Modelling of Bet v 1 Binding to Lipids

As birch pollen allergen enters epithelium of allergic patients via lipid rafts and caveola we began to analyse its putative amphiphilic and lipid ligands on atomic level using molecular modelling and computational ligand docking. We carry out 3D modelling docking with both experimentally verified Bet v 1 ligands as well as larger lipid molecules for which experimental affinity studies were not available. The results suggest that the hydrophobic cavity of Bet v 1 has different binding sites for different ligands and groups of ligand type-specific amino acids can be defined. Bet v 1 proteins may also be able to bind and transport more complex amphiphilic molecules like ceramides and sphingomyelins known to be enriched on caveolae/lipid rafts. Furthermore, the suggested binding mode, where the hydrophobic tail groups of lipids locate inside Bet v 1, while the polar head group may remain solvent accessible, would allow Bet v 1 to bind glycolipids, e.g. gangliosides, also rich on caveolae/lipid rafts. Taken together, this in silico work suggests that Bet v 1 bind to amphiphilic and lipid ligands present on the caveolae/lipid rafts and thus could provide a molecular mechanism for the pollen entry to epithelial tissue of allergic patients.     

Improvement in undergraduate medical education: a 10-year follow-up in Finland

Several studies have revealed that undergraduate medical education does not adequately prepare students for their work as physicians. There have been attempts to solve this problem in curriculum reforms in medical faculties. In this article, Finnish physicians' opinions on their undergraduate medical education are analysed. In 1988, a postal questionnaire was mailed to 2632 physicians registered during 1977-86, and altogether 1745 questionnaires were returned (66.3%). A follow-up study was done in 1998, and a questionnaire was sent to 2529 physicians who graduated between 1987 and 1996; 1822 questionnaires were returned (73.1%). Half of the respondents considered undergraduate education to correspond well with the requisite diagnostic skills and hospital doctors' work in general. In older and more traditional medical faculties (Helsinki, Oulu and Turku) education in primary healthcare work was considered insufficient. Also, more than 80% of the respondents felt they received too little teaching in administrative work. They reported that both traditional and younger, community-oriented faculties (Kuopio and Tampere) had considerably improved their education, especially in primary healthcare, during the 10-year follow-up. However, there were still clear differences between the education in the respective types of faculty as evaluated by their graduates. There is still room for improvements in undergraduate medical education, the better to meet the real needs of practising physicians in different fields of health care.     

Problems with condoms -- a population-based study among Finnish men and women.

OBJECTIVE: This study evaluates men's and women's opinions of condom use and problems with it in real life. METHODS: Random samples of men and women, aged 18-50 years, were drawn from the Finnish Population Register and were mailed a questionnaire on family planning. Response rates were 36% for men (706) and 58% for women (1136). Respondents were asked e.g. about condom use, whether they had had problems with it and why they used condoms. Moreover they were asked if they had received advice on how to use condoms. RESULTS: Among both men and women 87% had at some time used condoms. Of all men 37% and of women 34% reported that they had at some time had a failure with condom use; among both men and women one in four had experienced condom breakage. The use of condoms with the main purpose of preventing sexually transmitted diseases was somewhat low. The proportion of respondents having received advice on condom use was greater among younger men and women. CONCLUSION: A patient with problems in condom use is not uncommon in consultations in primary health care, and thus personnel working there hold a key position in promoting condom use. The role of school health care should be assured to offer basic sexual and reproductive counselling to every generation.     

A study of interleukin-1 cluster genes in susceptibility to and severity of multiple sclerosis

In this explorative study, interleukin-1 (IL-1) receptor antagonist (IL-1RA; polymorphism of variable number of tandem repeats: VNTR), IL-1alpha (-889), IL-1beta (-511) and IL-1beta (+3953) polymorphisms were studied in relation to susceptibility to and severity of multiple sclerosis (MS), in 93 MS patients and 400 normal controls. No associations were found for any polymorphisms, alone or in combination. However, in our MS cohort, females were found to be IL-1RA allele 2 carriers more frequently than males (33/49 vs. 16/44, p = 0.0028). Using a cohort of 109 controls, IL-1RA allele 2 carriers were more frequently women with MS than control women (33/49 vs. 23/43, odds ratio (OR) = 2.19, 95% confidence interval (CI) 1.02-4.72, p = 0.043, P(C) = ns). The data suggest that the IL-1 cluster genes make no major contribution to MS, but the tentative association between IL-1RA allele 2 and susceptibility of MS in women warrants further studies.     

