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mus309 mutation, defective in DNA double-strand break repair, affects intergenic but not intragenic meiotic recombination in Drosophila melanogaster.

The effect was investigated of the hypomorphic DNA double-strand break repair, notably synthesis-dependent strand annealing, deficient mutation mus309 on the third chromosome of Drosophila melanogaster on intergenic and intragenic meiotic recombination in the X chromosome. The results showed that the mutation significantly increases the frequency of intergenic crossing over in two of three gene intervals of the X chromosome studied. Interestingly the increase was most prevalent in the tip of the X chromosome where crossovers normally are least frequent per physical map unit length. In particular crossing over interference was also affected, indicating that the effect of the mus309 mutation involves preconditions of crossing over but not the event of crossing over itself. On the other hand, the results also show that most probably the mutation does not have any effect on intragenic recombination, i.e. gene conversion. These results are fully consistent with the present molecular models of meiotic crossing over initiated by double-strand breaks of DNA followed by formation of a single-end-invasion intermediate, or D-loop, which is subsequently processed to generate either crossover or non-crossover products involving formation of a double Holliday junction. In particular the results suggest that the mus309 gene is involved in resolution of the D-loop, thereby affecting the choice between double-strand-break repair (DSBR) and synthesis-dependent strand annealing (SDSA) pathways of meiotic recombination.

Animals↗

Protriptyline in obstructive sleep apnea: a double-blind trial.

We evaluated protriptyline, a nonsedating tricyclic antidepressant, as a treatment for obstructive sleep apnea in a double-blind crossover study of five men. After two weeks of treatment, with no change in body weight, daytime somnolence was markedly reduced and nocturnal oxygenation was improved, although apnea duration and frequency were not significantly decreased. Rapid-eye-movement (REM) stage time as a fraction of the total sleep time was reduced during treatment from 0.231 +/- 0.031 to 0.107 +/- 0.013 (mean +/- S.E.M.) (P less than 0.05). REM apnea time as a fraction of total sleep time was reduced from 0.145 +/- 0.022 to 0.054 +/- 0.006 (P less than 0.05). REM reduction during treatment with protriptyline can account for decreased REM apnea time. Similar decreases in REM stage time and REM apnea duration and similar improvement in oxygenation continued after six months of treatment. In addition, body weight, apnea, and arousal frequency were decreased at this time. Although the obstructive sleep apnea was not resolved, it was reduced. Protriptyline can be effective in patients with sleep apnea when the disorder is not life-threatening.

Adult↗

Lorazepam-enhancement of the antiemetic efficacy of dexamethasone and promethazine. A placebo-controlled study.

This investigation was designed with the objective of improving on currently available antiemetic regimens to counteract the disabling side effects of cancer chemotherapy. The combination of lorazepam, dexamethasone, and promethazine was compared with dexamethasone and promethazine without lorazepam in a double-blind crossover study. The initial study population consisted of 92 women (most with breast cancer) and 7 men; all received moderately or highly emetogenic chemotherapy. Complete data for both periods of therapy were available for 73 of these patients. Crossover analysis showed a highly significant effect of lorazepam in reducing the severity of nausea (p = .003); the severity of vomiting was also reduced, but less dramatically (p = .051). The frequency of all degrees of nausea and vomiting was less with lorazepam, but the difference was not statistically significant. It is concluded that lorazepam added to dexamethasone and promethazine provides an effective regimen for counteracting the emetic side effects of cancer chemotherapy.

Adult↗

Single dose nasal 17beta-estradiol administration reduces sympathovagal balance to the heart in postmenopausal women.

AIM: Long-term estrogen replacement therapy has favorable results on autonomic cardiovascular functions in postmenopausal women. Although acute estrogen administration has beneficial modulations on autonomic tone in animal studies, there are still controversies about the effects of acute estrogen on autonomic modulation to the heart in humans. The aim of this double-blind study was to investigate the acute effects of intranasal 17beta-estradiol administration on autonomic control of heart rate. METHODS: Nineteen postmenopausal women with typical hormone profiles were crossover randomized to 300 micro g nasal 17beta-estradiol (Aerodiol, Servier, Chambray-les-Tours, France) or an identical placebo at least 5 days apart. Both time domain and frequency domain heart rate variability (HRV) parameters were obtained during controlled respiration (CR) and handgrip exercise (HGE), before and 45 min after 17beta-estradiol or placebo administration. RESULTS: Baseline HRV parameters were similar for each occasion. Time domain indices obtained after 17beta-estradiol administration were not significantly different from results obtained with the placebo. In frequency domain parameters, 17beta-estradiol administration resulted in a reduced low frequency to high frequency ratio (LF/HF ratio) when compared with the placebo during CR (0.72 +/- 0.09 vs 1.00 +/- 0.15, P < 0.05) but not during HGE (3.03 +/- 0.37 vs 2.86 +/- 0.30, P > 0.05). CONCLUSION: A single intranasal 17beta-estradiol administration acutely reduced sympathovagal balance to the heart during the course of parasympathetic maneuver in healthy postmenopausal women.

