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PubMed1990

Naltrexone attenuates self-injurious behavior in mentally retarded subjects.

The effect of naltrexone on the frequency of self-injurious behavior (SIB) was investigated in 6 male subjects with profound mental retardation. Following a double-blind placebo-controlled crossover design, naltrexone was administered in a dose of 50 mg once daily for 3 consecutive weeks. In 2 of 5 subjects, a significant decrease of SIB frequency could be demonstrated, and in 1, a tendency to a reduction was found. No effect on duration of restrain time was found in 3 subjects. These data suggest that disturbances of the endogenous opioid systems may be involved in the pathophysiology of SIB of certain patients.

Administration, Oral↗
PubMed1990

Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome.

To determine whether early use of high-frequency jet ventilation reduces neonatal mortality or pulmonary morbidity rates, we randomly selected 42 infants with clinical and radiographic evidence of severe respiratory distress syndrome to receive either high-frequency jet ventilation or conventional ventilation. Separate sequential analyses (two-sided, alpha = 0.05, power = 0.95 to detect 85:15 advantage) were performed for mortality rates, air leaks, bronchopulmonary dysplasia, intraventricular hemorrhage, and assignment crossover, and a combined analysis was performed, with death overriding other outcome variables. Enrollment was completed when the combined analysis reached the sequential design boundary indicating no treatment difference. Mortality rates (19% among infants receiving high-frequency jet ventilation vs 24% among infants receiving conventional ventilation), the incidence of air leaks (48% vs 52%), bronchopulmonary dysplasia (39% vs 41%), and intraventricular hemorrhage (33% vs 43%), and assignment crossovers (14% vs 24%) did not differs significantly between the treatment groups. We conclude that early use of high-frequency jet ventilation does not prevent or substantially reduce mortality or morbidity rates associated with assisted ventilation.

Age Factors↗
PubMed1983

Desmopressin response of enuretic children. Effects of age and frequency of enuresis.

To characterize the children with enuresis likely to respond to desmopressin acetate, we performed a double-blind crossover study that included the use of a placebo. During the two weeks of desmopressin administration, six children (12%) had 13 or 14 dry nights, and 15 children (29%) had eight to 12 dry nights. Among the 17 children aged 9 years or older, with four to seven dry nights during the two-week baseline period, 12 children (71%) responded to desmopressin (eight to 14 dry nights). In contrast, none of the 15 children younger than 9 years of age with fewer than three dry nights before therapy responded. During the posttreatment period, only four of the 21 drug responders reported a persistent effect. Desmopressin may be effective in reducing the frequency of enuresis, especially in children older than 9 years of age without nightly enuresis.

Adolescent↗
PubMed1986

Efficacy and safety of sustained-release diltiazem in stable angina pectoris.

The safety and efficacy of a sustained-release preparation of diltiazem (diltiazem-SR), with dose levels of 240 and 360 mg/day, were assessed in 18 patients with stable angina of effort. A double-blind, placebo-controlled, randomized, crossover protocol was used. Diltiazem-SR, when given twice daily, reduced the frequency of weekly anginal attacks from 9.3 +/- 10.4 with placebo to 3.7 +/- 4.7 with 240 mg/day and to 3.1 +/- 4.7 with 360 mg/day (both p less than 0.01 compared with placebo). Treadmill time was increased from 410 +/- 180 seconds during the placebo phase to 519 +/- 177 seconds during the 240-mg/day dose and to 506 +/- 182 seconds during the 360-mg/day dose of diltiazem-SR (both p less than 0.01 compared with placebo). The time to the onset of angina and ischemic ST-segment depression were similarly prolonged by both doses of diltiazem-SR. The beneficial effects of diltiazem-SR appeared partly due to a reduction in the heart rate during submaximal exercise. Diltiazem-SR is effective and safe for the treatment of angina of effort when given twice daily.

Aged↗
PubMed1987

Analysis of intracellular small RNAs of mouse hepatitis virus: evidence for discontinuous transcription.

