Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics.

We did a follow-up study based upon a regional prescription register in Denmark. We identified all 435 women who in the period 1991-1996 had redeemed a prescription for CNS drugs during pregnancy. Among the rest of the pregnant women we randomly selected 1304 women who also had given birth to a child in the same region and period. We looked up the local health nurses Boel test results which were available for about 80%. Any abnormal test result was seen much more frequently among exposed (16%) than for not exposed (4%). The study has several limitations but raises concern that should be addressed in other and better designed studies.

Smoking, sex of the offspring, and risk of placental abruption, placenta previa, and preeclampsia: a population-based cohort study.

BACKGROUND: : Placental abruption, placenta previa, and preeclampsia are serious pregnancy complications with an increased risk of perinatal death. Smoking during pregnancy is associated with increased risk of abruption and placenta previa, and it reduces the risk of preeclampsia. We examined the association between mothers' smoking habits during pregnancy, taking the sex of the offspring into consideration, and the risk and prognosis of placental abruption, placenta previa, and preeclampsia METHODS: : We conducted the study in the County of North Jutland, Denmark. Using the 10-digit personal identification number given to every Danish citizen at birth, we linked data from the Danish Medical Birth Registry, including information on mother and child, to data from the Pharmaco-Epidemiological Prescription Database with data on all reimbursed prescriptions to use selected drugs as a proxy measure for some maternal diseases, and data from the Regional Hospital Discharge Registry, including the discharge diagnoses. Among 47,932 singleton births we included only births for which we had information about the mothers' smoking habits, leaving 46,313 births for analysis. RESULTS: : Smoking was associated with the risk of placental abruption (OR=1.99 (95% CI 1.72-2.30)) and placenta previa (OR=1.88 (95% CI 1.15-3.07)). Smoking was inversely associated with the risk of preeclampsia (OR=0.55 (95% CI 0.48-0.62)). After stratification for the sex of the offspring the risk estimate of smoking as risk factor for placenta previa decreased for male fetuses (OR=1.63 (95% CI 0.75-3.51)) and increased for female fetuses (OR=4.82 (95% CI 1.69-13.75)). CONCLUSION: : Female fetuses are more vulnerable than male to the negative effect of maternal smoking on placenta previa.

IL-10 augments the IFN-gamma and TNF-alpha induced TARC production in HaCaT cells: a possible mechanism in the inflammatory reaction of atopic dermatitis.

The CC-chemokine TARC is known to be a ligand for the CCR4 receptor which in turn is known to be expressed selectively on the Th(2)-subset of lymphocytes. Atopic dermatitis is generally believed to be a Th(2)-type disease, and TARC has been shown to be expressed in the skin lesions of a murine model of AD. IL-10 is an interleukine generally known for its ability to inhibit cytokine production, however it has been found to be highly expressed in the skin from AD patients. We show in this report that IL-10 is able to augment the TARC inducing effects of TNFalpha and IFNgamma in HaCaT cells, a property that may be important in the determination of the composition of the cells of the inflammation in the skin of AD patients. In addition, we show that the IL10 agonist IT 9302, a nona-peptide from the carboxylic end of IL-10, has the same effect on TARC production from HaCaT cells.

Locobase repair cream following CO2 laser skin resurfacing reduces interstitial fluid oozing.

