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PubMed1995

Effects of oxazepam on event-related brain potentials, EEG frequency bands, and vigilance performance.

Eighteen males performed two vigilance tasks with static and dynamic stimuli under the influence of oxazepam (20 and 40 mg) in a placebo-controlled, double blind, crossover design. Oxazepam dose-dependently impaired overall level of performance and aggravated the decrement with time in measures of accuracy and sensitivity relative to placebo. The drug reduced the amplitudes of the P1, N1, P2N2, and P3 (dose-dependently) waves of event-related potentials (ERPs). Oxazepam aggravated the linear decline with time of the P3 amplitude only. Oxazepam impaired accuracy was related to deterioration of central processing involved in stimulus discrimination (P2N2). Impairment of response-related performance measures (RT and RI) was associated with processing manifest in the P1, N1, and P3 waves. Oxazepam effects on the amplitudes of N1 and P3 correlated with drug effects on power in alpha 1 (8-10 Hz). Drug effects on overall performance and alpha were also related; the drug effect on response speed correlated only with the drug effect on beta 1 (12.5-21 Hz). Effects of time-on-task on performance and EEG were unrelated, but oxazepam induced performance declines with time may have been caused by declines in resource allocation, as manifest in the amplitude of P3. Time effects on EEG power bands and ERP amplitudes were not significantly related to the time course of oxazepam activity. A curious dissociation emerged: both oxazepam and time-on-task impaired performance, but the drug induced a decrease of theta and alpha 1 power, whereas time-on-task increased power. Various processes play a role in performance decrements with time, and various aspects of processing may be involved in signal-detection measures which makes terms such as sensitivity quite meaningless. So-called computational processing was indistinguishable from energetic processes, which questions the validity of the distinction between these two domains. Explanations of EEG activity in terms of a unidimensional theory of arousal are untenable.

Adult↗
PubMed1999

[Prevalence of psychiatric disorders in primary care using the PRIME-MD questionnaire].

OBJECTIVE: To quantify the frequency of psychiatric disorders detected by primary care doctors, using the PRIME-MD questionnaire, and by psychiatrists using a structured clinical interview. DESIGN: An observational, descriptive, crossover study, using a questionnaire. One of each two patients was selected until reaching the total number of patients. SETTING: The study was conducted in five primary care centres in Madrid. PATIENTS: To be included in the study, patients had to consent verbally, be able to understand the questions asked and have been previously diagnosed as psychotic or demented. 395 patients were recruited, of which 312 completed the study. INTERVENTIONS: The primary care doctor administered the PRIME-MD questionnaire to each patient, and then a psychiatrist conducted the SCAN interview. RESULTS: The time spent by the doctor on the PRIME-MD questionnaire was usually 10 minutes. The doctor had previously detected psychiatric pathology in 18.5% of his/her patients; with the PRIME-MD questionnaire he/she detected it in 53.5%. The psychiatrist with the SCAN detected psychiatric pathology in 41.3% of patients. CONCLUSIONS: The high frequency of psychiatric disorders in primary care patients and primary care doctors' lack of ability in detecting these disorders was confirmed by this study. The PRIME-MD questionnaire, an instrument for rapid detection of the most commonly found psychiatric disorders within primary care, may considerably improve this situation.

Cross-Sectional Studies↗
PubMed2000

Rye bread improves bowel function and decreases the concentrations of some compounds that are putative colon cancer risk markers in middle-aged women and men.

Cereal fiber may reduce the risk of colorectal cancer by diluting colonic contents due to increased fecal output, by accelerating intestinal transit, by increasing fecal frequency and by altering bacterial metabolism. The effects of whole-meal rye bread on some putative colon cancer risk markers were investigated in 17 healthy Finnish subjects using a randomized crossover trial with two 4-wk bread consumption periods and a 4-wk washout period between the bread periods. White wheat bread was used as a control. Test breads covered a minimum of 20% of the daily energy intake (range, 4330-14, 033 kJ/d). Intestinal transit time, stool weight, fecal bacterial enzyme activities and short-chain fatty acid, ammonia, diacylglycerol (DAG) and bile acid concentrations in feces (expressed per gram wet feces) were measured. Whole-meal rye bread significantly increased fecal output and fecal frequency and shortened mean intestinal transit time compared with wheat bread in both women and men. Activities of beta-glucuronidase and beta-glucosidase (expressed per gram wet feces) were significantly lower in men and urease activity significantly higher in women during the rye bread period (RBP). Fecal butyrate concentration was higher during the RBP in men. Fecal ammonia and DAG concentrations did not differ between bread periods. Fecal total and secondary bile acid concentrations were significantly lower during RBP in both women and men. This study shows that whole-meal rye bread significantly improves bowel function in healthy adults and may decrease the concentration of some compounds that are putative colon cancer risk markers.