Administration, Intranasal↗

Efficacy of diltiazem in the treatment of diffuse oesophageal spasm.

Calcium antagonist relax smooth muscle, a possible useful concept in treatment of diffuse oesophageal spasm. Therefore the effects of oral diltiazem (60 mg t.d.s.) and placebo were compared in eight patients with diffuse oesophageal spasm in a 10-week double-blind crossover study. The patients recorded the severity of chest pain and/or dysphagia in daily pain diaries using visual analogue scales. Chest pain index and dysphagia index were calculated by multiplying frequency with daily intensity of each individual symptom. When compared to placebo, diltiazem did not significantly change the overall dysphagia index and chest pain index. An individual sizeable reduction of dysphagia was attained on diltiazem in four out of six patients and in six out of eight patients suffering from chestpain. Side effects were not seen during diltiazem therapy. Diltiazem, in our study, did not yield in a significant improvement of symptoms in diffuse oesophageal spasm. Diltiazem, however, can offer relief in selected individual patients suffering from diffuse oesophageal spasm.

Adult↗

Development of distortion product emissions in the gerbil: "filter" response and signal delay.

Amplitude and phase responses of distortion product otoacoustic emissions as a function of stimulus frequency ratio were measured for frequencies between 2 and 48 kHz, in Mongolian gerbils (Meriones unguiculates) aged 15 to 30 days after birth. After baseline measurements, furosemide was administered to distinguish active from passive emissions. At all ages, structure in the form of multiple peaks was observed in the amplitude responses of specific odd-order emissions. This structure depended on the emission frequency, not the stimulus frequency ratio, and did not generally depend on the stimulus amplitude. Nor was it dependent on the functioning of the cochlear amplifier: At moderate stimulus levels, the observed emission distribution simply shifted to lower amplitudes when the cochlear amplifier was made temporarily dysfunctional by furosemide injection. The center frequencies and widths of the peaks in the amplitude response did not generally change with age, except that the relative amplitudes of the higher-frequency peaks were increased in younger animals. At 2 kHz, however, the distribution showed other evidence of maturation, with the frequency of maximum emission moving downward with age. The phase responses yielded estimates of the round trip signal (group or traveling wave) delay. At a given frequency, the active signal delay typically decreased substantially with increasing stimulus level. However, there was a rapid variation in delay as the stimulus level passed the normal active-passive crossover level. At stimulus levels measured relative to the active-passive crossover level, i.e., either 20 or 30 dB lower, the active signal delay decreased only slightly with age. Overall, both filter response and signal delay characteristics were found to be essentially mature near the onset of hearing.

Acoustic Stimulation↗

A comparison of Agiolax and lactulose in elderly patients with chronic constipation.

In a double-blind crossover study the efficacies of Agiolax, a combination of fibre and senna pod, and lactulose were compared in 77 long-stay elderly patients with chronic constipation. Mean daily bowel frequency, stool consistency and ease of evacuation were significantly greater with Agiolax than lactulose. The recommended dose was exceeded more frequently with lactulose than Agiolax (chi 2 = 8.38, p < 0.01). Adverse effects were not different for the 2 treatments. In long-stay elderly patients with chronic constipation Agiolax and lactulose were well tolerated, but Agiolax proved a more effective treatment.

Aged↗

Intrathecal baclofen for spastic hypertonia from stroke.

