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Heliox does not affect gas exchange during high-frequency oscillatory ventilation if tidal volume is held constant.

OBJECTIVE: To compare gas exchange with heliox and oxygen-enriched air during high-frequency oscillatory ventilation, while controlling for tidal volume, in a pediatric swine model of acute lung injury. We hypothesized that when tidal volume delivery is held constant, heliox does not alter gas exchange. DESIGN: Randomized, crossover trial. SETTING: University animal research laboratory. SUBJECTS: Ten swine (4.4-5.4 kg). INTERVENTIONS: Acute lung injury (A-a gradient of >300 mm Hg) was created using repeated saline lavage during conventional mechanical ventilation. The animals were then administered high-frequency oscillatory ventilation and ventilated with 60% oxygen/40% helium and 60% oxygen/40% nitrogen in a randomized, crossover trial. When changing gas mixtures within each animal, mean airway pressure (Paw = 16.8 +/- 0.3 cm H(2)O) and frequency (10 Hz) were held constant. Oscillation amplitude (DeltaP) was adjusted to maintain constant tidal volume delivery as measured by respiratory inductive plethysmography. Next, the animals were ventilated with 40% oxygen/60% helium and 40% oxygen/60% nitrogen in a randomized crossover trial, again controlling for tidal volume. MEASUREMENTS AND MAIN RESULTS: Gas exchange was assessed by arterial blood gas analysis after ventilation with each gas mixture. We demonstrated no significant difference in Paco(2) or Pao(2) between the heliox and oxygen-enriched air with either the 40% or 60% oxygen mixtures. The oscillation amplitude required to achieve the same tidal volume delivery was significantly less with heliox. CONCLUSIONS: We conclude that if tidal volume delivery is maintained constant, heliox does not alter gas exchange when compared with oxygen-enriched air. However, to achieve the same tidal volume delivery, a lower oscillation amplitude is required with heliox. The clinical benefit of heliox administration during high-frequency oscillatory ventilation has yet to be determined. Possible advantages of heliox include improved ventilation of larger patients when approaching the power limitations of the Sensormedics 3100A oscillator and a potential reduction in the oscillation amplitude delivered to the more proximal gas exchange units.

Animals↗

A comparison of bronchial drainage treatments in cystic fibrosis.

We compared standard chest physical therapy and postural drainage (CPT/PD) with a new airway clearance therapy called high-frequency chest wall oscillation (HFCWO) in a group of stable cystic fibrosis (CF) patients. In this crossover trial, 29 CF patients (15 males, 14 females), aged 7-47 years that met the inclusion criteria were randomly assigned to alternate CPT/PD and HFCWO, on a daily basis, over a 4 day period. Each patient received 2 days of each form of therapy; treatment frequency and the length of treatment were the same for both techniques. Expectorated secretions were collected during each 30 minute therapy session and for 15 minutes following treatment. The wet and dry weights of collected secretions were determined gravimetrically, and the therapy methods were compared. Significantly more sputum was expectorated during HFCWO than during CPT/PD as determined by both the wet (P < 0.001) and the dry (P < 0.01) measurements. This study suggests that HFCWO is at least as effective as manual CPT/PD in clearing secretions from the airways in patients with cystic fibrosis.

Adolescent↗

Comparison of the effectiveness of dihydroquinidine and quinidine on ventricular ectopy after acute and chronic administration.

The aim of this study was to compare the pharmacokinetics and antiarrhythmic activity of dihydroquinidine and quinidine in 14 patients (11 men, 3 women, aged 28 to 67 years) with heart disease and chronic, stable, high-frequency premature ventricular beats (PVB) (greater than 100/hr). A randomized, double-blind, crossover, placebo-controlled protocol was utilized. During Holter monitoring the patients were given either dihydroquinidine or quinidine as the gluconates in an oral solution (600 mg); blood samples were taken 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours later. The patients were then assigned to three successive treatment periods of 7 days each: dihydroquinidine HCl (900 mg/day), quinidine polygalacturonate (1,650 mg/day), or placebo. At the end of each period 24-hour Holter monitoring was carried out and a blood sample was taken for determination of drug concentration. By comparing the area under the curves dihydroquinidine was 59% as available as quinidine; rates of absorption and elimination were similar. Mean peak blood levels of dihydroquinidine and quinidine were 1.06 +/- 0.34 and 2.15 +/- 0.96 micrograms/ml, respectively. After dihydroquinidine, eight patients had a positive response (greater than 50% reduction in PVB frequency), while seven patients responded to quinidine. During maintenance treatment both dihydroquinidine (233 +/- 330) and quinidine (234 +/- 311) reduced the mean PVB frequency per hour compared to placebo (690 +/- 569). Nine patients (64%) on dihydroquinidine and eight (57%) on quinidine had greater than 70% decrease in mean PVB frequency per hour. Steady-state peak plasma concentrations of dihydroquinidine and quinidine were 1.10 +/- 0.41 and 2.24 +/- 1.13 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Proarrhythmic effect of pacemaker stimulation in patients with implanted cardioverter-defibrillators.