Adult↗
PubMed2001

Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.

BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.

Activities of Daily Living↗
PubMed1999

Human minisatellites, repeat DNA instability and meiotic recombination.

Minisatellites include some of the most variable loci in the human genome and are superb for dissecting processes of tandem repeat DNA instability. Single DNA molecule analysis has revealed different mutation processes operating in the soma and germline. Low-level somatic instability results in simple intra-allelic rearrangements. In contrast, high frequency germline instability involves complex gene conversions and is therefore recombinational in nature, almost certainly occurring at meiosis. To determine whether true meiotic crossovers occur at human minisatellites, we have used polymorphisms near the repeat array to recover recombinant DNA molecules directly from sperm DNA. Analysis of minisatellite MS32 has revealed an intense and highly localised meiotic crossover hotspot centred upstream of the array, the first example of a human hotspot defined at the molecular level. This hotspot extends into the beginning of the repeat array, resulting in unequal and equal crossovers. Array crossovers occur much less frequently than array conversions but appear to arise by a common process, most likely by alternative processing of a recombination initiation complex. The location of MS32 at the boundary of a recombination hotspot suggests that this locus has evolved as a by-product of localised meiotic recombination activity, and that minisatellites might in general mark recombinationally proficient hotspots or hot domains in the genome. Finally, sperm crossover analysis makes it possible to explore the molecular rules that govern human meiotic recombination, and to detect phenomena such as meiotic drive that could provide a possible connection between recombination and DNA sequence diversity itself.

DNA↗
PubMed1993

Inefficacy of propranolol in attenuation of drug-induced parkinsonian tremor.

We investigated the tremolytic effect of long-acting propranolol (propranolol-LA) in six subjects with drug-induced parkinsonism (DIP), using a double-blind, placebo-controlled, crossover experimental design. Subjects received propranolol-LA for 2 weeks and placebo for 2 weeks, with no change in neuroleptic treatment. Tremor frequency and amplitude were objectively quantified at the end of each 2-week period by computerized tremorgram recording. There were no significant differences in attenuation of DIP tremor by propranolol-LA and placebo. Previous investigations reported in the literature have found propranolol to attenuate the tremor of idiopathic parkinsonism (IPD). It is expected that DIP and IPD tremor would respond similarly to propranolol if a solely peripheral or spinal cord tremolytic action were operative. A possible differential attenuation of IPD tremor and DIP tremor provides support for the concept of a higher central tremolytic mechanism of beta-adrenergic receptor-blocking drugs.

Aged↗
PubMed1989

Effect of base pair mismatches on recombination via the RecBCD pathway.

The effect of base pair mismatches on recombination via the RecBCD pathway was studied in mutS and wild-type Escherichia coli, using substrates that contain single or multiple mismatches. Recombination between homologous DNA inserts in lambda phage and pBR322-derived plasmids forms phage-plasmid cointegrates that result from an odd numbers of crossovers. In the mutS host, when the sequence homology of a pair of 405 bp substrates decreased from 100% to 89%, the recombinant frequency decreased by about 9-fold, while in the wild-type host the decrease was about 240-fold. These results suggest that multiple mismatches can reduce recombinant frequencies by impeding the mechanism of recombination itself, and by provoking mismatch repair. Single mismatches in 31 bp substrates caused reductions in recombinant frequencies of 2- or 12-fold, depending on the location of the mismatch. However, unlike the reduction by multiple mismatches, the reduction of the recombinant frequencies by single mismatches was the same in both mutS and wild-type hosts. Thus a single mismatch is sufficient to impede recombination, and mismatch repair seems unable to act on single mismatches in very short homologies during recombination.

