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PubMed1991

Effect of atenolol and diltiazem on heart period variability in normal persons.

Several time and frequency domain measures of heart period variability are reduced 1 to 2 weeks after myocardial infarction, and a reduced standard deviation of normal RR intervals over a 24 h period (SDNN) is associated with increased mortality. The predictive accuracy of heart period variability may be reduced by drugs used to treat patients after myocardial infarction. Accordingly, a randomized, three period, placebo-controlled, crossover (Latin square) design was used to determine the effect of atenolol and diltiazem on time and frequency measures of heart period variability calculated from 24 h continuous electrocardiographic recordings during treatment with atenolol, diltiazem and placebo in 18 normal volunteers. During atenolol treatment, the 24 h average normal RR (NN) interval increased 24% (p less than 0.001). The three measures of tonic vagal activity were significantly increased (p less than 0.001) during atenolol treatment: percent of successive normal RR intervals greater than 50 ms = 69%, root mean square successive difference of normal RR intervals = 61% and high frequency power in the heart period power spectrum = 84%. Low frequency power also increased 45% (p less than 0.01), indicating that this variable also is an indicator of tonic vagal activity over 24 h. Diltiazem had no significant effect on the 24 h average NN interval or on any measure of heart period variability. The decreased mortality rate after myocardial infarction associated with beta-adrenergic blocker but not calcium channel blocker therapy may be attributed in part to an increase in vagal tone caused by beta-blockers.

Adult↗
PubMed2000

A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK Trial Group.

AIMS: Despite considerable experience with insulin lispro, few blinded comparisons with soluble insulin are available. This study compared insulin lispro with human soluble insulin in patients with Type 1 diabetes mellitus on multiple injection therapy who inject shortly before meals. METHODS: Glucose control, frequency of hypoglycaemia and patient preference were examined in the course of a prospective, randomized, double-blind, crossover comparison, with a 6-week run-in period and 12 weeks on each therapy. Ninety-three patients took part, all on multiple daily doses of insulin, with soluble insulin before meals and NPH (isophane) insulin at night. The main outcome measures were self-monitored blood glucose profiles, glycated haemoglobin, frequency of hypoglycaemic episodes, patient satisfaction and well-being and patient preference. RESULTS: Blood glucose levels were significantly lower after breakfast and lunch, but higher before breakfast, lunch and supper, in patients taking insulin lispro. Levels of HbA(1c) were 7.4 +/- 1.1% on Humulin S and 7.5 +/- 1.1% on insulin lispro (P = 0.807). The overall frequency of symptomatic hypoglycaemia did not differ, but patients on insulin lispro were less likely to experience hypoglycaemia between midnight and 6 a.m., and more likely to experience episodes from 6 a.m. to midday. Questionnaires completed by 84/87 patients at the end of the study showed that 43 (51%) were able to identify each insulin correctly, nine (11%) were incorrect, and 32 (38%) were unable to tell the insulins apart. No significant preference emerged: 35 (42%) opted for insulin lispro, 24 (29%) opted for Humulin S, while the remainder had no clear preference. CONCLUSIONS: Substitution of insulin lispro for soluble insulin in a multiple injection regimen improved post-prandial glucose control at the expense of an increase in fasting and pre-prandial glucose levels. Patients who already injected shortly before meals expressed no clear preference for the fast-acting analogue, and did not improve their overall control as a result of using it. Nocturnal hypoglycaemia was however, less frequent on insulin lispro, and may emerge as a robust indication for its use.

Adolescent↗
PubMed2006

Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations.

A previous polymorphism survey of the type 2 diabetes gene CAPN10 identified a segment showing an excess of polymorphism levels in all population samples, coinciding with localized breakdown of linkage disequilibrium (LD) in a sample of Hausa from Cameroon, but not in non-African samples. This raised the possibility that a recombination hotspot is present in all populations and we had insufficient power to detect it in the non-African data. To test this possibility, we estimated the crossover rate by sperm typing in five non-African men; these estimates were consistent with the LD decay in the non-African, but not in the Hausa data. Moreover, resequencing the orthologous region in a sample of Western chimpanzees did not show either an excess of polymorphism level or rapid LD decay, suggesting that the processes underlying the patterns observed in humans operated only on the human lineage. These results suggest that a hotspot of recombination has recently arisen in humans and has reached higher frequency in the Hausa than in non-Africans, or that there is no elevation in crossover rate in any human population, and the observed variation results from long-standing balancing selection.

