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Do chiasmata disappear? An examination of whether closely spaced chiasmata are liable to reduction or loss.

The questions of whether closely spaced crossovers could be misidentified as single chiasmata or could cancel out each other and whether exchange could occur without chiasma formation were examined in Locusta migratoria. Monochiasmate bivalents that showed differential sister chromatid staining following bromodeoxyuridine incorporation were screened for their patterns of label distribution. Half of the chiasmata were associated with an exchange between dark and lightly stained chromatids, as expected if recombination involved any two non-sister chromatids chosen at random. Two variant types of label distribution were also seen: approximately 10% of all monochiasmate bivalents had an anomalous distribution of dark and light chromatids around the chiasma, and in three of the 1365 bivalents screened a second type of anomalous pattern was observed for the first time, in which all four chromatids had a label exchange at the chiasma. The observed incidence of the latter was considerably less than expected if they originated through a four-strand double crossover with closely positioned exchanges. Analysis of label distribution patterns in monochiasmate bivalents did not produce evidence of the other configurations expected if two closely spaced exchanges could be misidentified as single chiasmata or could cancel one another out so as not to form a chiasma. We conclude that analysis of chiasma frequencies and distributions offers an accurate means of assessing recombination in organisms with favourable cytology.

Animals↗

A randomised controlled trial of topical glycopyrrolate, the first specific treatment for diabetic gustatory sweating.

The treatment of gustatory sweating in diabetes mellitus is usually with oral anti-cholinergic drugs, but these frequently lead to unacceptable side effects. Glycopyrrolate is an anti-muscarinic agent that can be applied topically and is efficacious in gustatory sweating occurring in other conditions. In a double-blind placebo-controlled crossover study, we assessed the value of glycopyrrolate in 13 diabetic patients with gustatory sweating. Sweating was measured by a sweat challenge, and diaries recorded by the patients throughout the 2 weeks of each treatment period. Compared to placebo, glycopyrrolate reduced the sweat response to a challenge by 82% (p < 0.01). The frequency of episodes of gustatory sweating during the treatment period was also reduced by 51% (p < 0.01), with a nearly 100% reduction in the frequency of episodes of severe sweating (p < 0.01). In conclusion, topically applied glycopyrrolate is a very effective treatment in reducing both the severity and frequency of diabetic gustatory sweating.

Administration, Topical↗

Morphologic analysis of digestive cancers from the registry of Vaud, Switzerland.

Detailed data and statistics per each morphological site of various digestive neoplasms were obtained for the period 1976-87 from the Vaud Cancer Registry datafile, a population-based cancer registration scheme covering about 530,000 inhabitants from the French-speaking part of Switzerland. Tabulations presented include absolute number of cases (1,041 oral and pharyngeal, 545 oesophageal, 1,131 gastric, 83 small intestine, 1,980 colon, 1,267 rectal, 357 liver, 328 gallbladder and 725 pancreatic cancers), percent distributions, age-standardised rates, sex ratios and 5-year survival. The report has essentially a descriptive value, and should be viewed as a contribution towards quantification, in a well surveilled population of the West-central part of Europe, of the proportional distribution of digestive neoplasms by morphological type, and corresponding incidence and survival rates. Among the points deserving specific attention, there are the elevated frequency of upper digestive tract cancers, the very high male-to-female ratios for squamous cell carcinomas, adenocarcinomas of the oesophagus and hepatocellular carcinomas of the liver, the female excesses in infiltrating carcinoids of the colon, transitional and squamous cell carcinomas of the rectum and adenocarcinomas of the gallbladder, and the crossover in male-to-female ratio in squamous cell carcinoma along the digestive tract (i.e. from 6.0 at the level of the mouth/pharynx to 0.5 in the rectum). As concerns survival, rates were higher for lymphomas and sarcomas than for carcinomas in oral cavity and stomach, similar for carcinoids and carcinomas in the small bowel (about 35% at 5 years), as well as for colon (34%) and rectal (37%) cancers. Some of the findings, such as the higher survival of carcinomas arising from polyps in the colon and rectum, or the higher proportion of cholangiocellular and combined cholangio- and hepatocellular carcinomas in females than in males find plausible prognostic or aetiologic correlates, but others, such as the large proportions of squamous and transitional cell cancers of the rectum in females are more difficult to explain. These and several other indications emerging from careful examination of the data herein presented underline the interest of morphological analyses of digestive tract cancers.

Adult↗

Fatigue increases the risk of injury from sharp devices in medical trainees: results from a case-crossover study.