Bacteriophage lambda↗
PubMed2001

Oxazepam alters action monitoring.

RATIONALE: Oxazepam has been demonstrated to slow reaction times and increase the rate of omission errors in attentional experiments. This suggests that action monitoring might also be impaired. OBJECTIVES: The present study used the event-related brain potential (ERP) technique to investigate this hypothesis. The P3b component to targets was taken as an indicator of the target evaluation process, and the response-locked error-related negativity (ERN) served as an indicator of action monitoring. We hypothesized that the amplitudes of ERN and P3b would be reduced as an effect of oxazepam. METHODS: A simple "oddball" reaction time experiment was conducted in a double-blind crossover study of 30 mg oxazepam versus placebo. In order to investigate variations in attentional allocation, separate experimental runs were undertaken with target frequencies of 50% and 80%. RESULTS: ERN and P3b amplitudes were lower in the 80% target condition than in the 50% condition. Oxazepam did not affect behavioral parameters but was associated with an ERN of lower amplitude than the placebo condition. ERN amplitude variations between target conditions remained unchanged. CONCLUSIONS: Although the intake of 30 mg oxazepam did not impair behavioral performance, measures of the electrophysiological recordings show that action monitoring processes were altered. We argue that this may be related to the anxiolytic properties of the drug and may constitute an important causal factor for behavioral impairments after the intake of oxazepam.

Adult↗
PubMed1989

Doxepin in the treatment of female detrusor overactivity: a randomized double-blind crossover study.

A total of 19 women with detrusor overactivity and associated symptoms completed a double-blind placebo-controlled crossover study of doxepin. All patients had previously failed to respond to conventional pharmacotherapy. Doxepin was given at bedtime in a single 50 mg. dose for the first 2 weeks and, if needed, the dose was increased with 25 mg. in the morning for the last week of the 3-week treatment period, which was followed by 2 weeks of washout before crossover. The preference for doxepin to placebo was statistically significant (p less than 0.01). Doxepin caused a significant decrease in the nighttime micturition frequency and the nighttime incontinence episodes (p less than 0.05). Urine loss at the standardized 1-hour pad weighing test decreased significantly during treatment with doxepin although statistical significance (p equals 0.07) was not obtained. Cystometric parameters (first sensation and maximum cystometric capacity) improved significantly during treatment with doxepin (p less than 0.06 and less than 0.04, respectively). Side effects were frequent but mild. Suggestions for use of this tricyclic antidepressant in women with detrusor overactivity and possible mechanisms of action are discussed.

Adult↗
PubMed2001

Estrogen replacement therapy and nocturnal periodic limb movements: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of estrogen replacement therapy on nocturnal periodic limb movements in a randomized, double-masked, placebo-controlled, crossover trial. METHODS: Seventy-one healthy postmenopausal women volunteered in answer to a newspaper announcement; 62 women completed the follow-up. Frequency of nocturnal body movements was measured with the static-charge-sensitive bed and all-night polysomnographic recordings. Serum estradiol (E2) and FSH concentrations were also measured at baseline and after each treatment period. The power of the study setup was 94%. RESULTS: Nearly half the women presented with episodes of periodic limb movements (30 of 62 women, or 48%, during placebo and 27, or 44%, during estrogen therapy). In 17 (27%) during placebo and 19 (31%) during estrogen therapy, frequency of periodic limb movements exceeded index level 5 per hour while subjects were in bed. Incidence or intensity of movements, movement durations, and movement intervals did not change with estrogen therapy. The arousal index was similar during the two treatments (medians = 1.7 for placebo and 1.3 for estrogen, P =.758). Variations in serum E2 concentration, age, and body mass index did not explain variations in movement activity. CONCLUSION: Estrogen replacement therapy in doses used to control climacteric symptoms does not alter the incidence or intensity of nocturnal periodic limb movements.

Administration, Cutaneous↗
PubMed2002

Donor properties of the vanadyl ion: reactions of vanadyl salicylaldimine beta-ketimine and acetylacetonato complexes with groups 14 and 15 Lewis acids.