BACKGROUND: We sought to determine the potential of right ventricular VVI backup pacing to induce ventricular tachyarrhythmias in patients with implanted cardioverter-defibrillators. METHODS AND RESULTS: All consecutive patients presenting exclusively with pacemaker-induced tachycardias (PITs) were included in a prospective study using a crossover protocol. Patients were randomized to either group 1 (augmentation of the baseline frequency of the pacemaker to 60 bpm) or group 2 (pacemaker turned off) and were followed up for 1 year and then crossed over to the other programming, looking for reoccurrence of PIT. Of 150 consecutive patients, 39 (26%) had PIT, 13 of them exclusively (8.6%). Forty of 1063 analyzed tachyarrhythmias of all the patients were PIT (3%). Before inclusion in the study, the patients had 2.7+/-0.9 PITs in 11+/-6.5 months with their pacemakers programmed empirically at 42.3 bpm. During the study phase, no PIT occurred while the pacemaker was turned off, whereas programming to 60 bpm led to the recurrence of PIT in 5 of 6 patients (1.4+/-0.6 per patient). At the end of the study, 9 patients underwent a prolonged follow-up with their pacemakers turned off, resulting in spontaneous episodes of ventricular tachycardia/fibrillation in 5 patients, but PITs were no longer observed. CONCLUSIONS: This crossover protocol proves the potential proarrhythmic effect of pacemaker stimulation in implantable cardioverter-defibrillator patients. Resulting PITs led to clinical symptoms and antitachycardia therapy by the implantable cardioverter-defibrillator. Thus, in patients presenting with PIT but without a pacemaker indication, the pacemaker feature should be turned off, or, alternatively, the longest possible escape interval should be programmed.

Arrhythmias, Cardiac↗

Comparison of effects of propranolol versus pindolol on sinus rate and pacing frequency in sick sinus syndrome.

Beta blockers in patients with sick sinus syndrome (SSS) may prevent supraventricular arrhythmias, systemic hypertension and myocardial ischemia, but may cause excessive depression of sinus node function. In 8 patients with SSS and a permanent pacemaker, the effect of chronic oral pindolol on sinus rate and pacing frequency was compared with that of propranolol in a double-blind crossover trial. In all patients the pacemaker was programmed to a rate of < or = 50 beats/min. Holter monitors, obtained at baseline and on each drug, were used to calculate peak ambulatory sinus rate, number of paced beats per day, maximal number of paced beats per hour, and percentage of hours with paced beats. The peak sinus rate with pindolol therapy was 24% higher than with propranolol (p = 0.001). During pindolol therapy, the number of paced beats per day and maximal paced beats per hour were reduced 54% (p = 0.04) and 61% (p = 0.02), respectively, compared with propranolol. Patients with SSS who require beta-blocker therapy for tachycardia, systemic hypertension or angina pectoris may have less bradycardia when treated with pindolol rather than propranolol. Beta blockers like pindolol, which cause less sinus node depression, may obviate the need for prophylactic permanent pacemakers in patients with SSS, and may help to prevent chronotropic incompetence and pacemaker syndrome in patients already treated with a VVI device.

Administration, Oral↗

Double-blind crossover comparison of human and porcine insulins in patients reporting lack of hypoglycaemia awareness.

There has been much debate about reports that some insulin-treated diabetic patients lose awareness of hypoglycaemic symptoms on changing from porcine to human insulin. In a double-blind, crossover study, we sought differences between porcine and human insulin in the frequency and characteristics of hypoglycaemic episodes among patients who reported a reduction of awareness of hypoglycaemia after changing treatment. We studied 50 patients referred by their physicians because of complaints of lack of awareness of hypoglycaemia on human insulin. They had had diabetes for a mean of 20 (SD 12) years and 70% had good or acceptable glycaemic control. Each patient was treated in a double-blind manner for four 1-month periods, two with human and two with porcine insulin, in random order. Only 2 patients correctly identified the sequence of insulin treatments used; 8 or 9 would have been expected to do so by chance alone. The mean percentage of hypoglycaemic episodes associated with reduced or absent awareness was 64% (SD 30%) for human insulin and 69% (31%) for porcine insulin. We could find no statistically significant differences between the insulin species with respect to glycaemic control or the frequency, timing, severity, or awareness of hypoglycaemia. Reduced hypoglycaemia awareness is common with both human and porcine insulins.