BACKGROUND: The cosmetic result after laser resurfacing depends not only on the type of laser and the technique used, but also on post-treatment care. The efficacy of Locobase Repair((R)) cream, which improves skin barrier function due to its content of natural skin analogue fats and cholesterol, was investigated. METHODS: A total of 18 Caucasian patients underwent resurfacing for acne scars. Laser treatment was performed with a Sharplan 1020 CO(2) laser and a Silk Touch scanner. Locobase Repair cream (a water-in-oil cream with 63% lipids including natural components of stratum corneum: cholesterol, ceramide and free fatty acids) was applied daily to one side of the face and petrolatum was applied to the other. In addition, both sides were treated with a 2% fusidic acid cream. RESULTS: There was a significant reduction of oozing during the first 2 days after CO(2) laser treatment on the sides treated with Locobase Repair cream (p < 0.05), CO(2) laser while from day 3 to day 7 no differences were demonstrated between the Locobase Repair cream and petrolatum. For the other parameters scored (scaling, oedema, erythema and pain), no significant differences between Locobase Repair cream and petrolatum were found. Furthermore, no significant differences were found between the two creams regarding the duration of wound healing and final cosmetic outcome. In all, 62% of the patients preferred to use Locobase Repair cream during the postoperative period, and 11% preferred petrolatum. The remaining 27% expressed no preferences. CONCLUSION: The use of Locobase Repair cream as a post laser resurfacing treatment reduces tissue fluid oozing during the first 2 postoperative days, indicating a quick restoration of skin barrier and hence possibly a reduction in the incidence of wound infections as well as enhancing patient compliance due to less fluid oozing.

[Hearing ability of Danish school children when starting and leaving school]. / Høreevnen hos danske skolebørn ved ind- og udskolingsundersøgelsen.

School health records for a group of Danish school children, who started school in 1977, 1987 and 1997, were studied in order to evaluate hearing ability at the time of starting school and leaving school. One thousand, six hundred and five children who were evaluated by audiometry were included in the study. We found a higher prevalence of hearing loss in children who started school in 1987 and 1997 compared to those who started in 1977. The typical hearing loss was in the high frequencies. At the end of school the hearing ability of children who had started school in 1977 was just as poor as of that of those who had started in 1987. Whether this hearing loss may lead to poorer learning capacities in the afflicted children should be evaluated by further studies that include information on exposure to noise.

Dermatology life quality index: data from Danish inpatients and outpatients.

The aim of the present study was to provide data on the reliability and validity of a Danish translation of the Dermatology Life Quality Index (DLQI), a short measure of the impact of dermatological diseases on quality of life. The DLQI was administered to 200 outpatients and 100 hospitalized patients suffering from a range of dermatological diseases and to 100 sex- and age-matched healthy controls. Mean scores, internal consistency and test-retest reliability were comparable to the results reported for the original English version. Hospitalized patients reported greater impairment of disease-related quality of life than outpatients, and patients with atopic dermatitis and psoriasis exhibited greater scores than patients suffering from other dermatological diseases. Discriminant, construct and predictive validities of the Danish translation of the DLQI were satisfactory, as indicated by significant associations between DLQI scores and physician-rated disease severity, disease duration and the time patients were willing to spend each day on a hypothetical effective treatment. The results also suggest that the emphasis Danish patients place on various aspects of disability covered by the questionnaire is similar to that of English patients. In conclusion, the Danish translation of the DLQI showed satisfactory reliability and the preliminary results indicate that this version is a valid measure, which can be used in both research and clinical settings.

Pharmacokinetics and metabolism of a vitamin D analogue (Seocalcitol) in rat and minipig.

1. Seocalcitol (EB 1089), a vitamin D analogue with strong antiproliferative effects in vitro and in vivo, is presently under clinical evaluation for the systemic treatment of various solid tumours. 2. The aim was to investigate the pharmacokinetics of Seocalcitol after single and multiple oral administration to rat and minipig. Furthermore, the hepatic metabolism of Seocalcitol was studied both in vitro and in vivo. In vitro metabolism was also investigated in human. 3. In rat, the pharmacokinetic profile of Seocalcitol (Cmax, AUC, Tmax, T(1/2)) was the same after single and oral administration. Pharmacokinetics were also demonstrated as dose-independent. The same was more difficult to evaluate in the minipig due to a great variation among individual animals. 4. In the male rat, the serum T(1/2) was 3 h, but in the female rat and minipig (both genders) T(1/2) = 8 h. 5. At Tmax the concentration of Seocalcitol in the liver (both species) was 10-fold higher than the concentration in serum. The major metabolites in the liver were various isomers of 26-hydroxy Seocalcitol, although the concentration of the individual isomers in rat and minipig were not the same. 6. The same metabolites were formed in vitro following incubations with rat, minipig and human S9 fractions.