Animals↗
PubMed2005

Exercise frequency and calcium intake predict 4-year bone changes in postmenopausal women.

The aim of this study was to examine the association of exercise frequency and calcium intake (CI) with change in regional and total bone mineral density (BMD) in a group of postmenopausal women completing 4 years of progressive strength training. One hundred sixty-seven calcium-supplemented (800 mg/day) sedentary women (56.1+/-4.5 years) randomized to a progressive strength training exercise program or to control were followed for 4 years. Fifty-four percent of the women were using hormone therapy (HT) at baseline. At 1 year, controls were permitted to begin the exercise program (crossovers). The final sample included 23 controls, 55 crossovers, and 89 randomized exercisers. Exercisers were instructed to complete two sets of six to eight repetitions of exercises at 70-80% of one repetition maximum, three times weekly. BMD was measured at baseline and thereafter annually using dual-energy X-ray absorptiometry. Four-year percentage exercise frequency (ExFreq) averaged 26.8%+/-20.1% for crossovers (including the first year at 0%), and 50.4%+/-26.7% for exercisers. Four-year total CI averaged 1,635+/-367 mg/day and supplemental calcium intake, 711+/-174 mg/day. In adjusted multiple linear regression models, ExFreq was positively and significantly related to changes in femur trochanter (FT) and neck (FN), lumbar spine (LS), and total body (TB) BMD. Among HT users, FT BMD increased 1.5%, and FN and LS BMD, 1.2% (p<0.01) for each standard deviation (SD) of percentage ExFreq (29.5% or 0.9 days/week). HT non-users gained 1.9% and 2.3% BMD at FT and FN, respectively, (p<0.05) for every SD of CI. The significant, positive, association between BMD change and ExFreq supports the long-term usefulness of strength training exercise for the prevention of osteoporosis in postmenopausal women, especially HT users. The positive relationship of CI to change in BMD among postmenopausal women not using HT has clinical implications in light of recent evidence of an increased health risk associated with HT.

Absorptiometry, Photon↗
PubMed1999

Stimulation of homologous recombination in plants by expression of the bacterial resolvase ruvC.

Targeted gene disruption exploits homologous recombination (HR) as a powerful reverse genetic tool, for example, in bacteria, yeast, and transgenic knockout mice, but it has not been applied to plants, owing to the low frequency of HR and the lack of recombinogenic mutants. To increase the frequency of HR in plants, we constructed transgenic tobacco lines carrying the Escherichia coli RuvC gene fused to a plant viral nuclear localization signal. We show that RuvC, encoding an endonuclease that binds to and resolves recombination intermediates (Holliday junctions) is properly transcribed in these lines and stimulates HR. We observed a 12-fold stimulation of somatic crossover between genomic sequences, a 11-fold stimulation of intrachromosomal recombination, and a 56-fold increase for the frequency of extrachromosomal recombination between plasmids cotransformed into young leaves via particle bombardment. This stimulating effect may be transferred to any plant species to obtain recombinogenic plants and thus constitutes an important step toward gene targeting.

Journal Article↗
PubMed2004

Reduction of daily life ischaemia by aspirin in patients with angina: underlying link between thromboxane A2 and macrophage colony stimulating factor.

OBJECTIVES: To evaluate whether aspirin reduces the incidence and frequency of daily life myocardial ischaemia in a cohort of patients with chronic stable coronary artery disease. SETTING: Tertiary referral centre. METHODS: 60 patients with chronic stable coronary artery disease underwent 48 hour Holter monitoring to assess the incidence and frequency of daily life myocardial ischaemia. Those with myocardial ischaemia (40/60) entered a double blind, crossover trial of aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48 hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro-TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor (MCSF), and interleukin (IL)-6 were measured. RESULTS: Aspirin reduced the total number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365 minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1 ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5 to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p < 0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of the ischaemic burden compared with placebo (p < 0.05). CONCLUSIONS: In patients with daily life ischaemia, aspirin reduces the incidence and frequency of ischaemic episodes as well as the systemic concentrations of haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow reductions through platelet, thrombin, and cytokine inhibition.

Adult↗
PubMed1980

ELISA for toxoplasma antibody detection: a comparison with other serodiagnostic tests.