BACKGROUND: Extreme fatigue in medical trainees likely compromises patient safety, but regulations that limit trainee work hours have been controversial. It is not known whether extreme fatigue compromises trainee safety in the healthcare workplace, but evidence of such a relationship would inform the current debate on trainee work practices. Our objective was to evaluate the relationship between fatigue and workplace injury risk among medical trainees and nontrainee healthcare workers. DESIGN: Case-crossover study. SETTING: Five academic medical centers in the United States and Canada. PARTICIPANTS: Healthcare workers reporting to employee healthcare clinics for evaluation of needlestick injuries and other injuries related to sharp instruments and devices (sharps injuries). Consenting workers completed a structured interview about work patterns, time at risk of injury, and frequency of fatigue. RESULTS: Of 350 interviewed subjects, 109 (31%) were medical trainees. Trainees worked more hours per week (P<.001) and slept less the night before an injury (P<.001) than did other healthcare workers. Fatigue increased injury risk in the study population as a whole (incidence rate ratio [IRR], 1.40 [95% confidence interval {CI}, 1.03-1.90]), but this effect was limited to medical trainees (IRR, 2.94 [95% CI, 1.71-5.07]) and was absent for other healthcare workers (IRR, 0.97 [95% CI, 0.66-1.42]) (P=.001).Conclusions. Long work hours and sleep deprivation among medical trainees result in fatigue, which is associated with a 3-fold increase in the risk of sharps injury. Efforts to reduce trainee work hours may result in reduced risk of sharps-related injuries among this group.

Academic Medical Centers↗

Mutants of Streptomyces roseosporus that express enhanced recombination within partially homologous genes.

Streptomyces roseosporus mutants that express enhanced recombination between partially homologous (homeologous) sequences were isolated by selection for recombination between the bacteriophage phi C31 derivative KC570 containing the Streptomyces coelicolor glucose kinase (glk) gene and the S. roseosporus chromosome. The frequencies of homeologous recombination in the ehr mutants were determined by measuring the chromosomal insertion frequencies of plasmids containing S. coelicolor glnA or whiG genes. S. roseosporus ehr mutants showed 10(2)- to 10(4)-fold increases in homeologous recombination relative to Ehr+ strains, but no increase in homologous recombination. Southern hybridization analysis revealed single unique sites for the insertion of each of the plasmids, and the crossovers occurred in frame and in proper translational register, yielding functional chimeric glnA and whiG genes.

Amino Acid Sequence↗

Propranolol and acetylsalicylic acid in migraine prophylaxis. Double-blind crossover study.

The aim of this double-blind crossover study was to compare the prophylactic effect of acetylsalicylic acid (ASA) with that of propranolol (PRP) in the treatment of migraine. Plasma concentrations of the two drugs were measured in order to investigate a possible relationship to the clinical effect. Compared to the pretreatment period, PRP and ASA reduced migraine index, frequency, duration, severity of attacks and headache days. Due to the limited number of patients, our results should be cautiously interpreted, however relevant the clinical improvement seemed. Improvement of migraine index was not related to different plasma levels of the two drugs.

Adolescent↗

Oxidative stress-induced homologous recombination as a novel mechanism for phenytoin-initiated toxicity.

Although the mechanism(s) of phenytoin-initiated toxicity is unknown, phenytoin can be enzymatically bioactivated to a reactive intermediate leading to increased formation of reactive oxygen species, which can damage essential macromolecules, including DNA. The oxidation of DNA can induce DNA double-strand breaks (DSBs), which may be repaired through homologous recombination. Increased levels of DSBs may induce hyper-recombination, leading to deleterious genetic changes. We hypothesize that these genetic changes mediate phenytoin-initiated toxicity. To investigate this hypothesis we used a Chinese hamster ovary cell line containing a neo direct repeat recombination substrate to determine whether phenytoin-initiated DNA oxidation increases homologous recombination. Cells were treated with 0 to 800 microM phenytoin for 5 or 24 h, and homologous recombination frequencies and recombinant product structures were determined. Phenytoin-initiated DNA oxidation was determined by measuring the formation of 8-hydroxy-2'-deoxyguanosine. We demonstrate that phenytoin increases both DNA oxidation and homologous recombination in a concentration- and time-dependent manner. All recombination products analyzed arose via gene conversion without associated crossover. Our data demonstrate that phenytoin-initiated DNA damage can induce homologous recombination, which may be a novel mechanism mediating phenytoin-initiated toxicity.

Animals↗

Azimilide pharmacokinetics following intravenous and oral administration of a solution and capsule formulation.