Reactions of organosilicon, -germanium, -tin, -lead, -antimony, and -tin tetrahalide Lewis acids with VO(salen) [H(2)salen = N,N'-bis(salicylidene)ethane-1,2-diamine], related vanadyl salicylaldimines, VO(acacen) [H(2)acacen = N,N'-bis(acetylacetonato)ethane-1,2-diamine], and VO(acac)(2) (acac = acetylacetonato) have been investigated, revealing VO(salen) and VO(acacen) to be significantly stronger vanadyl donors than VO(acac)(2). The vanadyl donor strength of VO(salen) significantly diminishes with the introduction of electron-withdrawing substituents on the salicylaldimine ligand, and the introduction of methyl substituents on the imine carbon atoms can result in a preference for phenolic over vanadyl oxygen donation. Vanadyl donation results in an increase in the vanadyl bond length, while it leaves the distance of vanadium from the basal plane relatively unaffected. Coordination of water trans to a vanadyl oxygen that is involved in a donor bond to tin or lead has little or no effect on the vanadyl bond length but results in a marked movement of vanadium toward the basal plane and a decrease of the V=O-D (D = Sn or Pb) bond angle by as much as 13 degrees, the latter reflecting a loss of multiple bond character of the vanadyl bond. Formation of a vanadyl donor bond results in a decrease in both the vanadyl stretching frequency (infrared spectrum) and energy of the e(pi) <-- b(2) transition (electronic spectrum), the latter being intimately related to the strength of the vanadyl donor bond, while the shift of the b(1) <-- b(2) transition to higher or lower energy is relatively small for vanadyl salicylaldimine and beta-ketimine complexes. Donation through the phenolic oxygen atoms results in an increase in the vanadyl stretching frequency and energy of the e(pi) <-- b(2) transition, which can result in e(pi) <-- b(2)/b(1) <-- b(2) energy crossover.

Journal Article↗
PubMed1998

Assaying genome-wide recombination and centromere functions with Arabidopsis tetrads.

During meiosis, crossover events generate new allelic combinations, yet the abundance of these genetic exchanges in individual cells has not been measured previously on a genomic level. To perform a genome-wide analysis of recombination, we monitored the assortment of genetic markers in meiotic tetrads from Arabidopsis. By determining the number and distribution of crossovers in individual meiotic cells, we demonstrated (i) surprisingly precise regulation of crossover number in each meiosis, (ii) considerably reduced recombination along chromosomes carrying ribosomal DNA arrays, and (iii) an inversely proportional relationship between recombination frequencies and chromosome size. This use of tetrad analysis also achieved precise mapping of all five Arabidopsis centromeres, localizing centromere functions in the intact chromosomes of a higher eukaryote.

Arabidopsis↗
PubMed1998

The CYP 3A4 inhibitor itraconazole has no effect on the pharmacokinetics of i.v. fentanyl.

We studied 10 healthy volunteers given itraconazole 200 mg orally, once daily or placebo for 4 days in a crossover study. i.v. fentanyl 3 micrograms kg-1 was given on day 4. Plasma concentrations of fentanyl were measured by radioimmunoassay and ventilatory frequency and peripheral arteriolar oxygen saturation were also measured. Fentanyl-induced subjective effects (drowsiness, itching, nausea, performance, feeling of drug effect) were measured by visual analogue scales. The pharmacokinetics and pharmacodynamics of fentanyl were similar after both itraconazole and placebo. Thus although itraconazole is a strong inhibitor of the cytochrome 3A enzymes responsible for metabolism of fentanyl in vitro, it did not affect the i.v. pharmacokinetics of fentanyl in humans.

Adult↗
PubMed1991

Detection of gene targeting by co-conversion of a single nucleotide change during replacement recombination at the immunoglobulin mu heavy chain locus.