[Pregnancy-related and work-related sick leave of pregnant women]. / Graviditetsrelaterede og arbejdsmaessige begrundelser for fravaersmelding af gravide.

Pregnant women are allowed sick leave (SL) due to obstetrical or occupational risk factors. The aim was to describe reasons for SL during pregnancy. Pregnant women in a Danish county applying for SL were consecutively included in the study during 12 months in 1991-92. Data were obtained by questionnaires mailed to the women and their medical doctors. Of 1483 pregnant women on SL, 994 participated. Approximately 96% were on SL due to obstetrical risk factors. Occupational factors contributed to SL in at least 50% of the cases, mainly when working in a standing or walking position or when lifting. The women were rarely replaced in other jobs before leaving work. On average the women were absent for 83 days before official pregnancy leave started. Although SL during pregnancy is overwhelmingly due to obstetrical risk factors, occupational factors often contribute. Occupational Health and Safety Organizations are rarely involved at the workplace before issuing a sick leave certificate.

Nocturia and polyuria in men referred with lower urinary tract symptoms, assessed using a 7-day frequency-volume chart.

OBJECTIVES: To investigate if a 7-day frequency-volume (FV) chart could identify nocturia on a polyuric basis in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: The study included 23 patients (mean age 62.8 years, range 42-78) with LUTS who were referred for the evaluation of potential BPH and 11 men (control subjects, mean age 63.3 years, range 58-69); all completed a 7-day FV chart investigation as outpatients. RESULTS: Nocturia was associated with nocturnal polyuria in 10 of 23 patients with LUTS; these 10 patients had a diminished diurnal variation of urine production, whereas 13 patients had a diurnal variation in urine production comparable with that in controls with no nocturia. The degree of nocturia correlated positively with nocturnal urine production but showed no relationship with sleep duration. The nocturnal polyuria in these patients was associated with a higher 24-h urine production and seemed at least partly to be caused by a higher fluid intake during daytime. CONCLUSION: Nocturia on a polyuric basis can be detected by using a FV chart. In these patients, a 3-day FV chart would be sufficient to detect nocturia on a polyuric basis and seems therefore to be a valuable tool in evaluating patients with LUTS referred for potential BPH.

A population-based study of antibiotic prescriptions for Danish children.

BACKGROUND: The aim of the study was to examine the use of systemic and topical antibiotics in relation to age and sex in Danish children. METHODS: We used the Pharmacoepidemiological Prescription Database to identify the individual prescriptions of antibiotics provided for all 0-to 15-year-old children in North Jutland County, Denmark, during 1997. The population was approximately 95000 children. RESULTS: We identified 44640 prescriptions for systemic antibiotics. The annual prescription rate was highest in the 1- to 2-year-olds, with 945 prescriptions/1000 children/year. One-half of these children received at least 1 prescription, and 12% received 3 or more prescriptions. Among the 11- to 15-year-old children 17% received one or more prescriptions. Overall 88% of the prescriptions were penicillins and 10% were macrolides. In children younger than 3 years 57% of prescriptions were for broad spectrum penicillins, but in children older than 6 years penicillin V was the most frequently used antibiotic. We identified 12 661 prescriptions for topical antibiotics used in eye infections. The prescription rate peaked in the 1- to 2-year-old children, one-third of whom received at least 1 prescription. CONCLUSIONS: Almost two-thirds of the 0- to 2-year-old children in the population were treated with either systemic or topical antibiotics during 1 year. Physicians prescribe mostly penicillins, but the proportion of broad spectrum penicillins for young children was so high, however, that enforcement of national guidelines should be reconsidered.

Multiple sclerosis and organic solvents.

