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PubMed2006

A corrected Haldane's map function to calculate genetic distances from recombination data.

The estimation of genetic distances from recombination data has no direct relationship due to the fact that multiple crossovers do not generate recombinant gametes that can be recognized in the progeny. The Haldane's map function is the most widely used mathematical formulation able to relate the observed recombination frequency with the actual number of crossovers. Here I show that the model in which the Haldane's correction is based on is not correct, and I present a modified map function that takes into consideration the actual number of recombinant gametes produced in cells in which different number of crossovers have occurred. My correction generates shorter genetic distances than the Haldane's one.

Chromosome Mapping↗
PubMed2002

Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots.

Previously, we reported that human immunodeficiency virus type 1 (HIV-1) recombines approximately two to three times per genome per replication cycle, an extremely high rate of recombination given the relatively small genome size of HIV-1. However, a recombination hot spot involving sequence of nonretroviral origin was identified in the vector system utilized, raising the possibility that this hot spot skewed the rate of recombination, and the rate of recombination observed was an overestimation. To address this issue, an HIV-1-derived vector system was used to examine the rate of recombination between autologous HIV-1 sequences after restricting replication to a single cycle in the absence of this hot spot. Viral DNA and RNA were analyzed by a combination of the heteroduplex tracking assay, restriction enzyme analysis, DNA sequencing, and reverse transcription-PCR. The results indicate that HIV-1 undergoes recombination at a minimum rate of 2.8 crossovers per genome per cycle. Again, this is a very high rate given the small size of the HIV-1 genome. The results also suggested that there might be local hot spots of recombination at different locations throughout the genome since 13 of the 33 strand transfers identified by DNA sequencing shared the same site of recombination with one or two other clones. Furthermore, identification of crossover segments also allowed examination of mutations at the point of recombination, since it has been predicted from some studies of cell-free systems that mutations may occur with a frequency of 30 to 50% at crossover junctions. However, DNA sequence analysis of crossover junctions indicated that homologous recombination during viral replication was not particularly mutagenic, indicating that there are other factors or conditions not yet reproduced in cell-free systems which contribute to fidelity during retroviral recombination.

Cell Line↗
PubMed2005

Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being.

OBJECTIVES: To elucidate if percutanous treatment with 10mg testosterone per day could enhance sexuality and psychological well-being in postmenopausal women presenting problems with low libido. Secondary to study the influence on blood lipids, hemoglobin and erythropoietin levels. METHODS: Fifty-three postmenopausal women participated. As a complement to their already on-going HRT, 10mg of a testosterone gel (Testogel, Besins-Iscovesco) or placebo was administered. Treatment continued for three plus three months in a double blind, randomized, crossover design. RESULTS: The scores concerning "frequency of sexual activity, orgasm and intercourse", "sexual arousal, fantasies and enjoyment", "satisfaction with orgasms", and "interest in sex" were all significally improved for testosterone addition as compared to placebo both before and after crossover. Testosterone levels increased more than 10-fold during treatment while DHT-levels were more than doubled. Estrogen levels were not affected during the addition of testosterone. Liver enzymes, total cholesterol, triglycerides, HDL and LDL revealed no significant differences between any of the periods or groups. Endometrial thickness did not change significantly during treatment. Hemoglobin and erythropoietin remained unchanged. No significant differences in the number of experienced side effects were found. CONCLUSION: Testosterone gel of 10mg had positive effects on several aspects of sexual life such as frequency of sexual activity, orgasm, arousal, fantasies and sexual interest in postmenopausal women on HRT. Several psychological variables were positively influenced. The given dose resulted in too high serum levels. Even if no negative effects were observed, monitoring of serum levels and a decreased dose should be considered in future studies.

Administration, Cutaneous↗
PubMed1984

Polarity in adenovirus recombination.