A method is described for detecting targeted events at the mu heavy chain gene which relies on co-conversion (or co-exchange) of a point mutation with a selectable marker contained on a replacement vector. The vector, designed for application to IgM producing hybridomas, contains a single nucleotide change within the region of homology with the target gene which encodes a different allotypic determinant of IgM. In a model system where homologous recombination corrected a defective mu gene, the length of homology between this nucleotide change and the position of the double strand break in the vector was found to have a critical influence on the co-conversion frequency. In the vector design ultimately used for targeting in hybridomas, one in 1000-2000 stable transformants produced IgM with the allotype encoded by the exogenous DNA, and Southern blot analysis confirmed that these were derived by targeted integration. The sensitivity of the screening procedure using a monoclonal antibody specific to this allotype enabled a targeted clone to be detected in a pool of stable transformants when present at a frequency at least as low as one per cent. Several different modifications of the target locus were obtained as a consequence of alternative crossover positions and, in some cases, vector DNA concatenation.

Alanine Transaminase↗
PubMed1999

Trial of a two-channel hearing aid (low-frequency compression-high-frequency linear amplification) with school age children.

OBJECTIVE: The study was designed to investigate the efficacy of a 2-channel hearing aid with low-frequency compression and high-frequency linear amplification on a group of school-age hearing aid wearers. DESIGN: The study was a single-center, 2-way crossover design in which 25 children (age 6 to 15 yr) were fitted with 2-channel hearing aids for 12 wk and with their own (single-channel) hearing aids for 12 wk, refitted according to published protocols. Speech perception in quiet and in noise was measured at the end of each 12 wk period; in addition, questionnaires were given to teachers, parents, and children. RESULTS: Two-channel hearing aids showed significantly higher mean scores for speech perception in noise and significantly higher composite questionnaire scores (reflecting aspects of satisfaction and benefit). Final choice of hearing aids at the end of the study by parents and children also favored the 2-channel device. CONCLUSIONS: The 2-channel hearing aids appear to be an acceptable management option for audiometrically suitable children. The results provide support for the 2-channel design rationale and suggest the need for further trials.

Adolescent↗
PubMed1998

A novel system with positive selection for the chromosomal integration of replicative plasmid DNA in Corynebacterium glutamicum.

A simple system has been developed for generating Corynebacterium glutamicum strains containing stable replicative plasmids integrated into the chromosome via homologous recombination. The system is based upon extremely strong incompatibility between two plasmids, which cannot be co-maintained even under antibiotic selective pressure. Integration of the resident plasmid that contained the trpD gene of C. glutamicum was achieved by introduction of a second plasmid and subsequent selection for the maintenance of both plasmids. Plasmid integrates positive for both plasmid markers were obtained at a frequency about 10(-3) of the normal transformation frequency with selection for the maintenance of only the second plasmid. Southern analysis revealed that the integration had occurred through a single-crossover homologous recombination between the trpD regions of the host genome and the plasmid. On the basis of the Campbell-type integration, chromosome walking was attempted by using Escherichia coli replication origins that were also present in the integrated plasmid. The chromosomal DNA was digested, ligated, and used to transform E. coli, which enabled recovery of the expected adjacent genomic DNA regions. The plasmid integrate was stably maintained for 30 generations under non-selective culture conditions, suggesting that the integrated sequences carrying a replicon active in the host were maintained as a stable chromosomal insert in C. glutamicum.

Blotting, Southern↗
PubMed1982

Construction of a genetic map for Caulobacter crescentus.

RP4-mediated conjugation has been used to transfer large fragments of chromosomal material in Caulobacter crescentus. In this system, conjugation proceeds from multiple origins, and haploid recombinants are recovered at frequencies of 10(-6) and 10(-7) per donor cell. The data from five-factor crosses were subjected to computer-assisted crossover analyses as a rapid method to determine marker order. Using this information and data from additional two- and three-factor crosses mediated by RP4 or the generalized transducing bacteriophage phi Cr30, we constructed the first genetic map for C. crescentus.

Bacteria↗
PubMed1977

Comparison between the effects of pindolol and propranolol on essential tremor.

The effects of 120 mg propranolol and 15 mg pindolol daily on positional tremor of 24 patients with benign essential tremor were analyzed with a double-blind crossover trial and electrical tremor recording. Compared with the placebo effect, tremor amplitude was smaller under propranolol and larger under pindolol, whereas the frequency did not change.

Adolescent↗