An ELISA method was developed for the measurement of toxoplasma IgG antibodies in human serum using antigen-coated polystyrene beads as a solid phase and anti human IgG-horse radish peroxidase conjugate as an enzymatic tracer. In order to assess ELISA sensitivity and specificity, a between methods comparison was made using 'conventional' serological tests as reference (dye-test, crossover-linked immunoassay, passive haemagglutination, indirect immunofluorescence). From an analysis of the group classifications obtained some considerations emerged: the ELISA specificity looks comparable with that of the 'reference' tests, as no sample classified as negative by all these tests was ELISA-positive, and vice versa; ELISA appears to correlate better with haemagglutination and immunofluorescence, on the basis of the respective class frequencies; in particular, the number of positives, which is much lower for the dye-test and crossover-linked immunoassay, suggests that a higher sensitivity is reached in the former cases.

Antibodies↗
PubMed1988

Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and a retrospective study of the same patients at two different ages.

Two studies were performed in children with cystic fibrosis (CF) to compare the efficacy and tolerability of pancreatic enzymes prepared as enteric-coated microspheres with that of a conventional enzyme preparation. The parameters evaluated included the following: fecal fat excretion, coefficient of fat absorption, daily caloric intake, percent of diet as fats, proteins and carbohydrates, increase in height and weight, frequency and consistency of stools, palatability of the preparation, and patient compliance. The first study was an open randomized crossover trial of an enteric-coated microsphere preparation (Pancrease) versus conventional pancreatin given alone or with cimetidine. With Pancrease compared to conventional pancreatin, a significant improvement was observed in all the digestive parameters in addition to better patient compliance. In the second study, the response of a group of CF patients given Pancrease for at least 3 months (3-67 months) was retrospectively compared with the response to conventional pancreatin, which had been given to the same patients from 10 months to 8 years earlier. In comparison to conventional pancreatin, Pancrease provided better digestive efficacy and greater increases in the growth rate of teenage patients. With Pancrease, the number of daily dosage units is decreased even when fat intake is increased. No adverse reactions were seen with either of the enzyme preparations used in these studies.

Adolescent↗
PubMed1997

Generation of coronavirus spike deletion variants by high-frequency recombination at regions of predicted RNA secondary structure.

Coronavirus RNA evolves in the central nervous systems (CNS) of mice during persistent infection. This evolution can be monitored by detection of a viral quasispecies of spike deletion variants (SDVs) (C. L. Rowe, S. C. Baker, M. J. Nathan, and J. O. Fleming, J. Virol. 71:2959-2969, 1997). We and others have found that the deletions cluster in the region from 1,200 to 1,800 nucleotides from the 5' end of the spike gene sequence, termed the "hypervariable" region. To address how SDVs might arise, we generated the predicted folding structures of the positive- and negative-strand senses of the entire 4,139-nt spike RNA sequence. We found that a prominent, isolated stem-loop structure is coincident with the hypervariable region in each structure. To determine if this predicted stem-loop is a "hot spot" for RNA recombination, we assessed whether this region of the spike is more frequently deleted than three other selected regions of the spike sequence in a population of viral sequences isolated from the CNS of acutely and persistently infected mice. Using differential colony hybridization of cloned spike reverse transcription-PCR products, we detected SDVs in which the hot spot was deleted but did not detect SDVs in which other regions of the spike sequence were exclusively deleted. Furthermore, sequence analysis and mapping of the crossover sites of 25 distinct patterns of SDVs showed that the majority of crossover sites clustered to two regions at the base of the isolated stem-loop, which we designated as high-frequency recombination sites 1 and 2. Interestingly, the majority of the left and right crossover sites of the SDVs were directly across from or proximal to one another, suggesting that these SDVs are likely generated by intramolecular recombination. Overall, our results are consistent with there being an important role for the spike RNA secondary structure as a contributing factor in the generation of SDVs during persistent infection.

Base Sequence↗
PubMed1990

Two families of low-copy-number repeats are interspersed on Xp22.3: implications for the high frequency of deletions in this region.