The distributions of the crossovers necessary to generate ts+ genomes have been examined in a collection of clonally unrelated ts+ recombinants from a set of ts X ts adenovirus crosses. In a cross between two parents that are grossly heterologous between map units 80.2 and 91.5, the distribution of crossovers was significantly skewed toward the left-hand end of the genome, with a declining frequency proceeding rightward. This gradient of recombination was modified by the removal of the right-hand heterology and by the presence of another region of heterology between map units 3.67 and 10.11. In a cross where the ts markers were flanked by both heterologies, no gradient was observed and ts+ recombinants were characterized by a higher rate of supernumerary crossovers. In a cross designed so that one ts marker was internal to two heterologies, crossovers were found disproportionately between the second ts marker and the nearby heterology. In addition, ts+ recombinants formed by crossing over internal to the heterologies again were accompanied by a high frequency of supernumerary crossovers. Finally, ts+ recombinant frequencies in crosses identical except for the presence of either one or two flanking heterologies were markedly lower in the latter case. These data, taken together, suggest that a major pathway of adenovirus recombination initiates at, or near, the molecular termini and is perhaps driven by the displaced single strands produced during DNA replication. Internal initiation, on the other hand, may employ these single strands to form genetic "patches."

Adenoviridae↗
PubMed1989

Reciprocal recombination and the evolution of the ribosomal gene family of Drosophila melanogaster.

The role of reciprocal recombination in the coevolution of the ribosomal RNA gene family on the X and Y chromosomes of Drosophila melanogaster was assessed by determining the frequency and nature of such exchange. In order to detect exchange events within the ribosomal RNA gene family, both flanking markers and restriction fragment length polymorphisms within the tandemly repeated gene family were used. The vast majority of crossovers between flanking markers were within the ribosomal RNA gene region, indicating that this region is a hotspot for heterochromatic recombination. The frequency of crossovers within the ribosomal RNA gene region was approximately 10(-4) in both X/X and X/Y individuals. In conjunction with published X chromosome-specific and Y chromosome-specific sequences and restriction patterns, the data indicate that reciprocal recombination alone cannot be responsible for the observed variation in natural populations.

Animals↗
PubMed2001

Origin of constant loss in ionic conductors.

We have analyzed the constant loss contribution to the ac conductivity in the frequency range 10 Hz-1 MHz and temperatures down to 8 K, for two Li ionic conductors, one crystalline (Li(0.18)La(0.61)TiO(3)) and the other glassy (61SiO(2);35Li(2)O.3Al(2)O3.P(2)O(5)). As temperature is increased a crossover is observed from a nearly constant loss to a fractional power law frequency dependence of the ac conductivity. At any fixed frequency omega, this crossover occurs at a temperature T such that omega approximately nu(0)exp(-E(m)/k(B)T), where nu(0) is the attempt frequency and E(m) is identified with the barrier for Li+ ions to leave their wells.

Journal Article↗
PubMed2003

Chromosomal aberration frequencies in patients with thalassaemia major undergoing therapy with deferiprone and deferoxamine in a comparative crossover study.

Measurements of chromosomal aberrations were made in 10 thalassaemia major patients treated long-term with deferiprone (at least 5 years) and compared with an equal number of patients matched for age, sex and iron overload, treated long-term with deferoxamine. Two blood samples were collected from each patient, 7 and 20 days after a transfusion episode, and the frequency of chromosomal aberrations (gaps, breaks and exchanges) in the patients' circulating lymphocytes analysed in both samples using standard cytogenetic staining techniques. The frequency of reciprocal translocations was also analysed using fluorescence in situ hybridization. Relatively low frequencies of cells with stable and unstable aberrations were seen at both sampling times in all patients, with no statistically significant differences between sexes. Chromosomal aberrations were less frequent in patients treated long-term with deferiprone than in patients treated with deferoxamine, although the difference did not reach statistical significance. After the second blood sample had been collected, all patients had their iron chelation therapy switched to the other chelator. Patients treated long-term with deferiprone had their therapy switched to deferoxamine and patients treated long-term with deferoxamine had their therapy switched to deferiprone. After the switch, two further blood samples were collected 7 and 20 days after transfusion for each of the next two transfusion cycles in all patients. Analysis of the post-switch samples also revealed a slightly higher frequency of chromosomal aberrations during therapy with deferoxamine than with deferiprone at all time points. A small, but statistically significant, increase in cells with aberrations was observed at the first post-switch assessment in the group of patients whose therapy was switched from deferiprone to deferoxamine, whereas the switch from deferoxamine to deferiprone was associated with a decrease in the frequency of chromosomal aberrations. The results of the study demonstrate that, in a clinical setting, deferiprone has no greater clastogenic activity than that of deferoxamine.