We investigated a possible causal relation between exposure to organic solvents in Danish workers (housepainters, typographers/printers, carpenters/cabinetmakers) and onset of multiple sclerosis. Data on men included in the Danish Multiple Sclerosis Register (3,241 men) were linked with data from the 1970 census from the National Bureau of Statistics in Denmark, which has data on occupational status for 1,768,846 men between 15 and 74 years of age. From this census, we ascertained a group of 124,766 "solvent-exposed" men and an "unexposed" group of 87,501 male electricians, bricklayers, and butchers. Over a follow-up period of 20 years, we observed no increase in the incidence of multiple sclerosis among men presumed to be exposed to organic solvents. It was not possible to obtain data on potential confounders, and the study design has some potential for selection bias. Nevertheless, the study does not support existing hypotheses regarding an association between occupational exposure to organic solvents and multiple sclerosis.

Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist.

The present paper describes the structural modifications leading to the discovery of a new series of quinoline-containing cys-LT1 receptor (LTD4 receptor) antagonists. A structural optimization with respect to the in vitro receptor binding, the in vivo brochoconstriction, and the toxicological effect in the form of peroxisomal proliferation was performed in order to achieve the target compound OT4003. OT4003 ((S)-(+)-E-2-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxyl++ +-hexanoic acid) was found to be a potent and selective inhibitor of [3H]LTD4 specific binding to guinea pig lung membranes (IC50 2.4 +/- 1.0 nM), and also a potent, orally active, antagonist of LTD4 induced bronchoconstriction in guinea pigs [ED50 0.14 (ED16 0.1-ED84 0.4) mg/kg; 4 h pretreatment]. The enantiomerically pure OT4003 was prepared using a short convergent synthesis, including an enzymatic resolution step.

The rat subcutaneous air sac model: a new and simple method for in vivo screening of antiangiogenesis.

An experimental rat model, the Subcutaneous Air Sac (SAS) model, was developed to provide an animal model in which neo-vascularization can be easily assessed in situ and quantified using a radiolabelled plasma marker. The SAS model was designed to replace a previous model where neovascularization was induced by chemical injury of rat or rabbit cornea or by implantation of tumour cells intracorneally, a methodology which is believed to cause severe pain to the animals. In the SAS model the air sac replaces the cornea as a transparent avascular substratum in which vascularization can be observed. The air sac is induced by injection of air subcutaneously on the back of the animal. After 8 to 10 days a sufficient air sac has been established. The animal is anaesthesized and by a minor operation the cellulose sponge is implanted upon the air sac under the skin. The vasoproliferative effect of the cellulose sponge causes formation of new vessels which are macroscopically visible 10 days after implantation. The ability of the in vivo SAS model to show an antiangiogenic effect of a systemically applied test compound was investigated using the fumagillin analogue TNP-470 (ochloro-acetylcarbamoyl)-fumagillol) as a positive control at dose levels of 0, 1, 2.5, 5 and 10 mg/kg/day given subcutaneously for 10 days. The neo-angiogenesis was scored both in situ using a subjective point system and by measuring the 125I-activity of the implant and the membrane after an intravenous injection of 125I-labelled antibodies. The neo-angiogenesis was reduced by approximately 45-50% in animals treated with 5 or 10 mg/kg/day of TNP-470 compared to animals treated with the vehicle. The animals treated with 10 mg/kg/day TNP-470 showed signs of toxicity. The SAS model is considered highly relevant for in vivo testing of potential antiangiogenic drugs on humane grounds. The high reproducibility, the low cost and the technical simplicity of the method makes it attractive.

Is semen quality related to the year of birth among Danish infertility clients?