We have previously shown the presence of multiple small leader-containing RNA species in mouse hepatitis virus (MHV)-infected cells. In this paper, we have analyzed the origin, structure, and mechanism of synthesis of these small RNAs. Using cDNA probes specific for leader RNA and genes A, D, and F, we demonstrate that subsets of these small RNAs were derived from the various viral genes. These subsets have discrete and reproducible sizes, varying with the gene from which they are derived. The size of each subset correlates with regions of secondary structure, whose free energy ranges from -1.6 to -77.1 kcal/mol, in each of the mRNAs examined. In addition, identical subsets were detected on the replicative intermediate (RI) RNA, suggesting that they represent functional transcriptional intermediates. The biological significance of these small RNAs is further supported by the detection of leader-containing RNAs of 47, 50, and 57 nucleotides in length, which correspond to the crossover sites in two MHV recombinant viruses. These data, coupled with the high frequency of RNA recombination during MHV infection, suggest that the viral polymerase may pause in or around regions of secondary structure, thereby generating pools of free leader-containing RNA intermediates which can reassociate with the template, acting as primers for the synthesis of full-length or recombinant RNAs. These data suggest that MHV transcription uses a discontinuous and nonprocessive mechanism in which RNA polymerase allows the partial RNA products to be dissociated from the template temporarily during the process of transcription.

DNA↗
PubMed2005

Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.

BACKGROUND: The objective of this study was to compare the efficacy and tolerability of molsidomine prolonged-release 16 mg once-a-day (o.a.d.) with 8 mg twice-a-day (b.i.d.) and placebo in patients with stable angina pectoris. METHODS: After a run-in placebo period of 7 days, the two formulations were compared acutely and then chronically (2 weeks) using cycloergometric tests and a randomized, multicenter, double-blind, double-dummy, crossover design in 533 patients. The quality of life was assessed using the frequency of anginal crises and nitrate sublingual tablets consumption. RESULTS: Both formulations significantly improved exercise test parameters compared with placebo, being it after acute drug intake or after a 2-week treatment period and independently of spontaneous diurnal variation in exercise tolerance. Noninferiority of molsidomine 16 mg compared with 8 mg was demonstrated with a statistically significant superiority of the 16-mg formulation from 14 to 24 h postintake. Both treatments reduced incidence of anginal attacks and use of sublingual isosorbide dinitrate tablets. Tolerability of active drugs was satisfactory, the incidence of drug-related headache being not significantly different from placebo. Only hypotension was significantly more frequent with molsidomine 16 mg than with placebo, pretrial diastolic blood pressure being significantly lower in these patients than in those who did not develop hypotension during the study. CONCLUSIONS: Both molsidomine formulations were effective in controlling patients' angina, did not induce any habituation and were well tolerated. However, the once-daily 16-mg formulation tended to provide better 24-h protection against myocardial ischemia than the 8-mg b.i.d. formulation.

Adult↗
PubMed1980

Molsidomine in the treatment of patients with angina pectoris.

Molsidomine, a new long-acting vasodilator, was administered intravenously (0.03 mg per kilogram of body weight) to two groups of six patients with stable anginapectoris. In the first group, studied during exercise-induced angina, the drug shortened the duration of pain and reduced electrocardiographically measured ST-segment depression, mean systemic arterial pressure, and mean pulmonary wedge pressure. Cardiac output and heart rate remained unchanged. In the second group, studied during pacing-induced angina, the drug reduced both left ventricular pressures and angiographically estimated ventricular volumes and improved the ejection fraction. In a double-blind crossover comparison with a placebo, molsidomine (2 mg three times daily) reduced the frequency of anginal attacks and the consumption of nitroglycerin tablets in 14 patients. During exercise testing on a treadmill a statistically significant reduction in ST-segment depression lasted for up to six hours. These studies suggest that molsidomine acts like nitroglycerin but its effects last longer. We conclude that molsidomine is effective in preventing the symptoms of angina pectoris. (N Engl J Med 302:1-6, 1980).

Adult↗
PubMed2006

Meiotic segregation analysis in spermatozoa of pericentric inversion carriers using fluorescence in-situ hybridization.