Midazolam 12 mg is moderately counteracted by 250 mg caffeine in man

OBJECTIVE: Caffeine (Caf) counteracts various effects of benzodiazepines (BZDs). Since the effects of zolpidem, a short-acting atypical GABA(A)-BZD agonist, were not antagonized by Caf, we studied an interaction between Caf and midazolam (Mid) in healthy volunteers. SUBJECTS, MATERIALS AND METHODS: In Study 1, 108 healthy students divided to 6 parallel groups were given Mid 12 mg (capsule) and Caf 125 and 250 mg (in decaffeinated coffee), alone and in combinations in the double-blind placebo-controlled manner. Objective and subjective tests were done before and at 45 and 90 min after intake. Ranked delta-values (changes from baseline) were analyzed by one-way contrast ANOVA and Scheffe's tests. In Study 2, six healthy subjects took Mid 15 mg (tablet) with and without Caf 300 mg. The dynamic effects were analyzed as in Study 1 and the plasma concentrations were assayed. RESULTS: In Study 1, learn effects after placebo (ad + 15%) were seen for letter cancellation and digit symbol substitution tests. Midazolam alone significantly (p < 0.05 vs. delta-placebo) reduced letter cancellation and digit symbol substitution, lowered flicker fusion, impaired digit learning and caused subjective calmness on VAS. Caffeine alone did not differ from placebo objectively, yet improved quick-wittedness and contentedness on VAS. In the combinations, Mid + Caf 125 mg differed from placebo objectively as Mid alone, whereas Mid + Caf 250 mg did not. Mid + Caf 250 mg differed from Mid on digit substitution, but did not differ from Mid+Caf 150 mg in impairing memory and causing subjective sedation. In Study 2, Mid 15 mg caused sedation and Caf 300 mg increased plasma Mid at 45 min. Mid + Caf did not differ from Mid alone objectively, but did so subjectively on VAS (p > 0.05). CONCLUSION: In conclusion, in a parallel group study, sedative effects of Mid 12 mg were only moderately antagonized by Caf 250 mg but not by Caf 125 mg. In a cross-over study, a weak interaction was found subjectively but not in objective measures.     

Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine.

1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three-way ANOVA, paired t-test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l-1 on day 6 and 85 micrograms l-1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l-1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of GABAergic activity and thyrotropin secretion in male rats

The effect of GABA on basal and stimulated TSH secretion was studied in male rats. The effects of drugs on basal TSH levels were not consistent. Muscimol(0.5 mg/kg subcutaneously, but not 2 mg/kg) increased whereas baclofen (10 mg/kg intraperitoneally), amino-oxyacetic acid (AOAA, 20 mg/kg intraperitoneally) and bicuculline (2 mg/kg intraperitoneally, but not 1 or 4 mg/kg) decreased basal TSH concentrations. Muscimol, AOAA and baclofen dose-dependently reversed the TSH cold-response, as did a large dose of di-n-propylacetate (DPA, 400 mg/kg intraperitoneally) and 500 mg/kg (but not 50, 100 or 1500 mg/kg intraperitoneally) of GABA itself. Bicuculline was not effective alone. Neither did it modify the effects of muscimol, AOAA and GABA on the cold-stimulated TSH response. None of the drugs studied (AOAA, GABA, bicuculline) modified TRH-induced (100 ng intraperitoneally) TSH-response. GABA injected into the third ventricle (5-50 microgram/rat) or into the medial basal hypothalamus (MBH, 5 microgram/rat) had no effect on the basal TSH levels. However, the TSH cold-response was inhibited when GABA (5 microgram/rat) was infused into the MBH but not when it was infused into the third ventricle (5-50 microgram/rat). The results suggest that GABAergic pathways may have an inhibitory effect on the stimulated TSH secretion in male rats. The locus of this inhibition is not situated in the anterior pituitary, but possibly in the MBH.