Comparative assessment of Vibrio virulence in marine fish larvae.

Vibrionaceae infections are a major obstacle for marine larviculture; however, little is known about virulence differences of Vibrio strains. The virulence of Vibrio strains, mostly isolated from vibriosis outbreaks in farmed fish, was tested in larval challenge trials with cod (Gadus morhua), turbot (Scophthalmus maximus) and halibut (Hippoglossus hippoglossus) using a multiwell dish assays with single-egg/larvae cultures. The strains differed significantly in virulence as some caused a high mortality of larva reaching 100% mortality after a few days, while others had no or only marginal effects on survival. Some Vibrio strains were pathogenic in all of the larva species, while some caused disease only in one of the species. Twenty-nine of the Vibrio anguillarum strains increased the mortality of larvae from at least one fish species; however, pathogenicity of the strains differed markedly. Other Vibrio species had no or less pronounced effects on larval mortalities. Iron uptake has been related to V. anguillarum virulence; however, the presence or absence of the plasmid pJM1 encoding anguibactin did not correlate with virulence. The genomes of V. anguillarum were compared (D. Castillo, P.W. D'Alvise, M. Middelboe & L. Gram, unpublished data) and most of the high-virulent strains had acquired virulence genes from other pathogenic Vibrio.

Socio-economic inequalities in first-time use of antidepressants: a population-based study.

OBJECTIVE: To analyse whether first-time use of antidepressants (incidence) and selection of TCAs (tricyclic antidepressants) versus new-generation drugs are associated with socio-economic status and psychiatric history. METHOD: We conducted a population-based cohort study using registry data covering Funen County, Denmark. A total of 305,953 adult residents without antidepressant prescriptions 5 years prior to the study period (1998) were included. RESULTS: The 1-year incidence rate of antidepressant prescription (1.7%) increased with age. It was higher in people who were female, less educated, unemployed, those receiving old-age or disability pension, low-income groups, and singles. The proportion prescribed new-generation antidepressants (82%) showed no difference according to socio-economic variables (education, annual income and socio-economic group), but was higher among the young and single. Admission to psychiatric hospital within 4 years prior to the study period was associated with high-incidence rate of antidepressant prescription and overall a preference for the new-generation antidepressants. CONCLUSION: Socio-economic status did not seem to influence the selection of TCAs versus new-generation antidepressants. Compatible with the general epidemiology of depression, low socio-economic status was associated with a high number of first-time users of antidepressants in the population, and the incidence rate increased with age.

Use of sumatriptan in Denmark in 1994-5: an epidemiological analysis of nationwide prescription data.

AIMS: We describe the use of medication with symptomatic relief of migraine as specific indication by analysing prescription data from the entire Danish population in 1994 and 1995. METHODS: The data for sumatriptan were analysed at the level of the individual user. We used aggregated data for ergotamine drugs. RESULTS: Sumatriptan constituted 46% of the total amount of defined daily doses (DDD) sold and 94% of the total pharmacy retail price expenses in the drug-group studied. In total, 43389 users of sumatriptan were identified who presented 340148 prescriptions, corresponding to 2.2 million DDD of sumatriptan. The quarterly consumption increased by 50% during the study period. Tablets accounted for 92% of consumption. The 1 year period prevalence of use of sumatriptan among persons 16 years and older was 7.8 per 1000 in 1995 with a female to male prevalence ratio of 3.8:1. Use was most common in the age interval 35-54 years. Regional differences in use, which were not large, were positively correlated to the degree of urbanization. The incidence of use of sumatriptan was estimated at 3.6 per 1000 person-years. The intensity of use of sumatriptan varied greatly with 1.1% of patients (n = 507) using 60 DDD or more within 30 days at some time during the observation period. Long-term high use of tablets was common in this group. CONCLUSIONS: We conclude that sumatriptan had a considerable impact on the treatment of migraine with prescription drugs in Denmark. The underlying reasons for high use of the drug in a smaller fraction of the patients deserve further study.