Adolescent↗

A double-blind crossover comparison of clomipramine and desipramine in the treatment of panic disorder.

OBJECTIVE: To compare the efficacy of clomipramine hydrochloride (CMI), a serotonin reuptake inhibitor with the noradrenergic tricyclic antidepressant agent, and desipramine hydrochloride (DMI) for patients with panic disorder (PD). METHOD: Following a 2-week, single-blind placebo washout phase, 17 PD outpatients completed a 16-week, double-blind, crossover comparison of CMI and DMI. Key outcome measures included panic attacks frequency, the NIMH Global Scales for Anxiety, Depression and Impairment, Hamilton Anxiety Scale (Psychic and Somatic Subscales), Zung Anxiety Inventory (Raw and Index Subscales) and the Spielberger State Anxiety Scale. RESULTS: Both CMI and DMI led to significant improvement from baseline placebo state in panic attacks frequency and behavioral ratings (p<0.001). CMI led to a greater reduction in the frequency of panic attacks (p=0.028) and was superior to DMI on ratings of anxiety: NIMH Global Anxiety, Zung Anxiety Scale (Raw and Index) and the Spielberger Anxiety Scale. No difference was found between the drugs on the NIMH Global Impairment Scale and the Hamilton Somatic and Psychic Scales. CONCLUSION: Both drugs appeared to have significant therapeutic effects in patients with PD, but CMI appeared to be more effective. The effectiveness of the serotonergic drug suggests that the role of the serotonergic system in the pathogenesis of PD should be further explored.

Adult↗

Cardiac vagal response to water ingestion in normal human subjects.

In healthy young subjects there is direct evidence for sympathetic vasoconstrictor activation after drinking water, but this is not accompanied by an increase in arterial blood pressure. A marked pressor response to water ingestion has, however, been observed in elderly subjects and in patients with autonomic failure. We examined the effect of water ingestion on haemodynamic variables and heart rate variability (HRV) markers of cardiac vagal control in ten healthy young subjects and four cardiac transplant recipients with confirmed persistent cardiac vagal denervation. In a random order crossover protocol, changes in heart rate, blood pressure and measures of high frequency (HF) HRV were compared over time following the ingestion of 500 ml and 20 ml (control) of tap water. In healthy subjects, after drinking 500 ml of water the heart rate fell from 67.6+/-2.0 (mean+/-S.E.M.) to 60.7+/-2.4 beats/min (P<0.01), and the bradycardic response peaked between 20 and 25 min. There were no significant changes in arterial blood pressure. Over the same time course, water ingestion caused increases in measurements of HF HRV: root-mean-square of successive RR interval differences (RMSSD) increased by 13+/-2.7 ms after 500 ml versus 2+/-3.1 ms after 20 ml (P<0.05); HF power increased by 686+/-400 versus -63+/-322 (P<0.01). In transplant recipients water ingestion was followed by a pressor response (range 13 to 29 mmHg). These results provide evidence that water ingestion in normal subjects is followed by an increase in cardiac vagal control that may counteract the pressor effects of sympathetic activation. We suggest that in the elderly, in transplant recipients and in autonomic failure, loss of this buffering mechanism explains the pressor response to drinking water.

Adult↗

Comparison of the clinical efficacy of standard and mucoadhesive-based nasal decongestants.

AIMS: To compare two xylometazoline 0.1% preparations: reference commercial solution (RS) and test mucoadhesive solution (TS). METHODS: Twenty subjects with perennial allergic rhinitis (age range 18-69 years, 5 atopic, 7 men) applied randomly in turn TS and RS for 5 days in a double-blind crossover clinical trial. Nasal airflow resistance (NAR), nasal symptoms (6 grade scoring), frequency of application (times/day), and side-effects were recorded. RESULTS: Mean ratio TS/RS of areas under the resistance/time curves for NAR +/- 90% CI: 3.56 +/- 0.92; mean TS-RS differences +/- 95% CI: for congestion: -1.12 +/- 0.59, for frequency of application: -1.10 +/- 0.20. Subjects experienced fewer side-effects with TS. CONCLUSIONS: A mucoadhesive solution with a decongestant had a greater and longer lasting effect on nasal congestion in subjects with perennial allergic rhinitis than the commercially available decongestant solution. It also caused fewer side effects.

Adult↗

13-year follow-up of the German angioplasty bypass surgery investigation.