Adolescent↗
PubMed1995

Analysis of Tn5 inversion events in Escherichia coli plasmids.

The ability of the bacterial transposon Tn5 to undergo sequence inversion in Rec+ Escherichia coli cells as a result of recombination between its duplicated IS50 elements was examined using specially designed plasmid constructs. Surprisingly, recombination events in the IS50 elements that led to crossover and therefore Tn5 inversion could be detected at a frequency of only 10(-5). This was approximately an order of magnitude lower than the frequency of IS50 recombination that led to conversion events (i.e. non-reciprocal recombination) without crossover, and at least two orders of magnitude lower than the frequency of intermolecular recombination between IS50 elements on two different plasmids. These rare conversion and inversion events in Tn5 appeared to be due to intramolecular recombination and not simply to multiple rounds of reciprocal crossing over, since the heterodimeric intermediates that would be generated during the latter process could be readily isolated but were shown to yield a completely different set of plasmid products upon resolution.

Chromosome Inversion↗
PubMed1986

High-frequency ventilation versus conventional ventilation in dogs with right ventricular dysfunction.

A randomized crossover protocol was used to compare conventional mechanical ventilation (CMV) and high-frequency ventilation (HFV) in mongrel dogs experiencing right ventricular dysfunction after right ventriculotomy. When inspired oxygen, pH, PCO2, core temperature, and preload were held constant, cardiac output increased significantly (p less than .05) from 1.16 +/- 0.24 to 1.38 +/- 0.25 L/min and pulmonary vascular resistance decreased significantly (p less than .05) from 734 +/- 257 to 554 +/- 169 dyne X sec/cm5 during HFV relative to CMV. We also noted a significant (p less than .05) increase in mean arterial pressure from 116 +/- 27 to 124 +/- 23 mm Hg and a significant (p less than .05) increase in left ventricular stroke work from 10.2 +/- 3.5 to 12.3 +/- 2.6 g X m during HFV. During the inspiratory phase of CMV there were increases in CVP, pulmonary artery pressure, and systemic arterial pressure, and decreases in pulmonary artery flow which did not occur during HFV. HFV may be preferable to CMV in the presence of right ventricular dysfunction.

Animals↗
PubMed2002

Genetic control of mammalian meiotic recombination. I. Variation in exchange frequencies among males from inbred mouse strains.

Genetic background effects on the frequency of meiotic recombination have long been suspected in mice but never demonstrated in a systematic manner, especially in inbred strains. We used a recently described immunostaining technique to assess meiotic exchange patterns in male mice. We found that among four different inbred strains--CAST/Ei, A/J, C57BL/6, and SPRET/Ei--the mean number of meiotic exchanges per cell and, thus, the recombination rates in these genetic backgrounds were significantly different. These frequencies ranged from a low of 21.5 exchanges in CAST/Ei to a high of 24.9 in SPRET/Ei. We also found that, as expected, these crossover events were nonrandomly distributed and displayed positive interference. However, we found no evidence for significant differences in the patterns of crossover positioning between strains with different exchange frequencies. From our observations of >10,000 autosomal synaptonemal complexes, we conclude that achiasmate bivalents arise in the male mouse at a frequency of 0.1%. Thus, special mechanisms that segregate achiasmate chromosomes are unlikely to be an important component of mammalian male meiosis.

Animals↗
PubMed1999

Genetic recombination of poliovirus in vitro and in vivo: temperature-dependent alteration of crossover sites.