BACKGROUND: There is circumstantial evidence that human sperm count may have declined during past decades. The purpose of this study was to identify the association between semen quality and year of birth. METHODS: The study comprised 8608 men consulting four Danish medical centres from 1968 to 1992 because of infertility. Data on semen quality and urogenital disorders were obtained from medical records while lifestyle data were collected from a subset of the population by a postal questionnaire (response 80%). Semen characteristics were analysed as a linear function of year of birth, centre, season and calendar year at time of semen examination, sexual abstinence and lifestyle factors. Effects of age were accounted for by restriction and stratified analysis. RESULTS: The sperm count declined with increasing year of birth at two of the four centres, but this association disappeared when confounders were adjusted for. Within the subset of men born 1950-1970 we revealed a decrease in the average sperm count by 1.9 mill/ml (95% confidence interval [CI]: 1.45, 2.27) per one advancing year of birth. This finding was consistent across centres even after adjustment for effects of covariates. The proportion of morphologically normal sperm cells changed in parallel with the sperm count, while semen volume did not decline in any time periods. CONCLUSIONS: We found a birth cohort effect on sperm count and morphology among Danish infertile men born after 1950 but not in men born in the first part of the century. The findings are compatible with an environmental impact during prenatal life but the evidence is far from unequivocal.

Toxicity of 1,25-dihydroxyvitamin D3, tacalcitol, and calcipotriol after topical treatment in rats.

To investigate and compare the effects on calcium metabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogs tacalcitol and calcipotriol after topical treatment, we treated groups of rats topically once daily with three dose levels of each test compound in a vehicle of propylene glycol plus ethanol for 28 d. The urinary calcium excretion was measured after 14 d, and serum calcium and parathyroid hormone were measured at termination. The rats were autopsied, and the kidneys were examined microscopically for mineralizations. Based on the urinary calcium excretion and the serum calcium level, calcipotriol was found to be 60 times less calcemic, and tacalcitol was slightly less calcemic, than 1,25(OH)2D3 after repeated topical application to rats. Serum parathyroid hormone was suppressed to a lower degree by calcipotriol and tacalcitol than by 1,25(OH)2D3, and the incidence and severity of renal corticomedullary mineralization were higher in rats treated with 1,25(OH)2D3 and tacalcitol than with calcipotriol. We conclude that calcipotriol is much less calcemic than 1,25(OH)2D3 or tacalcitol when applied topically to rats in a vehicle that enhances penetration into the skin. We attribute the lower calcemic effect of calcipotriol to the pharmacokinetic profile of the compound, particularly its rapid metabolization into inactive compounds.

[Cheese-packers' disease--respiratory complaints at a cheese-packing dairy]. / Ostepakkersyge--luftvejsklager på et skimmelostepakkeri.

Twenty-one present and three former employees working in the paching room of a cheese-making dairy underwent clinical examinations including symptom history, smoking habits, chest examination, and pulmonary function tests. Blood samples were drawn to determine level of peripheral eosinophil count and antibodies to microorganisms detected by air samples. Air sample concentrations of Penicillium camemberti var. candidum, used in the cheese-production, were very high (> 6000 colony forming units per cubic metre of air). In 15 of the 24 exposed workers, precipitating antibodies towards this fungus were detected, but no antibodies were detected in a reference consisting of pooled blood from 1000 donors. Of the sixteen workers with airway symptoms five had asthma requiring treatment. Two-thirds of the symptomatic cheeseworkers but only half of those without symptoms had precipitating antibodies. The high frequency of precipitating antibodies together with the clinical causes of the airway symptoms indicates an aetiological relationship between airway symptoms and heavy exposure to Penicillium camemberti.

[What did the consumers get out of the examination at a clinic of occupational medicine?]. / Hvad fik brugerne ud af undersøgelse på arbejdsmedicinsk klinik?

In order to evaluate the function of a department of occupational medicine regarding consumer satisfaction, a mailed questionnaire was sent to 605 patients examined at the Department of Occupational Medicine, Aalborg Sygehus, during the period 01.10.1988-31.12.1989. A similar questionnaire was sent to the persons referring the patients to the department. Seventy-three percent of the patients and 76% of the persons referring patients participated in the investigation. Of the patients 44% had their expectations fulfilled, of the persons referring 78%. Half of the patients and 69% of the persons referring found the advice given relevant in relation to the health problem. Satisfaction among patients was related to whether the patients expected to start a compensation case or suffered from a chronic disease for which treatment was difficult. There was a difference between the expectations of the patients and persons referring the patients examination.