The locations of two families of low-copy-number repeats (CRI-S232 and G1.3) in the physical and genetic maps of the distal short arm of the human X chromosome (Xp22.3) have been determined. Single-copy fragments flanking several repeat elements from each family have been cloned and assigned to specific intervals on a deletion map of Xp22.3. Physical distances between these loci and previously isolated Xp22.3 markers have been determined by pulsed-field gel electrophoresis (PFGE). The positions of some of these markers on the genetic map of the region have been established by segregation analysis in CEPH families. Four members of the CRI-S232 family have been localized within 3 Mb on Xp22.3, interspersed with two members of the G1.3 family. Both deletion and PFGE mapping data suggest that a CpG island localized in a specific position on the map might be associated with the Kallmann syndrome gene. Unlike the previously reported data on hyperpolymorphic minisatellite sequences, no increase in the recombination rate was detected around the CRI-S233 repeats. The presence of several repeat elements in a region with a very high frequency of deletions, such as Xp22.3, is highly suggestive of the occurrence of unequal crossovers between the various elements, leading to deletion events.

Chromosome Deletion↗
PubMed2005

Short-term effect of transdermal estrogen on autonomic nervous modulation in postmenopausal women.

OBJECTIVE: To evaluate the effect of short-term transdermal estradiol-l7b on cardiac autonomic nervous modulation in postmenopausal women. DESIGN: Prospective study. SETTING: A tertiary medical center. PATIENT(S): Twenty-one postmenopausal women. INTERVENTION(S): Transdermal estradiol or placebo therapy for 3 weeks in randomized, double-blinded, crossover fashion. MAIN OUTCOME MEASURE(S): Heart rate variability measures in both time and frequency domains, serum biochemistry, and climacteric symptoms were compared among baseline, placebo and transdermal estrogen therapies. RESULT(S): Plasma concentration of estradiol rose significantly from 11.0 +/- 5.2 pg/ml to 48.2 +/- 34.0 pg/ml after transdermal estrogen. The standard deviation of RR-interval increased significantly from 30.3 +/- 9.9 ms (placebo) to 31.3 +/- 7.4 ms (transdermal estrogen), and the coefficient of variation of RR-interval increased significantly as compared with the baseline session. The total power was marginally increased as compared among baseline, placebo, and transdermal estrogen sessions. The irritability symptom decreased significantly after transdermal estrogen therapy, as compared with baseline and placebo treatment. CONCLUSION(S): Transdermal estradiol for 3 weeks could significantly increase the global heart rate variability and reduce the irritability symptom in the postmenopausal women. Short-term transdermal estrogen for 3 weeks could improve cardiac autonomic nervous modulation and climacteric symptoms, and might have some cardioprotective effect in postmenopausal women.

Administration, Cutaneous↗
PubMed1994

A prospective evaluation of benzocaine-associated methemoglobinemia in human beings.

STUDY OBJECTIVE: This study determined the frequency and severity of benzocaine-associated methemoglobinemia in routine clinical use. DESIGN: Prospective, crossover, convenience study. SETTING: Gastroenterology clinic at a US Army medical center functioning as a community hospital and tertiary referral center. PARTICIPANTS: Healthy adult volunteers and patient volunteers undergoing an upper gastrointestinal endoscopic procedure. INTERVENTIONS: Baseline methemoglobin levels were measured. Subjects then received a 2-second spray of benzocaine to the oropharynx. Venous blood for methemoglobin analysis was collected 20, 40, and 60 minutes after benzocaine dosing and analyzed using a co-oximeter. RESULTS: A statistically significant (P < .05) increase in methemoglobin level between baseline (0.8 +/- 0.2%) and 20-, 40-, and 60-minute measurements (0.9 +/- 0.2%) was identified using one-way analysis of variance followed by Fisher's protected least-squares difference. CONCLUSION: A 2-second spray of 20% benzocaine applied to the oropharynx of human beings induces a statistically significant, but clinically insignificant, increase in methemoglobin levels.

Adult↗
PubMed1983

Unequal crossing-over associated with asymmetrical synapsis between nomadic elements in the Drosophila melanogaster genome.

The molecular structure of reciprocal duplications and deficiencies produced by unequal crossing-over at the white (w) locus of Drosophila melanogaster females heterozygous for the alleles w(a) and w(a4) has been examined. A transposable, copia-like element is found at the rearrangement breakpoints. Further characterization indicates that asymmetrical pairing between two copies of this element, which are at least 60 kilobases apart in the parental chromosomes, followed by a crossover within the paired elements, is responsible for the duplication and deficiencies observed. The frequency of these events is high compared with normal homologous exchange, implying that synaptic pairing during meiosis must be sufficiently flexible as to allow efficient recognition of sequences located in nonidentical positions on homologous chromosomes. These results suggest a possible mechanism for the generation of tandem duplications in eukaryotic organisms.