Genetic recombination that occurs with high frequency during poliovirus genome replication is a process whose molecular mechanism is poorly understood. Studies of genetic recombination in a cell-free system in vitro and in infected tissue culture cells in vivo have led to the unexpected observation that temperature strongly influences the loci at which cross-over between the two recombining RNA strands occurs. Specifically, cross-over between two genetically marked RNA strands in vitro and in vivo at 34 degrees C occurred over a wide range of the genome. In contrast, recombination in vivo at 37 and 40 degrees C yielded cross-over patterns that had shifted dramatically to a region encoding nonstructural proteins. Preferential selection of recombinants at 37 and 40 degrees C was ruled out by analyses of the growth kinetics of the recombinants. During the studies of recombination in the cell-free system we found that there is a direct correlation between the ability of a poliovirus RNA molecule to replicate in the cell-free system and its capacity to complement de novo virus synthesis programmed by another viral RNA.

Binding Sites↗
PubMed2001

Calcium antagonists as an add-on therapy for drug-resistant epilepsy.

BACKGROUND: As up to 30% of patients with epilepsy do not have their seizures controlled with current treatments, there have been continuous attempts to find new antiepileptic drugs based on increasing knowledge of cellular and molecular biology involved in the genesis of epilepsy and seizures. Calcium has been established to play a major role in seizure occurrence, thus, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for effect on epileptic seizures. OBJECTIVES: To evaluate the effects of calcium antagonists on seizures, side effects, quality of life and cognition, when used as an add-on therapy for patients with drug-resistant epilepsy. SEARCH STRATEGY: We searched MEDLINE from 1966 to 2000 and the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2001). SELECTION CRITERIA: Randomized placebo-controlled add-on trials of any calcium antagonists in patients with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. For crossover trials, the first treatment period was treated as a parallel trial. Analyses were by intention to treat. Due to problems acquiring the data needed from crossover trials, overall results from these trials were summarised in tables. MAIN RESULTS: Eleven trials were included. One parallel and seven crossover trials of flunarizine, two crossover trials of nimodipine and one crossover trial of nifedipine. For flunarizine, the odds ratio (OR) (95% Confidence Intervals (CIs)I) for a 50% or greater reduction in seizure frequency for the parallel trial was 1.64 (0.55, 4.94) indicating a non-significant advantage for flunarizine. We were unable to acquire data for this outcome from the seven crossover trials. The overall OR (95% CI) for treatment withdrawal for flunarizine was 5.83 (2.06, 16.45) indicating patients were significantly more likely to have flunarizine withdrawn than placebo. No side effects were statistically associated with flunarizine. For nifedipine we were unable to acquire the data we required from the two crossover trials for our specified outcomes. For the outcomes reported in the trials, nifedipine had no significant effect in seizures frequency. For nimodipine, we only had data from the first treatment period from one of the two crossover trials (17 subjects). The ORs (95% CIs) for a 50% or greater reduction in seizure frequency was 11.34 (1.00, 128.03) and for treatment withdrawal was 2.46 (0.22, 27.75). REVIEWER'S CONCLUSIONS: Flunarizine may have a weak effect on seizure frequency, but had a significant withdrawal rate probably due to side effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Anticonvulsants↗
PubMed1990

Use of interplasmid recombination to generate stable selectable markers for yeast transformation: application to studies of actin gene control.

A plasmid recombination system has been developed that relies upon interplasmid exchanges for yeast cell viability. Two types of plasmids, one carrying the LEU2 allele inserted within yeast actin gene sequences and the other carrying 2-microns plasmid DNA and an intact actin gene, were constructed. Neither plasmid alone yielded transformants in the haploid Leu- strain AH22, but when cotransformed, a number of colonies were obtained. Southern blot analysis revealed that transformants arose because of recombination events within the homologous actin sequences that transferred the LEU2 gene to the actin gene on the 2-microns plasmid. The recombinant plasmids could be recovered, and sequence analysis of one recombination site revealed that the exchange event was faithful at the nucleotide level. The resulting recombinant plasmids carried a defective actin gene and presumably arose because of a double-crossover event. Deletion mutations that prevented actin gene expression on one donor plasmid enabled the recovery at a high frequency of transformants resulting primarily from single-crossover events between the two plasmids. This was presumably because such events no longer generated an intact actin gene on a multicopy plasmid. Infrequently a transformant from a plasmid with an intact gene was recovered, but in these cases the plasmid was not present in multiple copies. These cells exhibited a slower growth rate, and Northern blot analysis revealed an elevated level of actin mRNA.