BACKGROUND: Pericentric inversions are structural chromosomal abnormalities resulting from two breaks, one on either side of the centromere, within the same chromosome, followed by 180 degrees rotation and reunion of the inverted segment. They can perturb spermatogenesis and lead to the production of unbalanced gametes through the formation of an inversion loop. METHODS: We report here the analysis of the meiotic segregation in spermatozoa from six pericentric inversion carriers by multicolour fluorescence in-situ hybridization (FISH) and review the literature. RESULTS: The frequencies of the non-recombinant products (inversion or normal chromosomes) were 80% for the inv(20), 91.41% for the inv(12), 99.43% for the inv(2), 68.12% for the inv(1), 97% for the inv(8)(p12q21) and 60.94% for the inv(8)(p12q24.1). The meiotic segregation of 20 pericentric inversions (including ours) is now available. The frequency of unbalanced spermatozoa varies from 0 to 37.85%. The probability of a crossover within the inverted segment is affected by the chromosome and region involved, the length of the inverted segment and the location of the breakpoints. CONCLUSIONS: No recombinant chromosomes were produced when the inverted segment involved <30% of the chromosome length (independent of the size of the inverted segment). Between 30 and 50%, few recombinant chromosomes were produced, inducing a slightly increased risk of aneusomy of recombination in the offspring. The risk of aneusomy became very important when the inverted segment was >50% of the chromosome length. Studies on spermatozoa from inversion carriers help in the comprehension of the mechanisms of meiotic segregation. They should be integrated in the genetic exploration of the infertile men to give them a personalized risk assessment of unbalanced spermatozoa.

Adult↗
PubMed1985

Human X chromosome markers and Duchenne muscular dystrophy.

Two DNA markers, a random DNA fragment 754 and the cDNA sequence encoding the gene for ornithine transcarbamylase (OTC) have been studied in kindreds segregating for Duchenne muscular dystrophy. 754 and OTC are located close physically to the mutation in the region Xp21 below the breakpoints in two Duchenne females. The genetic distance was found to be approximately 10cM between 754 and DMD (two crossovers in 26 meioses) and to be approximately 10cM between OTC and DMD (two crossovers in 26 meioses). Physical data suggest the order DMD-754-OTC. The frequency of recombination compared to physical distance between these markers and DMD suggests that there may be a hot spot of recombination. The relevance of these observations for the isolation of the DMD mutation and clinical use of these probes is discussed.

Chromosome Mapping↗
PubMed1985

A double-blind multiple crossover trial evaluating a transdermal nitroglycerin system vs placebo.

Fifty-six patients with angina pectoris on effort participated in a 28-day study comparing a transdermal nitroglycerin system (TNS) against placebo. The protocol was based on a regular double-blind multi-crossover pattern. The variables recorded included daily sublingual nitroglycerin requirement, daily anginal attack frequency, and a subjective patient evaluation of each day on a visual analog scale. TNS dosage ranged from 10 cm2 (5 mg per 24 h) to 60 cm2 (30 mg per 24 h) based on the patient's dosage prior to commencement of the study. All other medication was continued unchanged. The results demonstrate improvement on active therapy in the patient group using greater than or equal to 20 cm2 TNS whereas no significant improvement in patients using 10 cm2 TNS was seen. In the higher dose group, the mean number of daily anginal attacks was 2.5 on placebo and 1.4 on active therapy (P less than 0.0001). Corresponding mean daily sublingual nitroglycerin requirement was 3.6 on placebo and 2.3 on active therapy (P less than 0.0001). Although TNS therapy was associated with significant improvement in the group using the higher dosage, the results suggest the development of tolerance on active therapy. The possibility of rebound effect and the absence of demonstrable efficacy in the low dose group require further investigation.

Administration, Topical↗
PubMed2005

Localization and speech-identification ability of hearing-impaired listeners using phase-preserving amplification.

OBJECTIVE: The purpose of these experiments was to determine the ability of hearing-impaired listeners to localize and to identify speech in noise using phase-preserving and non-phase-preserving amplification. DESIGN: These abilities were measured 4 times over each of two 16-week periods, using a randomized, single-blinded, within-subject crossover design. Listeners were fitted bilaterally, using the National Acoustic Laboratories linear frequency-gain characteristic with a digital hearing aid programmed in one of two ways: (1) with a linear-phase filter and (2) with filters designed to compensate for the magnitude and phase anomalies caused by the hearing aid fitting, thus preserving interaural phase. Listeners identified a word and its location in background noise with a speech-shaped spectrum. RESULTS: Immediately after fitting, both hearing aid programs reduced the listeners' ability to localize the speech in noise. The phase-preserving processing had a less detrimental effect on localization ability immediately after fitting. After 3 weeks, performance improved such that, for localization in noise, there was no detrimental effect of amplification and no difference between the two processing strategies. Over 16 weeks, speech understanding in noise improved. Speech understanding for phase-preserving processing was slightly and significantly better than linear-phase processing at 16 weeks. CONCLUSIONS: Localization ability using phase-preserving amplification does not differ from localization ability using traditional non-phase-preserving amplification after just 3 weeks of use. Listeners quickly acclimated to altered spatial cues. Phase-preserving amplification provided a 2.3% advantage for speech intelligibility in noise after 16 weeks.