BACKGROUND AND PURPOSE: We sought to determine whether continuous intrathecal delivery of baclofen can effectively decrease spastic hypertonia due to stroke. METHODS: Stroke patients with >6 months of intractable spasticity were screened via a randomized, double-blind, placebo-controlled crossover design of either intrathecal normal saline or 50 microgram baclofen. Those who dropped an average of 2 points in either their affected lower extremity side Ashworth or Penn spasm frequency scores were then offered computer-controlled pump implantation for continuous ITB and followed prospectively for up to 12 months. RESULTS: In 21 stroke patients 6 hours after the active drug bolus, the average (+/-SD) lower extremity Ashworth score on the affected extremities decreased from 3.3+/-1.2 to 1.4+/-0.7 (P<0.0001), spasm score from 1.2+/-1.2 to 0.1+/-0.3 (P=0.0224), and reflex score from 2.1+/-1.2 to 0.1+/-0.5 (P<0.0001). The average upper extremity Ashworth score on the affected extremities decreased from 2.8+/-1.1 to 1.8+/-0.8 (P<0.0001), spasm score from 0.7+/-1.0 to 0.2+/-0.4 (P=0.1544), and reflex score from 2.1+/-0.9 to 1.2+/-0.9 (P=0.0004). All active drug scores were statistically different from placebo scores at 6 hours (P<0.05). With up to 12 months of continuous infusion of ITB in 17 implanted patients, the average lower extremity Ashworth score on the affected extremities decreased from 3.7+/-1.0 to 1.8+/-1.1 (P<0.0001), the spasm score dropped from 1.2+/-1.3 to 0.6+/-1.0 (P=0.4282), and the reflex score decreased from 2.4+/-1.3 to 1.0+/-1.3 (P<0.0001). The average upper extremity Ashworth score in the affected extremities decreased from 3.2+/-1.1 to 1.8+/-0.9 (P<0.0001), the spasm score dropped from 0.7+/-1.0 to 0.3+/-0.8 (P=0.8685), and the reflex score decreased from 2.4+/-0.8 to 1.5+/-1.2 (P=0.3337). The average continuous ITB dose required to attain these effects was 268 microgram/d. CONCLUSIONS: Intrathecal infusion of baclofen is capable of maintaining a reduction in the spastic hypertonia resulting from stroke.

Adolescent↗

A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.

OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient's overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.

Adrenergic alpha-Agonists↗

A prospective randomized double blind placebo controlled crossover study of fluoxetine efficacy in the prophylaxis of chronic daily headache in children and adolescents.

Thirty-two children (21 female and 11 male), between 7 and 14 years old, with chronic daily headache (CDH) were consecutively included in a prospective, randomized, double blind, placebo controlled crossover study. The patients were divided in group I (fluoxetine vs. placebo), with 17 patients and group II (placebo vs. fluoxetine), with 15 patients. After one month of baseline headache frequency recording, the patients received fluoxetine in dosages from 0.25 to 0.50 mg/kg for three months. A wash out period of one month was followed by another three months treatment period. Results showed a significant decrease in headache frequency in the study period [78% reduction in group I (p<0.025), and 45% reduction in group II (p=0.025)]. Gastrointestinal adverse effects were observed in nine patients (29%) that received fluoxetine, compared with 3 (10%), with placebo. We conclude that fluoxetine efficacy is not higher than placebo in the prophylaxis of CDH in children and adolescents.

Adolescent↗

Duplication of the human immunoglobulin heavy chain gamma 2 gene.

The five C gamma genes in the human immunoglobulin heavy chain region show nonrandom association and segregation as haplotypes. From the study of genetic variation in C gamma genes of 58 healthy Caucasian volunteers, we have identified a haplotype that involves a duplication of C gamma 2. This haplotype contains both the 13.5-kilobase (kb) and 25-kb BamHI fragment alleles of C gamma 2. In addition, the patterns and relative intensity of BamHI fragments containing C gamma genes were those expected for genomic DNA containing three copies of C gamma 2 for every two copies of the four other C gamma genes. A new EcoRI polymorphism in C gamma 4 was useful in defining the haplotype containing the duplication. Alleles of the C gamma genes in the duplication haplotype, including Gm markers of C gamma 1 and C gamma 3 and DNA polymorphisms of C psi gamma, C gamma 2, and C gamma 4, were consistent with its origin from an unequal crossover between the two common C gamma haplotypes, H1 and H2. This recombinant haplotype, which has been designated H2;1(gamma 2 dup) to reflect its origin, occurred with a frequency of .043 in a random sample of 116 chromosomes.

Alleles↗

A method to assess sodium intake in populations.