Journal Article↗
PubMed1974

The distribution of crossovers along unreplicated lambda bacteriophage chromosomes.

The distribution of crossovers along unreplicated chromosomes of bacteriophage lambda has been examined by determining the density distributions and genotypes of particles in the progenies of crosses of density-labeled by ordinary parents in the presence of genetic blocks to replication. The Red and Rec systems combined produce crossovers primarily near the ends (especially the right end) of the chromosome. Removal of the generalized lambda recombination functions by red and gam mutations results in loss of these terminal crossovers; coupled with this loss is a disappearance of the differential dependence of recombination frequencies in terminal and central intervals on DNA synthesis. Removal of the bacterial system by a recA mutation results in severe depression of crossing over among unreplicated phage, with the few recombinants produced by the lambda system occurring near the right end.

Chromosome Mapping↗
PubMed1989

Effects of cisapride on ano-rectal sphincter function.

To investigate the effects of cisapride, a motility-inducing agent, on ano-rectal sphincter functions, standard manometry was performed in 10 healthy male volunteers after 5 days on a 20-mg dose of cisapride in a placebo-controlled double-blind randomized crossover fashion. All subjects kept stool diaries during the experiment. Cisapride significantly increased stool frequency by adding soft and liquid stools; in addition, anal resting pressure was reduced with cisapride in seven of the 10 subjects; mean resting pressure decreased by 16%, while all other measurements were not altered. This suggests that cisapride may act directly on the smooth muscle of the internal anal sphincter. It also supports the view that enhanced defaecation in chronic constipation induced by cisapride may not be achieved by propulsive motor activity in the colon but also by a decreased anal sphincter tone.

Adult↗
PubMed1986

Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis.

The prophylactic effects of the antiprostaglandin agent mefenamic acid on migraine attacks were compared with propranolol or placebo in a double-blind crossover study of 29 patients. In the 17 patients who completed the trial the frequency of attacks and their total duration were significantly reduced during mefenamic acid therapy or propranolol therapy as compared to placebo. There were no significant effects of mefenamic acid or propranolol on average duration or severity of migraine attacks. The study suggests that mefenamic acid and propranolol are equally effective for migraine prophylaxis.

Adult↗
PubMed2004

Mouse strains with an active H2-Ea meiotic recombination hot spot exhibit increased levels of H2-Ea-specific DNA breaks in testicular germ cells.

We devised a sensitive method for the site-specific detection of rare meiotic DNA strand breaks in germ cell-enriched testicular cell populations from mice that possess or lack an active recombination hot spot at the H2-Ea gene. Using germ cells from adult animals, we found an excellent correlation between the frequency of DNA breaks in the 418-bp H2-Ea hot spot and crossover activity. The temporal appearance of DNA breaks was also studied in 7- to 18-day-old mice with an active hot spot during the first waves of spermatogenesis. The number of DNA breaks detected rose as leptotene and zygotene spermatocytes populate the testis with a peak at day 14 postpartum, when leptotene, zygotene, and early pachytene spermatocytes are the most common meiotic prophase I cell types. The number of DNA breaks drops precipitously 1 day later, when middle to late pachytene spermatocytes become the dominant subtype. The recombination-related breaks in the hot spot likely reflect SPO11-induced double-strand breaks and/or recombination intermediates containing free 3' hydroxyl groups.

Animals↗
PubMed1986

A randomized, double-blind, crossover study of phenobarbital and mephobarbital.

Some pediatric neurologists maintain that mephobarbital (Mebaral) causes fewer behavioral side effects than phenobarbital. Because this hypothesis has not been previously tested, we conducted a prospective, double-blind, randomized, crossover study of these two anticonvulsants. Both drugs were equally effective in reducing the frequency of seizure, although serum phenobarbital levels were significantly higher when the patients were taking phenobarbital compared to mephobarbital. As measured by the Abbott Parent Questionnaire, there was no significant deterioration of behavior with either phenobarbital or mephobarbital, regardless of which drug was administered first.

Child↗