AIMS: The German Angioplasty Bypass Surgery Investigation was designed to compare symptomatic efficacy and safety of percutaneous coronary balloon angioplasty (PTCA) with coronary artery bypass surgery (CABG) in patients with symptomatic multi-vessel disease. This follow-up study was performed to determine the long-term outcome of patients following these interventions. METHODS AND RESULTS: From 1986 to 1991, 359 patients with angina CCS class II-IV, age below 75 years, and coronary multi-vessel disease requiring revascularization of at least two major coronary vessels were recruited at eight German centres and randomized to PTCA or CABG. From 337 patients undergoing the planned procedure, 324 patients could be followed-up (96%). Baseline parameters were identical in both groups, 2.2+/-0.6 vessels were treated in CABG patients, whereas 1.9+/-0.5 vessels were treated in PTCA patients. Thirty-seven per cent of surgical patients received internal mammary artery grafts, while no stents were used in patients undergoing PTCA. At the end of the 13-year follow-up period, the degree of angina, the degree of dyspnea, and the utilization of nitrates were comparable in both groups. With a total number of 76 deaths, Kaplan-Meier analysis revealed a comparable distribution in both groups. Although time to first re-intervention was significantly shorter in the PTCA group, P<0.001, frequencies of re-intervention (CABG, n=94; PTCA, n=136) and crossover rates (CABG to PTCA, n=49; PTCA to CABG, n=51) were comparable in both groups. CONCLUSION: The results of our 13-year follow-up suggest that in patients with symptomatic multi-vessel disease, both PTCA and CABG are associated with a comparable long-term survival and symptomatic efficacy. How far these results may be altered by developments such as drug-eluting stents or off-pump surgery remains to be determined.

Adult↗

Generating molecular diversity by homologous recombination in Escherichia coli.

We explored the use of recE-mediated homologous recombination to generate molecular diversity in Escherichia coli. Two homologous genes were placed on different phagemid vectors each comprising multiple EcoRI restriction sites and overlapping N- and C-terminal portions of beta-lactamase. By co-infection of these phage into RecE+ EcoRI+ E.coli, we were able to introduce double-strand breaks into these vectors, allowing efficient homologous recombination (in up to 10% of bacteria) by the recE pathway and selection of the recombinants by resistance to ampicillin. Recombination gave single crossovers; these were more frequent near the EcoRI sites and the recombination frequency increased with the target length and degree of homology. The system was used to create a large combinatorial chicken antibody library (10(10)) for display on filamentous phage and to isolate several antibody fragments with binding affinities in the 10-100 nM range.

Animals↗

Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study.

Auditory P50 and N100 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated. The amplitude and latency changes of the electric and magnetic P50 and N100 were insignificant. Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison.

Adult↗

Exposure plus prevention of bingeing vs. exposure plus prevention of vomiting in bulimia nervosa. A crossover study.

In a crossover study, 11 bulimic patients divided into two groups of six and five patients underwent six sessions of exposure and response prevention of bingeing (ERPB) or exposure and response prevention of vomiting (ERPV) over 3 weeks. After a buffer period of 3 weeks, they were crossed over to six sessions of the other treatment. High drop-out rates, particularly during the ERPB phases, precluded full use of the crossover design. The two treatments yielded similar reduction in binge-vomit frequencies and in other between-session measures. Within-session measures, however, showed significant differences between the two treatments. ERPB was less time-consuming and led to greater reductions of urges to binge, anxiety, and liking of food. Overall improvement of patients in both groups was reasonable and further supports the usefulness of exposure techniques in the treatment of bulimic patients.

Adolescent↗

The Arabidopsis MutS homolog AtMSH4 functions at an early step in recombination: evidence for two classes of recombination in Arabidopsis.

MSH4, a meiosis-specific member of the MutS-homolog family of genes, is required for normal levels of recombination and fertility in budding yeast, mouse, and Caenorhabditis elegans. In this paper, we report the identification and characterization of the Arabidopsis homolog of MSH4 (AtMSH4). We demonstrate that AtMSH4 expression can only be detected in floral tissues, consistent with a role in reproduction. Immunofluorescence studies indicate that its expression is limited to early meiotic prophase I, preceding the synapsis of homologous chromosomes. A T-DNA insertional mutant (Atmsh4) exhibited normal vegetative growth but a severe reduction in fertility, consistent with a meiotic defect; this was confirmed by cytological analysis of meiosis. RNAi-induced down-regulation of the MSH4 gene resulted in a similar fertility and meiotic phenotype. We demonstrate that prophase I chromosome synapsis is delayed and may be incomplete in Atmsh4, and metaphase I chiasma frequency is greatly reduced to approximately 15% of wild type, leading to univalence and nondisjunction. We show that these residual chiasmata are randomly distributed among cells and chromosomes. These features of chiasma frequency and distribution in Atmsh4 show close parallels to MSH4-independent crossovers in budding yeast that have been proposed to originate by a separate pathway. Furthermore, the characteristics of the MSH4-independent chiasmata in the Atmsh4 mutant closely parallel those of second-pathway crossovers that have been postulated from Arabidopsis crossover analysis and mathematical modeling. Taken together, this evidence strongly indicates that Arabidopsis possesses two crossover pathways.