Actins↗
PubMed1996

Homologous RNA recombination in brome mosaic virus: AU-rich sequences decrease the accuracy of crossovers.

Brome mosaic virus, a tripartite positive-stranded RNA virus of plants, was used for the determination of sequence requirements of imprecise (aberrant) homologous recombination. A 23-nucleotide (nt) region that included a 6-nt UUAAAA sequence (designated the AU sequence) common between wild-type RNA2 and mutant RNA3 supported both precise and imprecise homologous recombination, though the latter occurred with lower frequency. Doubling the length of the 6-nt AU sequence in RNA3 increased the incidence of imprecise crossovers by nearly threefold. Duplication or triplication of the length of the AU sequence in both RNA2 and RNA3 further raised the frequency of imprecise crossovers. The majority of imprecise crosses were located within or close to the extended AU sequence. Imprecise recombinants contained either nucleotide substitutions, nontemplated nucleotides, small deletions, or small sequence duplications within the region of crossovers. Deletion of the AU sequence from the homologous region in RNA3 resulted in the accumulation of only precise homologous recombinants. Our results provide experimental evidence that AU sequences can facilitate the formation of imprecise homologous recombinants. The generation of small additions or deletions can be explained by a misannealing mechanism within the AU sequences, while replicase errors during RNA copying might explain the occurrence of nucleotide substitutions or nontemplated nucleotides.

Base Sequence↗
PubMed1992

Experimental study of high-frequency two-way jet ventilation.

BACKGROUND AND METHODS: A new mode of jet ventilation, high-frequency two-way jet ventilation, was devised and introduced to increase CO2 elimination. High-frequency two-way jet ventilation was achieved by adding reverse jet pulses inside the trachea through an intratracheal reverse jet system to the expiratory phase of common high-frequency jet ventilation. The ventilatory efficiency and features of high-frequency two-way jet ventilation were investigated and compared with those features of high-frequency jet ventilation in ten dogs in the same experimental condition. Random sample selection and randomized crossover trial were used for comparison between high-frequency two-way jet ventilation and high-frequency jet ventilation. Peak inspiratory pressure, end-expiratory pressure, and the arterial blood gas variables (PaO2, PaCO2, and pH) were measured during the study. RESULTS: PaCO2 with high-frequency two-way jet ventilation was about 35% lower than that with high-frequency jet ventilation (from 45 to 29 torr [6.0 to 3.9 kPa], p less than .01). Simultaneously, peak inspiratory pressure and end-expiratory pressure during high-frequency two-way jet ventilation were significantly lower than those same variables measured during high-frequency jet ventilation. End-expiratory pressure of high-frequency two-way jet ventilation was a negative pressure (-2.45 +/- 0.45 cm H2O). The pH of high-frequency two-way jet ventilation was significantly higher than that of high-frequency jet ventilation. CONCLUSIONS: Compared with high-frequency jet ventilation, high-frequency two-way jet ventilation demonstrated a ventilatory feature of increasing CO2 elimination and simultaneously decreasing airway pressure.

Animals↗
PubMed1998

Desmopressin in the treatment of daytime urinary frequency in patients with multiple sclerosis.