Aged↗
PubMed2003

Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure.

OBJECTIVE: Positive end-expiratory pressure (PEEP) and recruitment maneuvers (RMs) may partially reverse atelectasis and reduce ventilation-associated lung injury. The purposes of this study were to assess a) magnitude and duration of RM effects on arterial oxygenation and on requirements for oxygenation support (Fio2/PEEP) in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) receiving ventilation with low tidal volumes and high levels of PEEP; and b) frequency of adverse respiratory and circulatory events attributable to RMs. DESIGN: Prospective, randomized, crossover study. SETTING: Thirty-four intensive care units at 19 hospitals. PATIENTS: Seventy-two patients with early ALI/ARDS. Baseline PEEP and Fio2 were 13.8 +/- 3.0 cm H2O and 0.39 +/- 0.10, respectively (mean +/- sd). INTERVENTIONS: We conducted RMs by applying continuous positive airway pressure of 35-40 cm H2O for 30 secs. We conducted sham RMs on alternate days. We monitored oxyhemoglobin saturation by pulse oximetry (SpO2), Fio2/PEEP, blood pressure, and heart rate for 8 hrs after RMs and sham RMs. We examined chest radiographs for barotrauma. MEASUREMENTS AND MAIN RESULTS: Responses to RMs were variable. Greatest increments from baseline SpO2 within 10 mins after RMs were larger than after sham RMs (1.7 +/- 0.2 vs. 0.6 +/- 0.3 %, mean +/- SEM, p < .01). Systolic blood pressure decreased more +/- 1.1 mm Hg, p < .01). Changes in Fio2/PEEP requirements were not significantly different at any time after RMs vs. sham RMs. Barotrauma was apparent on first radiographs after one RM and one sham RM. CONCLUSIONS: In ALI/ARDS patients receiving mechanical ventilation with low tidal volumes and high PEEP, short-term effects of RMs as conducted in this study are variable. Beneficial effects on gas exchange in responders appear to be of brief duration. More information is needed to determine the role of recruitment maneuvers in the management of ALI/ARDS.

Blood Pressure↗
PubMed2006

Single polymer molecules in a protein nanopore in the limit of a strong polymer-pore attraction.

The capture and release of single poly(ethylene glycol) molecules by the alpha-Hemolysin pore are observed as time-resolved reversible steps in ion conductance. The capture on rate, inferred from the step frequency, decreases monotonically with polymer size. However, the polymer residence time shows a crossover behavior, first increasing and then decreasing with molecular weight. Our interpretation is that, in the case of polymers which are too large to be accommodated within the pore, the out-of-the-pore part of the molecule pulls on the trapped part, thus acting as an entropic spring.

Bacterial Toxins↗
PubMed1999

Triggering of myocardial infarction by cocaine.

BACKGROUND: Cocaine has been implicated as a trigger of acute myocardial infarction in patients with and those without underlying coronary atherosclerosis. However, the magnitude of the increase in risk of acute myocardial infarction immediately after cocaine use remains unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3946 patients (1282 women) with acute myocardial infarction an average of 4 days after infarction onset. Data were collected on the use of cocaine and other potential triggers of myocardial infarction. We compared the reported use of cocaine in the hour preceding the onset of myocardial infarction symptoms with its expected frequency by using self-matched control data based on the case-crossover study design. Of the 3946 patients interviewed, 38 (1%) reported cocaine use in the prior year and 9 reported use within the 60 minutes preceding the onset of infarction symptoms. Compared with nonusers, cocaine users were more likely to be male (87% vs 67%, P=0.01), current cigarette smokers (84% vs 32%, P<0.001), younger (44+/-8 vs 61+/-13 years, P<0.001), and minority group members (63% vs 11%, P<0.001). The risk of myocardial infarction onset was elevated 23.7 times over baseline (95% CI 8.5 to 66.3) in the 60 minutes after cocaine use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk. This finding suggests that studying the pathophysiological changes produced by cocaine may provide insights into the mechanisms by which myocardial infarction is triggered by other stressors.

Adult↗
PubMed2006

Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin.

