.

We have applied Cre-mediated double lox recombination to embryonic stem (ES) cells to facilitate repeated knock-ins at a target locus, thus helping to assure correct temporal and spatial transgene expression in mice. Using homologous recombination, we inserted a double lox cassette a few nucleo-tides before the authentic ATG start of MHL-1, the gene coding for the major subunit of the asialoglycoprotein receptor. The cassette carries a marker gene bounded by heterospecific lox sites that cannot recombine with each other, but which can undergo recombination with like sites on an incoming double lox targeting vector. Cre-mediated replacement of the lox-delimited genomic segment at MHL-1 with targeting DNA occurs at a frequency three times that of random DNA integration and is sufficiently robust that correctly targeted ES colonies can be identified by PCR screening without relying on any drug selection procedure. Moreover, double lox recombination at the MHL-1 locus is not dependent on the presence or absence of a transcriptionally active promoter at the genomic target. The strategy and vectors described here are generally applicable to designing double lox targeted knock-ins at any locus in ES cells and should prove useful in more precise molecular engineering of the mouse genome.

3T3 Cells↗

PubMedDate not supplied

Acute inositol does not attenuate m-CPP-induced anxiety, mydriasis and endocrine effects in panic disorder.

Many anti-panic drugs, administered chronically, can block pharmacologically-induced "panic attacks"; acutely they often exacerbate panic disorder. Theories of action need to account for this biphasic effect. Chronic inositol had previously shown efficacy against panic disorder. The authors investigated the effect of a single dose of 20 g inositol on an m-CPP challenge in a double-blind placebo-controlled crossover trial in panic-disorder patients. Seven patients had robust psychological, physiological and endocrine responses to 0.08 mg m-CPP i.v.; inositol had virtually no effect on these responses, although it had some acute effects during the evening before the challenge. A similar trial involving chronic inositol would be of interest.

Anti-Anxiety Agents↗

PubMed2006

Direct detection of double-stranded DNA: Molecular methods and applications for DNA diagnostics.

Methodologies to detect DNA sequences with high sensitivity and specificity have tremendous potential as molecular diagnostic agents. Most current methods exploit the ability of single-stranded DNA (ssDNA) to base pair with high specificity to a complementary molecule. However, recent advances in robust techniques for recognition of DNA in the major and minor groove have made possible the direct detection of double-stranded DNA (dsDNA), without the need for denaturation, renaturation, or hybridization. This review will describe the progress in adapting polyamides, triplex DNA, and engineered zinc finger DNA-binding proteins as dsDNA diagnostic systems. In particular, the sequence-enabled reassembly (SEER) method, involving the use of custom zinc finger proteins, offers the potential for direct detection of dsDNA in cells, with implications for cell-based diagnostics and therapeutics.

Amino Acid Sequence↗

PubMed2026

Efficacy of a high-frequency repetitive transcranial magnetic stimulation for craving reduction in adolescents with gaming disorder: a 4-week randomized control trial with 24-week follow-up.

BACKGROUND: With the widespread popularity of online gaming, gaming addiction has come under scrutiny. While there is ongoing research on the diagnosis and treatment of gaming disorder among adolescents, the clinical robustness and reliability of intervention strategies remain uncertain. METHODS: A 4-week, double-blind, randomized, sham-controlled clinical trial was conducted to evaluate the efficacy of noninvasive, high-frequency repetitive transcranial magnetic stimulation (rTMS) in alleviating psychological craving in adolescents diagnosed with gaming disorder. Sham rTMS was administered to the control group using the tilted-coil method. Both groups of participants were treated with SSRI medications. A total of 80 adolescents with gaming disorder participated in this study, and 73 ultimately completed the 24-week follow-up. The primary outcome was the change in craving levels before and after the rTMS intervention, as assessed by the Visual Analogue Scale (VAS). Secondary outcomes included changes in anxiety and depression levels before and after the intervention, as assessed by the HAMA and HAMD. RESULTS: We assessed levels of psychological craving, anxiety, and depression among adolescents with gaming disorder at baseline, after completing a 4-week intervention, and at a 24-week follow-up post-intervention. Our repeated-measures MANOVA results, adjusted for course variables, revealed a significant main effect of rTMS intervention on psychological craving levels in adolescents addicted to online games (F(11, 781) = 11.238, P < 0.001, partial η² = 0.142), as well as significant main effects on time (F(11, 781) = 6.809; P < 0.001, partial η² = 0.091) and group effects (F(1, 71) = 26.707, P < 0.001, partial η² = 0.282). In addition, repeated-measures ANOVA results showed significant time effects for anxiety (F(2, 142) = 20.747, P < 0.001, partial η² = 0.234) and depression levels (F(2, 142) = 22.277, P < 0.001, partial η² = 0.285) among adolescents with gaming disorder, with nonsignificant between-group effects and no intergroup interaction. In the active stimulation group, changes in psychological craving levels after 4 weeks of treatment were significantly and positively correlated with changes in anxiety levels after 4 weeks of treatment in adolescents addicted to online games (r = 0.335, P < 0.05). CONCLUSION: Our findings indicate that high-frequency rTMS targeting the left dorsolateral prefrontal cortex may be a promising approach for reducing psychological craving in adolescents with gaming disorder. TRIAL REGISTRATION: ChiCTR2500102979 in chictr.org.cn, registered on May 22, 2025.