Dietary sodium measurement in populations has severe limitations whether assessment is based on urinary excretion or on food intake methods. We have validated a simple instrument to determine total dietary sodium intake of populations in a pilot study of 10 women, 20 to 36 years old. Sodium intake determined by means of the sodium measurement instrument was correlated with sodium intake from food analysis, sodium intake calculated from food composition tables, and measurement of 24-hour urinary sodium excretion. Sodium values obtained with the instrument are based on regression equations, which incorporate information as follows: an average measure of 7 days' actual table salt use, the average sodium contribution of 17 high-sodium foods from a food frequency checklist maintained for 7 days, a calculation of drinking water sodium, and measurements of height and weight to establish 24-hour energy needs, a surrogate estimate of sodium found in all foods not included in the food frequency checklist. Participants were studied for 16 days: 7 consecutive days on either a 2,000-mg or a 3,500-mg sodium diet, 2 days' adjustment, and 7 days' crossover. Participants were allowed to select foods from a diverse menu, eat at fast-food restaurants, and consume alcohol if desired. Mean of 7-day sodium intake obtained with the instrument was significantly correlated with mean of 7-day sodium intake determined by food analysis (r = .80), from food composition tables (r = .62), and from urinary excretion (r = .56).

Adult↗

Oral sustained-release nitroglycerin in chronic stable angina: a multicenter, double-blind, randomized crossover trial.

Forty-six patients with stable angina pectoris were randomized to receive either oral sustained-release nitroglycerin (SRNG, 6.5 mg) or placebo (P) 3 times a day for a 2-week double-blind trial. They were investigated for the frequency of anginal episodes, for sublingual nitroglycerin consumption and for exercise tolerance. There was a slight but significant decrease in the number of anginal episodes (6.4 +/- 1.5 episodes/week with P, 4.9 +/- 1.7 with SRNG, p less than 0.005) and sublingual nitroglycerin consumption (3.9 +/- 1 tablets/week with P, 2.7 +/- 1 with SRNG, p less than 0.005). The patients performed 3 upright multistage (increments of 30 W every 3 minutes) exercise tests on a bicycle ergometer before the start of the study and 1 hour after the intake of SRNG or P, at the end of each double-blind phase. Exercise capacity, expressed as exercise duration, increased from 8.9 +/- 3.8 minutes with P to 10.2 +/- 3.8 minutes with SRNG (14.6%; p less than 0.001). At symptom-limited exercise, ST depression was significantly reduced (p less than 0.05) during the SRNG phase. Thirty-four patients (74%) reached a higher peak heart rate (139 beats/min with P, 145 beats/min with SRNG; p less than 0.001) and 35 patients (76%) a higher rate-pressure product (+6%; p less than 0.001). These changes in exercise tolerance are relatively modest and at least 11 patients would have benefited from larger doses of nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Frequency dependent effects of class I antiarrhythmic agents studied in patients with implanted pacemakers.

Use and frequency dependency are common properties of Class I antiarrhythmic agents, which block cardiac sodium channels in vitro. The purpose of this study was to examine the rate dependent effects of Class I agents on ventricular conduction in humans in a crossover fashion. Twelve patients with implanted pacemakers who required antiarrhythmic therapy were studied. Four Class I agents were administered as follows: lidocaine, 1 mg/kg bolus followed by 4 mg/min infusion; disopyramide, 1 mg/kg bolus followed by 0.02 mg/kg per hour; aprindine, 1 mg/kg bolus followed by 4 mg/min infusion; and flecainide, 100 mg/day orally for 1 week. Trains of ventricular test stimuli between 70-180 ppm were applied during stable VVI pacing at 60 ppm. QRS duration was determined using signal-averaged as well as standard ECGs. Lidocaine produced significant QRS prolongation at rates > 110 ppm (3.0% +/- 1.4% at 120 ppm, P < 0.05; 7.2% +/- 1.8% at 180 ppm, P < 0.01). Aprindine, disopyramide, and flecainide produced significant QRS prolongation at rates as low as 70 ppm and in a frequency dependent manner: 12.7% +/- 1.5%, 9.6% +/- 1.6%, and 13.3% +/- 2.8% at 70 ppm, respectively, (P < 0.01); 21.6% +/- 0.6%, 14.7% +/- 2.4%, and 29.9% +/- 4.2% at 180 ppm, respectively, (P < 0.01). Time constants of the single exponential development of QRS prolongation when the pacing rate was abruptly increased to 150 ppm were 0.09 +/- 0.02 sec for lidocaine, 5.1 +/- 1.2 sec for aprindine, 8.1 +/- 1.7 sec for disopyramide, and 11.9 +/- 1.4 sec for flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

A case-crossover study of occupational traumatic hand injury: methods and initial findings.