OBJECTIVE: Strategies for preventing hypoglycemia during exercise in children with type 1 diabetes have not been well studied. The Diabetes Research in Children Network (DirecNet) Study Group conducted a study to determine whether stopping basal insulin could reduce the frequency of hypoglycemia occurring during exercise. RESEARCH DESIGN AND METHODS: Using a randomized crossover design, 49 children 8-17 years of age with type 1 diabetes on insulin pump therapy were studied during structured exercise sessions on 2 days. On day 1, basal insulin was stopped during exercise, and on day 2 it was continued. Each exercise session, performed from approximately 4:00-5:00 p.m., consisted of four 15-min treadmill cycles at a target heart rate of 140 bpm (interspersed with three 5-min rest breaks over 75 min), followed by a 45-min observation period. Frequently sampled glucose concentrations (measured in the DirecNet Central Laboratory) were measured before, during, and after the exercise. RESULTS: Hypoglycemia (< or = 70 mg/dl) during exercise occurred less frequently when the basal insulin was discontinued than when it was continued (16 vs. 43%; P = 0.003). Hyperglycemia (increase from baseline of > or = 20% to > or = 200 mg/dl) 45 min after the completion of exercise was more frequent without basal insulin (27 vs. 4%; P = 0.002). There were no cases of abnormal blood ketone levels. CONCLUSIONS: Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with type 1 diabetes, but the risk of hyperglycemia is increased.

Adolescent↗
PubMed1983

Statistical analysis of multilocus recombination.

A general formula for the frequency of different recombinant gamete types, in terms of the underlying distribution of crossovers, is derived. This formula may be applied to any theoretical model of recombination in which it is assumed that there is no chromatid interference. Multiple-locus recombination data may be evaluated by using this formula in conjunction with a maximum likelihood procedure. The validity of any model of recombination may be tested in such a fashion. The possibilities are demonstrated through application to a generalized noninterference model of crossing over described in a previous paper (Risch and Lange, 1979, Annals of Human Genetics 43, 61-70).

Animals↗
PubMed1993

Nondisjunction of chromosome 15: origin and recombination.

Thirty-two cases of uniparental disomy (UPD), ascertained from Prader-Willi syndrome patients (N = 27) and Angelman syndrome patients (N = 5), are used to investigate the pattern of recombination associated with nondisjunction of chromosome 15. In addition, the meiotic stage of nondisjunction is inferred by using markers mapping near the centromere. Two basic approaches to the analysis of recombination are utilized. Standard methods of centromere mapping are employed to determine the level of recombination in specific pairwise intervals along the chromosome. This method shows a significant reduction in recombination for two of five intervals examined. Second, the observed frequency of each recombinant class (i.e., zero, one, two, three, or more observable crossovers) is compared with expected values. This is useful for testing whether the reduction in recombination can be attributed solely to a proportion of cases with no recombination at all (because of asynapsis), with the remaining groups showing normal recombination (or even excess recombination), or whether recombination is uniformly reduced. Analysis of maternal UPD(15) data shows a slight reduction in the multiple-recombinant classes, with a corresponding increase in both the zero- and one-recombinant classes over expected values. The majority, more than 82%, of the extra chromosomes in maternal UPD(15) cases are due to meiotic I nondisjunction events. In contrast, most paternal UPD(15) cases so far examined appear to have a postzygotic origin of the extra paternal chromosome.

Aneuploidy↗
PubMed2005

The Drosophila meiotic mutant mei-352 is an allele of klp3A and reveals a role for a kinesin-like protein in crossover distribution.

The semisterile meiotic mutant mei-352 alters the distribution of meiotic exchanges without greatly affecting their total frequency. We show that the mei-352 mutation is an allele of the klp3A gene, which encodes a kinesin-like protein of the Kinesin-4 family. The semisterility observed in mei-352 females results from a known defect of klp3A oocytes in mediating pronuclear fusion. Interestingly, other klp3A alleles also exhibit defects in meiotic recombination similar to those of mei-352. Finally, we show that the Klp3A protein localizes within the oocyte nucleus during meiotic prophase, the time at which exchange distribution is established, and extensively colocalizes with DNA. The parallel of the klp3A phenotype with a meiotic defect observed for kar3 mutants in yeast suggests a role for kinesins in early meiosis and might reflect a previously suggested role for this class of kinesins in chromosome condensation.

Alleles↗