Humans↗

PubMed2006

A synergistic effect on the production of S-adenosyl-L-methionine in Pichia pastoris by knocking in of S-adenosyl-L-methionine synthase and knocking out of cystathionine-beta synthase.

Two strategies of metabolic engineering have been used, individually or combined, to alter the metabolic flux to improve the production of S-adenosyl-L-methionine (SAM) in Pichia pastoris. One is over expressing SAM synthase by knock-in technique, the other is the disruption of cystathionine-beta synthase (CBS) by knock-out technique. Strain Gsam with ectopic SAM synthase gene produced 20 times of SAM comparing to the starter strain GS115. Disruption of CBS in GS115 only doubled its SAM production. However, disruption of CBS in Gsam results in a robust increase of SAM production, more than 56 times of the strain GS115. Thus, we report for the first time a synergistic effect on the production of SAM in yeast by the combination of knock-in and knock-out techniques. Furthermore, we optimize the cultural conditions for the genetically modified strain Gsam-cbs to produce SAM. The maximum yield of SAM reaches 3.6g/L in shake flask and 13.5g/L in a 5L fermentor, indicating that it could be used for industrial fermentation to produce large scale of SAM.

Bioreactors↗

PubMed2004

Lack of evidence for mu-opioid regulation of a socially mediated separation response.

Maternal potentiation of ultrasonic vocalization (USV) occurs when, after a brief contact with the dam, reisolated infant rats produce USV at a rate as much as double or triple their calling rate in the initial isolation. Potentiation occurs most robustly when the dam is alert (active) but is also elicited by an anesthetized dam (passive). The possible role of mu-opioid receptors in control of both active and passive potentiation was tested using the mu-preferring receptor agonist morphine and antagonist naltrexone. While high levels of morphine did suppress USV rate in both the initial and the second isolation, neither agonist nor antagonist demonstrated an effect specific to potentiation. That is, no dose of morphine or naltrexone suppressed or enhanced the response to the active dam, and only the highest dose of morphine prevented potentiation with the passive dam. The results do not support the possibility that activation of mu-receptors by endogenous opioids regulates the increase in USV caused by maternal potentiation.

Animals↗

PubMed2003

The effect of social factors on the anxiolytic efficacy of buspirone in male rats, male mice, and men.

Earlier findings suggest that housing conditions in laboratory animals and life events in humans influence the efficacy of anxiolytic drugs. Here we report on the impact of social isolation on buspirone efficacy in male mice and rats as assessed by the elevated plus-maze. In addition, the impact of social support on buspirone efficacy was assessed in male patients. When administered 30 min before testing and irrespective of housing conditions, buspirone significantly suppressed locomotor activity both in mice (6 mg/kg) and rats (10 mg/kg) and, as such, other behavioral changes observed at this time point must be seen as behaviorally nonselective. However, these locomotor disruptive effects of buspirone were not evident in either species at longer injection-test intervals (2 and 4 h). When given 2 h prior to testing, a low (3 mg/kg) but not high (10 mg/kg) dose of buspirone increased the frequency of open arm exploration in rats (but not mice) irrespective of housing conditions. At the longest injection-test interval used (4 h), buspirone increased the duration of open arm exploration in individually housed, but not group-housed, rats. Similar, though somewhat less robust, effects were observed in male mice at this time. In a double-blind placebo-controlled study with male patients, chronic buspirone treatment (3 x 10 mg daily for 6 weeks) produced a highly significant reduction in scores on the Hamilton Rating Scale for Anxiety (HAM-A). Multiple regression analysis of social support received by patients indicated that the support of nonrelatives (but not of family or other relatives) was a strong positive predictor of buspirone efficacy. Taken together, our data support the hypothesis that social conditions affect the anxiolytic efficacy of buspirone. Results are discussed in relation to differences in the social organization of the three species investigated.

Aged↗