Twenty two patients with multiple sclerosis, complaining of frequency of day time micturition, completed a double blind crossover trial of desmopressin (DDAVP nasal spray) versus placebo. There was a significant decrease in micturition frequency in the 6 hour post-treatment period from 3.1 voids after placebo to 2.4 voids and a significant reduction in urinary volume after desmopressin. Eighty per cent of patients preferred the active treatment phase. Mean 24 hour urinary volume did not differ between active and placebo treatments and patients did not complain of increased night time frequency. Transient symptoms of hyponatraemia occurred in one patient but these resolved within 48 hours of stopping desmopressin. There were otherwise no side effects and mean serum sodium concentrations of the group remained unchanged throughout the study. The clinical indications for prescribing daytime desmopressin are discussed and the importance of patient compliance stressed.

Adolescent↗
PubMed1999

Chromosome size-dependent control of meiotic reciprocal recombination in Saccharomyces cerevisiae: the role of crossover interference.

In the yeast Saccharomyces cerevisiae, small chromosomes undergo meiotic reciprocal recombination (crossing over) at rates (centimorgans per kilobases) greater than those of large chromosomes, and recombination rates respond directly to changes in the total size of a chromosomal DNA molecule. This phenomenon, termed chromosome size-dependent control of meiotic reciprocal recombination, has been suggested to be important for ensuring that homologous chromosomes cross over during meiosis. The mechanism of this regulation was investigated by analyzing recombination in identical genetic intervals present on different size chromosomes. The results indicate that chromosome size-dependent control is due to different amounts of crossover interference. Large chromosomes have high levels of interference while small chromosomes have much lower levels of interference. A model for how crossover interference directly responds to chromosome size is presented. In addition, chromosome size-dependent control was shown to lower the frequency of homologous chromosomes that failed to undergo crossovers, suggesting that this control is an integral part of the mechanism for ensuring meiotic crossing over between homologous chromosomes.

Chromosomes, Fungal↗
PubMed1994

Sustained inflations improve respiratory compliance during high-frequency oscillatory ventilation but not during large tidal volume positive-pressure ventilation in rabbits.

OBJECTIVE: To determine whether volume recruitment maneuvers that induce significant lung reexpansion during high-frequency oscillatory ventilation are also of value during conventional positive-pressure ventilation. DESIGN: Crossover comparison of volume recruitment maneuvers administered during high-frequency oscillatory ventilation and positive-pressure ventilation in normal and surfactant-deficient adult rabbits. SETTING: Laboratory. SUBJECTS: Nineteen adult New Zealand white rabbits (weight 2.3 to 3.3 kg). METHODS: Respiratory system compliance was measured plethysmographically before and after sustained inflations in six normal and five saline-lavaged anesthetized rabbits, using both ventilators over a range of mean and end-expiratory pressures. RESULTS: Under conditions where sustained inflations during high-frequency oscillatory ventilation at 15 Hz increased respiratory system compliance 50 +/- 28%, sustained inflations during conventional positive-pressure ventilation at a rate of 30 to 40 breaths/min and tidal volumes of 14 to 17 mL/kg did not change respiratory system compliance (mean change 3 +/- 9%). Sustained inflations during conventional positive-pressure ventilation could not be made effective by increasing the positive end-expiratory pressure level to equal the mean pressure during high-frequency oscillatory ventilation. Sustained inflations on conventional positive-pressure ventilation remained ineffective up to positive end-expiratory pressure levels of 17.5 cm H2O. In lavaged rabbits, sustained inflations increased respiratory system compliance 49 +/- 14% during high-frequency oscillatory ventilation and 0 +/- 3% during conventional positive-pressure ventilation. Sustained inflations increased compliance significantly during conventional positive-pressure ventilation only when ventilating with tidal volumes of 7 mL/kg and low end-expiratory pressure. CONCLUSIONS: Active recruitment of lung volume during high-frequency oscillatory ventilation appears necessary, because small pressure/volume cycles adequate to support high-frequency gas transport are not able to reexpand atelectatic lung units without the aid of a sustained inflation. We conclude that volume recruitment maneuvers improve respiratory system compliance substantially during high-frequency oscillatory ventilation at 15 Hz, but these maneuvers offer potential risk and no benefit during conventional positive-pressure ventilation with large tidal volumes or when using smaller tidal volumes and high levels of positive end-expiratory pressure.

Airway Resistance↗