Azimilide dihydrochloride (NE-10064) is a novel class III anti-arrhythmic agent that blocks both the slowly and rapidly acting components of the delayed rectifier potassium current of human atrial and ventricular myocytes. In clinical studies, azimilide reduced the frequency of symptomatic episodes of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. This study was conducted to characterize azimilide pharmacokinetics following single-dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral solution, and a 150 mg orally administered capsule. This was a three-period, randomized, crossover study in 27 healthy, drug-free (including caffeine and alcohol), non-smoking male volunteers (mean [SD]; age, 25.9 [1.0] years; weight 74.3 [0.7] kg; 23 Caucasians and 4 Hispanics). Blood and urine samples were collected for 27 days and analyzed for azimilide using HPLC with UV detection. Subjects were monitored for adverse events and abnormalities in clinical laboratory tests, vital signs, and electrocardiography (including Holter monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg (38%), renal clearance = 0.014 L/h/kg (35%), steady-state volume of distribution = 13.2 L/kg (23%), and terminal exponential half-life = 78.8 h (44%). Similar parameter estimates were obtained following oral administration. Both the oral solution and capsule formulations were completely absorbed. In addition, the rate (Cmax) and extent of absorption (AUC) following oral administration of the capsule dosage form were bioequivalent to the oral solution with means for times of maximum blood concentration of 7.08 and 7.18 hours for the oral solution and capsule, respectively. Azimilide dihydrochloride was generally well tolerated in all subjects.

Administration, Oral↗

Randomized controlled pilot trial of a hand-held patient-oriented, insulin regimen optimizer.

A robust, hand-held, patient-oriented insulin regimen optimizer (POIRO) has been developed. Relevant information is entered by selecting appropriate items from choices displayed on a touch-sensitive screen rather than a conventional keyboard. All data items are recorded, together with their time and date of entry, and may be recalled at any time with glucose values displayed graphically to provide an overview of glycaemic control. When requested, an integral, hybrid, statistical and rule-based expert system program uses all available data to suggest an optimum insulin dose within physician determined, pre-set limits. POIRO has been formally evaluated in a randomized crossover pilot trial, comparing two 3 week periods with and without decision support, in six patients with type 1 diabetes. Mean (SE) pre-prandial blood glucose levels were significantly lower during the period when decision support was available (7.5 (0.4) versus 8.9 (0.4) mmol/l, p = 0.015) with no increase in the frequency or severity of hypoglycaemia. The device, which was well received by the patients, may offer a relatively inexpensive method of providing expert diabetic advice at a distance. The persistence of improved glycaemic control, even after decision support was switched off, suggests the device could be used intermittently by patients and may have educational value.

Algorithms↗

Lack of systematic effects of the 5-hydroxytryptamine 3 receptor antagonist ICS 205-930 on gastric emptying and antral motor activity in patients with primary anorexia nervosa.

1. The 5-hydroxytryptamine 3 receptor antagonist, ICS 205-930, has been reported to have potent effects on gastric smooth muscle and to enhance gastric emptying in animals, but findings in man have been inconsistent. 2. This study investigated the effects of ICS 205-930 on gastric emptying of an isotopically labelled semisolid 1168 kJ meal and on antral contractility in patients with primary anorexia nervosa, a condition frequently associated with impaired gastric motor function. 3. Thirteen female patients (age 18-39 years, median 22 years; percentage of ideal body weight 52-90%, median 66%) participated each in two studies, in which 0.15-0.18 mg kg-1 ICS 205-930 or placebo were infused i.v. in crossover, double-blind fashion. Gastric emptying and antral contractility were recorded scintigraphically for 50 min. 4. ICS 205-930 did not affect gastric emptying: the mean percentage of meal remaining in the stomach after 50 min (69.6% +/- 3.2 s.e. mean) was nearly identical to that after placebo (70.7 +/- 3.3%). 5. Amplitude, frequency and propagation velocity of antral contractions differed only little after ICS 205-930 and placebo, respectively. 6. The results show that ICS 205-930 has no effect on the impaired gastric motor activity in primary anorexia nervosa and thus provide further evidence that the compound does not have prominent prokinetic effects in man.

Adult↗

Acute effects of sertraline, amitriptyline, and placebo on the psychomotor performance of healthy subjects over 50 years of age.