Amino Acid Sequence↗

The effects of aminophylline on sleep and sleep-disordered breathing in patients with obstructive sleep apnea syndrome.

The methylxanthine derivatives are known to have respiratory stimulant properties. To determine whether these drugs would improve obstructive sleep apnea, 10 male patients with obstructive sleep apnea (OSA) (Apnea Index greater than 15/h) were given infusions of aminophylline and a saline placebo on 2 separate nights a week apart, using a randomized crossover design. There was a significant decrease during aminophylline infusion in the frequency of those apneas, which contained periods of complete respiratory inactivity (central and mixed apneas; placebo, 4.3 +/- 1.8/h; aminophylline, 0.7 +/- 0.5/h; p less than 0.05). There was no change in either the frequency (placebo, 31.8 +/- 5.9/h; aminophylline, 28.7 +/- 8.7/h; NS) or duration of obstructive apneas. Mean and minimal arterial oxygen saturation values were also unchanged. Sleep architecture was markedly disturbed by aminophylline. There was a reduction in sleep efficiency (placebo, 84.8 +/- 2.0%; aminophylline, 60.2 +/- 5.0%; p less than 0.005), an increase in sleep fragmentation (sleep stage shifts/h: placebo, 11.6 +/- 1.3: aminophylline, 21.0 +/- 2.9; p less than 0.05) and less Stage 2 and more Stage 1 non-REM sleep. We conclude that aminophylline reduces central apnea and the central component of mixed apneas but has no effect on obstructive apnea. Theophylline is therefore unlikely to be therapeutically useful in patients with OSA, and because it leads to marked sleep disruption, its long-term use could conceivably increase the propensity to upper airway occlusion during sleep.

Aminophylline↗

Gene-centromere mapping of 312 loci in pink salmon by half-tetrad analysis.

We estimated recombination rates between 312 loci and their centromeres in gynogenetic diploid pink salmon (Oncorhynchus gorbuscha) that we produced by initiating development with irradiated sperm and blocking the maternal second meiotic division. Amplified fragment length polymorphisms (AFLPs) were significantly more centromeric than loci identified by three other techniques (allozymes, microsatellites, and PCR using primer sequences from interspersed nuclear elements). The near absence of AFLPs in distal regions could limit their utility in constructing linkage maps. A large proportion of loci had frequency of second division segregation (y) values approaching 1.0, indicating near complete crossover interference on many chromosome arms. As predicted from models of chromosomal evolution in salmonids based upon results with allozyme loci, all duplicated microsatellite loci that shared alleles (isoloci) had y values of nearly 1.0.

Animals↗

Triiodothyronine treatment for Raynaud's phenomenon: a controlled trial.

The effects of 80 micrograms triiodothyronine (T3) daily were compared with placebo in a double blind controlled crossover trial in 18 patients with Raynaud's phenomenon. Reductions in the frequency, duration and severity of attacks while taking T3 were gradual but highly significant. Four of 6 subjects had skin ulcer healing. Skin temperatures in the hands increased significantly. The skin temperature recovery times after cold exposure were significantly shorter during T3 therapy compared with placebo. Although large dosages of T3 were well tolerated, 6 patients experienced episodic palpitations, and slight but significant increases in heart rate and pulse pressure were observed. Evaluation of the use of physiological doses of T3 (60 micrograms daily or less) in the treatment of Raynaud's phenomenon is suggested.

Adolescent↗

Celiprolol and atenolol in angina--effects on left ventricular function.

Celiprolol, 400 mg once daily, and atenolol, 100 mg once daily, were compared in a double-blind placebo-controlled crossover study of 16 patients with stable angina. Both drugs reduced angina frequency and delayed the onset of ischaemia during exercise, although only celiprolol prolonged exercise time. Celiprolol produced less suppression of heart rate than atenolol during exercise, and atenolol, but not celiprolol, lowered resting and exercise cardiac output. Thus, the ancillary properties of celiprolol, including partial beta 2-adrenoceptor agonist activity and direct vasodilating activity, have detectable effects on cardiac function that may be beneficial in patients with angina.

Adrenergic beta-Antagonists↗