Drug related hospital admissions. Results from an intervention program.

As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance. A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%. There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments. The intervention may have had an non-specific effect on avoidable DRHs.

Drug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention.

Three hundred and thirty-three consecutive patients in a medical ward were evaluated in a high-intensity monitoring scheme for drug events as a cause of hospitalization. Taking into consideration only 'definite' and 'probable' drug events, we found 36 cases (10.8%) of all admissions to be drug-related hospitalizations (DRH). Of these, 8.1% were adverse drug reactions and 2.7% were therapeutic failures due to ineffective dosage. In 8 cases (2.4%) the drug event could definitely have been avoided, and a further 13 cases (3.9%) were considered to have been potentially avoidable if appropriate measures had been taken by the health service. In 19 cases (53%) the referring physician was unaware of the drug-related problem. Those patients admitted because of a drug event were taking significantly more drugs than other individuals. The avoidable drug events pointed to the primary health care physicians as the appropriate targets for preventive measures in terms of intensified drug education. The study demonstrated that a reliable estimate of the DRH rate requires active data collection by a qualified health service worker in close collaboration with the patient's family doctor in cases of suspected DRH.

Inadequate dosing and pharmacokinetic variability as confounding factors in assessment of efficacy of antidepressants.

The scientific literature on tricyclic antidepressants contains few studies on the dose-effect relationship, and this aspect of the treatment has for many years been given little attention. However, recent reviews point out inadequate dosing as an important factor in "drug resistant depressions." Tricyclic antidepressants have a narrow therapeutic range and standard doses, which are frequently recommended, will not be therapeutic in some patients and toxic in other patients. Use of flexible dose schemes, which has been customary in clinical trials, carry a considerable risk of underdosing because common side effects occur at subtherapeutic doses. Dosing according to therapeutic effect is not feasible in light of the slow and variable rate of response. Much of the difficulties in establishing a dose-effect relationship appears to be related to the considerable pharmacokinetic variability. The major source of this variability is the genetic polymorphism related to the sparteine/debrisoquine oxygenase. For some of the tricyclic antidepressants, a concentration effect relationship has been established, but almost exclusively on the basis of retrospective studies. The dose-response problem is particularly important in clinical trials. Apparent differences or equivalence between a new drug and the control therapy thus may entirely be related to differences in doses of the two drugs. For tricyclic antidepressants, the use of flexible dose schedules and poor control of compliance may often lead to underdosing and a response rate below the real potentials of these drugs. Underdosing combined with a high rate of placebo response will increase the type 2 error risk considerably and may ultimately lead to the introduction of drugs that are less effective than the classical drugs.

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants.

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.

Intellectual and social function of patients surviving cardiac arrest outside the hospital.

Thirteen survivors of cardiac arrest outside the hospital were examined by clinical and psychological tests 1-3 years after the incidence, and compared to a matched control group of 13 patients with acute myocardial infarction without cardiac arrest. Psychological tests revealed that 7 patients with previous cardiac arrest and 4 control patients had mild-moderate to moderate-severe dementia. The demential symptoms were not detectable by a clinical interview. Four patients in each group exhibited pronounced anxiety symptoms. There were no clear differences between the two groups in respect of changes in cardiac function and social status after the incidence.

Quantitative rating of manic states. Correlation between clinical assessment and Biegel's Objective Rating Scale.

We have investigated Biegel's manic-state rating scale and found the interrater reliability high when the scale was administered both by nurses and psychiatrists. In our study of validation, we tested each item of the scale for calibration, ascending monotonicity and dispersion parallel to a global clinical assessment of the manic state. Six of the scale items were then found valid and those items differed from the valid items in studies of Biegel by including increased social contact. Like Biegel, we found a positive correlation between items concerned with depressed mood, indicating a fluctuation in the mood of manic patients during 8 hours of observation.