A double-blind, placebo-controlled, crossover study in 12 subjects (greater than or equal to 50 years) compared the effects of single oral doses of sertraline (100 mg) and amitriptyline (50 mg) with placebo as assessed by psychomotor function testing. Unlike sertraline and placebo, amitriptyline increased tracking error severity and impaired digit/symbol substitution. Sertraline slightly improved flicker frequency recognition. Both active drugs caused subjective drowsiness, although amitriptyline's effect was greater and of longer duration. Both drugs impaired subjectively assessed performance. Sertraline caused nausea, and amitriptyline, dry mouth; sertraline tended to increase supine systolic blood pressure. The authors conclude that sertraline has a considerably less detrimental effect on psychomotor performance and may have a slight activating effect not found with amitriptyline.

1-Naphthylamine↗

Improvement of sleep quality in elderly people by controlled-release melatonin.

Melatonin, produced by the pineal gland at night, has a role in regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomised, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week's washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p < 0.001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p < 0.001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p = 0.088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.

Aged↗

Intensive insulin therapy with insulin lispro in patients with type 1 diabetes reduces the frequency of hypoglycemic episodes.

In a randomized, open-label, controlled cross-over trial, 107 patients with type 1 diabetes were treated with either regular human insulin or insulin lispro, a rapid-acting insulin analogue. After a lead-in period of 2 to 4 weeks, the patients were randomized to receive intensified insulin treatment with one of the insulins. NPH-human insulin was used for basal substitution in both groups. The crossover took place after 3 months of treatment. Efficacy and safety of the drugs were established by the assessment of hemoglobin A1c, pretest blood glucose, 1 and 2-hour postprandial glucose excursions, number of hypoglycemic episodes, daily insulin doses, body weight, insulin antibodies, and the number and severity of adverse events. A questionnaire comprised of four primary domains was used to measure some quality of life aspects of the patients. Both treatment regimens were well tolerated. While no differences were seen in the hemoglobin A1c values, there was a trend for a decrease in the pretest blood glucose levels and significant decreases of the 1 and 2-hour postprandial glucose excursions in the patients treated with insulin lispro. The number of hypoglycemic episodes was also significantly lower in the insulin lispro treatment period. The evaluation of the quality of life questionnaire revealed an improvement in the patients treatment satisfaction for the insulin lispro group. During treatment with insulin lispro, the basal insulin doses increased slightly. However, the total daily insulin doses decreased to a greater extent with insulin lispro as compared to regular human insulin. Human insulin-specific antibody binding values at endpoint were not different for the two treatments. In conclusion, intensive insulin treatment with insulin lispro therapy results in improved postprandial glycemic control and HbA1c levels at least equal to the treatment with regular human insulin but with less hypoglycemia and more treatment satisfaction for the patient.

Adult↗

Prospective randomized crossover trial comparing fibre with lactulose in the treatment of idiopathic chronic constipation.

BACKGROUND: Fibre is often recommended as the first-choice treatment but its effects can be uneven. The aim of the study was to compare the clinical efficacy and tolerability of fibre versus lactulose in outpatients with chronic constipation. METHODS: In a prospective randomized crossover trial, patients were randomized to receive fibre or lactulose for four weeks. Between treatments, patients had at least one week free of laxatives. RESULTS: 50 patients, of median age 50 years (range, 18-85) were recruited and 39 patients completed the trial. Compared to fibre, lactulose resulted in significantly higher mean bowel frequency (7.3, 95% CI 5.7 to 8.9 vs. 5.5, 95% CI 4.4 to 6.5; p=0.001) and stool consistency score (3.4, 95% CI 3.1 to 3.7 vs. 2.9, 95% CI 2.5 to 3.3; p=0.018). Scores for ease of evacuation were similar. The frequencies of adverse effects were not significantly different, but greater in the lactulose group. Mean patients' recorded improvement score was significantly higher after taking lactulose than fibre (6.2, 95% CI 5.5 to 7.0 vs. 4.8, 95% CI 4.0 to 5.9; p=0.017). Of the 39 patients who completed the trial, 24 (61.5%) preferred lactulose and 14 (35.9%) preferred fibre. CONCLUSIONS: Lactulose had better efficacy than fibre for chronic constipation in ambulant patients, although both treatments were equally well tolerated in terms of adverse effects.

Adolescent↗

Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis.

The amino acid lysine is an agent that has been proposed for treating the clinical symptoms of recurrent herpes simplex labialis. This study examined the efficacy of long-term prophylactic lysine supplementation. Twenty-six volunteers with a history of frequently recurring herpetic lesions completed a 12-month double-blind crossovers study. The experimental group received daily oral supplements of 1,000 mg 1-lysine. Serum samples were analyzed at scheduled intervals. In most instances, members of the lysine group reported significantly fewer lesions than the control group. Similarly, those who were taken off lysine supplementation generally showed a significant increase in lesion frequency. Quantitative hematologic measurements revealed the most clinically useful relationship. Data from this sample population indicated that when a person's serum lysine concentration exceeded 165 nmol/ml there was a corresponding significant decrease in recurrence rate. Conversely, the frequency rate increased significantly as concentration levels fell below 165 nmol/ml. These results suggest that prophylactic lysine may be useful in managing selected cases of recurrent herpes simplex labialis if serum lysine levels can be maintained at adequate concentrations.