BACKGROUND: Acute hand injury is the leading cause of occupational injury treated in United States' hospital emergency departments (e.g., laceration, crush or fracture). To identify risk factors for traumatic hand injuries, we conducted a case-crossover study of transient exposures (e.g., being rushed) for acute occupational traumatic hand injury. METHODS: The case-crossover method, which uses subjects as their own controls, was used to identify risk factors for occupational hand injury. Two hundred and thirty-two subjects were recruited from 17 occupational health clinics in New England and interviewed by telephone a median of 1.2 days after their injury. The a priori hazard period was defined as 10 min before the injury. Two control periods were used: one was 60-70 min prior to the injury (matched-pair interval analysis); the other was the total work-time exposed, on average, in the previous month (usual frequency analysis). RESULTS: In the usual frequency analysis, the relative risk for using malfunctioning or different-from-usual equipment or tools in the hazard period was 25.5 (95% confidence interval = 18.4-35.2). Relative risks were also significantly elevated for performing a task using an unusual work method, doing an unusual task, being distracted, or being rushed. Wearing gloves appeared to be protective (relative risk = 0.8, 95% CI = 0.5-1.2). Matched-pair interval analysis, where appropriate, provided similar findings but had much wider confidence intervals. CONCLUSIONS: This study demonstrates that the case-crossover design is a feasible and efficient method for studying transient risk factors for sudden-onset traumatic occupational hand injury. The usual frequency analysis proved more useful than the match-pair approach to control period selection.

Accidents, Occupational↗

Assessment of antiarrhythmic drug efficacy in the treatment of supraventricular arrhythmias.

Few guidelines exist for judging the efficacy of antiarrhythmic drugs in patients with supraventricular arrhythmias. Useful definitions concerning the frequency and duration of supraventricular arrhythmias are offered, and complete and partial efficacy criteria are outlined for noninvasive electrocardiographic and invasive electrophysiologic techniques. Several open label, double-blind, parallel and crossover study designs are suggested for efficacy studies concerning the termination and prevention of supraventricular tachycardia. These recommendations are useful for designing new drug trials needed to evaluate properly the efficacy of antiarrhythmic agents in the treatment of various supraventricular arrhythmias.

Adult↗

The mechanism of RNA recombination in poliovirus.

We have investigated RNA recombination among poliovirus genomes by analyzing both intratypic and intertypic recombinant crosses involving the same defined genetic markers. Sequence analysis of the recombinant junctions of 13 nonsibling intertypic recombinants showed that intertypic RNA recombination is not site-specific, nor does it require extensive homology between the recombining parents at the crossover site. To discriminate between breaking-rejoining and copy choice mechanisms of RNA recombination, we have inhibited the replication of the recombining parents independently and found opposite effects on the frequency of genetic recombination in intratypic crosses. The results strongly support a copy choice mechanism for RNA recombination, in which the viral RNA polymerase switches templates during negative strand synthesis.

Base Sequence↗

Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson's disease.

OBJECTIVES: To evaluate the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) by delivering stimulation at higher intensity and frequency over longer time than in previous research. Promising beneficial effects on movement during or after rTMS have been reported. METHODS: Ten patients with idiopathic PD were enrolled in a randomized crossover study comparing active versus sham rTMS to the supplementary motor area (SMA). Assessments included reaction and movement times (RT/MT), quantitative spiral analysis, timed motor performance tests, United Parkinson's Disease Rating Scale (UPDRS), patient self-report and guess as to stimulation condition. RESULTS: Two of 10 patients could not tolerate the protocol. Thirty to 45 min following stimulation, active rTMS as compared with sham stimulation worsened spiral drawing (P=0.001) and prolonged RT in the most affected limb (P=0.030). No other significant differences were detected. CONCLUSIONS: We sought clinically promising improvement in PD but found subclinical worsening of complex and preparatory movement following rTMS to SMA. These results raise safety concerns regarding the persistence of dysfunction induced by rTMS while supporting the value of rTMS as a research tool. Studies aimed at understanding basic mechanisms and timing of rTMS effects are needed.

Aged↗