Adolescent↗

Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy.

Low-resolution brain electromagnetic tomography (LORETA) showed a functional deterioration of the fronto-temporo-parietal network of the right hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil. The aim of this study was to determine the effects of modafinil on cognitive and thymopsychic variables in patients with narcolepsy and investigate whether neurophysiological vigilance changes correlate with cognitive and subjective vigilance alterations at the behavioral level. In a double-blind, placebo-controlled crossover design, EEG-LORETA and psychometric data were obtained during midmorning hours in 15 narcoleptics before and after 3 weeks of placebo or 400 mg modafinil. Cognitive investigations included the Pauli Test and complex reaction time. Thymopsychic/psychophysiological evaluation comprised drive, mood, affectivity, wakefulness, depression, anxiety, the Symptom Checklist 90 and critical flicker frequency. The Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) were performed too. Cognitive performance (Pauli Test) was significantly better after modafinil than after placebo. Concerning reaction time and thymopsychic variables, no significant differences were observed. Correlation analyses revealed that a decrease in prefrontal delta, theta and alpha-1 power correlated with an improvement in cognitive performance. Moreover, drowsiness was positively correlated with theta power in parietal and medial prefrontal regions and beta-1 and beta-2 power in occipital regions. A less significant correlation was observed between midmorning EEG LORETA and the MSLT; between EEG LORETA and the ESS, the correlation was even weaker. In conclusion, modafinil did not influence thymopsychic variables in narcolepsy, but it significantly improved cognitive performance, which may be related to medial prefrontal activity processes identified by LORETA.

Adult↗

Cibenzoline for treatment of ventricular arrhythmias: a double-blind placebo-controlled study.

Cibenzoline, a new class I antiarrhythmic drug, was administered to 24 patients with frequent (greater than 30/h) premature ventricular complexes. Three patients discontinued the medication because of epigastric distress before repeat ambulatory electrocardiography. Of the remaining 21 patients, 13 responded to 130 mg twice daily by more than 75% suppression of premature ventricular complex frequency and 6 additional patients responded to 160 mg twice daily during an open-label titration phase. Events of ventricular tachycardia (greater than or equal to 3 beats) were totally suppressed in 9 of 10 patients and markedly diminished in the 1 remaining patient. During a double-blind placebo-controlled crossover phase in 16 patients (21 patients minus 2 nonresponders and 3 who developed side effects), cibenzoline suppressed the number of premature ventricular complexes per 24 hours (4,075 +/- 868 to 1,758 +/- 1,089, p = 0.02), the number of events of ventricular tachycardia (31 +/- 30 to 2 +/- 0, p = 0.01) and the number of premature ventricular complex pairs (61 +/- 28 to 25 +/- 21, p = 0.01). Cibenzoline plasma concentration was 59 to 421 ng/ml in responders and higher (387, 758 and 852 ng/ml, respectively) in the three subjects with side effects (right bundle branch block in one, hypotension in one, gastrointestinal upset and central nervous system complaints in one). Cibenzoline plasma concentration correlated with PR interval (r = 0.55, p = 0.0106) and corrected QT interval (r = 0.58, p = 0.0054). Further clinical investigation of this new antiarrhythmic agent is needed.

Adult↗

Synergistic anticholinergic and antiserotonergic effects in humans.

Animal research suggests an important interactive role for ascending cholinergic and serotonergic systems in modulation of cerebral function. Employing a randomized, double-blind, crossover design, 11 healthy young adults were tested in each of four conditions: (1) placebo, (2) fenfluramine (a serotonin depleting agent), (3) scopolamine (a muscarinic antagonist), and (4) fenfluramine and scopolamine. P3 latency was slowed by the dual drug treatment to an extent greater than the sum of individual drug effects. EEG mean frequency was decreased by behavioral activation, and this decrease was reversed by the combined drug treatment but not by single drugs. In contrast, verbal memory, EEG alpha power, and P3 amplitude were significantly affected only by scopolamine. No drug effects were found for the N1 and P2 potentials. The results provide the first demonstration of combined anticholinergic and antiserotonergic effects in humans, and offer partial support to the concept of an interactive role of cholinergic and serotonergic systems in cerebral mechanisms.

Adult↗