Absence of association between an intercellular adhesion molecule 1 gene E469K polymorphism and Alzheimer's disease in Finnish patients

Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.     

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.     

The association of preceding traumatic brain injury with mental disorders,alcoholism and criminality: the Northern Finland 1966 Birth Cohort Study

The purpose of this study was to test the hypothesis that traumatic brain injury (TBI) during childhood and adolescence is associated with psychiatric disorders, heavy alcohol use and criminal offenses in adulthood. We made use of an unselected, general population birth cohort (n=12058) in Northern Finland, which was followed up prospectively up to the age of 31. The data on TBIs of the cohort members were collected from the hospital case notes of the outpatient clinics of the hospitals in the region and from the Finnish Hospital Discharge Registers (FHDR). The data on mental disorders including alcohol diagnoses were also collected from the FHDR after a careful validation process. The Ministry of Justice provided information on criminal offenses for all subjects. The final number of subjects in our study was 5589 males and 5345 females. We found that after controlling for confounders, TBI during childhood or adolescence increased the risk of developing mental disorders two-fold (OR 2.1, 95% CI 1.1-3.6) and TBI was significantly related to later mental disorder with coexisting criminality in male cohort members (OR 4.1, 95% CI 1.2-13.6). The results support the TBI's association with psychiatric morbidity, which should not be overlooked when treating psychiatric patients, especially those with comorbid criminality.     

The influence of heredity for psoriasis on the ILAR classification of juvenile idiopathic arthritis

OBJECTIVE: To evaluate how heredity for psoriasis influences classification according to the International League of Associations for Rheumatology (ILAR). Heredity for psoriasis is currently both an exclusion and an inclusion criterion for different types of childhood arthritis according to ILAR classification criteria. METHODS: Twenty physicians in 5 Nordic countries prospectively collected data from the incident cases in their catchment areas over an 18 month period beginning July 1, 1997. Clinical and serological data from the first year of disease were collected. RESULTS: Of the 321 patients included who could be classified according to ILAR criteria for childhood arthritis, 50 (15.6%) patients were excluded from 55 classification events and fulfilled criteria for "other arthritis 1" i.e., did not fulfill criteria for any of the other classification categories, primarily because of heredity for psoriasis. If psoriasis in second degree relatives was disregarded as an exclusion criterion, only 8.7% of the patients remained in the "other arthritis 1" subgroup. For 20.6% of the whole group, heredity for psoriasis in a first or second degree relative (or both) and its distribution among arthritis subgroups did not differ except for juvenile psoriatic arthritis. CONCLUSION: We suggest that second degree heredity for psoriasis be withdrawn as an exclusion criterion from the ILAR criteria.     

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.     

Radioimmunotherapy with 90Y-Labeled Monoclonal Antibodies in a Nude Mouse Ovarian Cancer Model

Tumor stroma contains much fibrin, and so monoclonal antifibrin antibody can accumulate in tumors. We treated nude mice bearing human ovarian carcinoma xenografts with ⁹⁰Y-labeled monoclonal antifibrin antibody Fab fragments administered intratumorally. The survival time vs. a control group was significantly prolonged and tumor growth rate was decreased. Another group of animals was treated with ⁹⁰Y-labeled OC 125-monoclonal antibody; these mice received the antibodies intratumorally, intraperitoneally or intravenously. The survival time was longest in the intratumorally treated group. There was no significant difference in survival between ⁹⁰Y-labeled OC 125 and antifibrin in the intratumorally treated animal groups. The tissue activity distribution studies revealed that bone marrow is the critical organ. Intratumorally injected monoclonal ⁹⁰Y-antifibrin antibodies were retained at least 36h (up to 50% of injected activity per gram tumor tissue) in the xenograft after one treatment, causing cell death. Beta-camera imaging and immunohistochemistry were performed for studies of the correlation between ⁹⁰Y activity and fibrin distribution in tumor specimens. These results were in concordance. In conclusion, intratumoral administration seems suitable for radioimmunotherapy, with an antibody that targets stromal structures. The accumulation can be successfully monitored by a beta-camera.     

Evaluation of PAP and PSA gene expression in prostatic hyperplasia and prostatic carcinoma using northern-blot analyses,in situ hybridization and immunohistochemical stainings with monoclonal and bispecific antibodies

In this report we have investigated levels of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) gene expression in prostatic carcinoma (Ca) and benign prostatic hyperplasia (BPH) specimens. Northern-blot analyses of total prostatic mRNA indicated that there was a tendency towards lower amounts of PAP mRNA and PSA mRNA in the Ca specimens than in the BPH specimens, although, because of the great variation in the expression levels of both mRNAs, these differences were not statistically significant. In situ hybridization analyses clearly showed that both PAP and PSA mRNAs were confined to the columnar epithelial cells and that stromal cells were devoid of these mRNAs. In addition, PAP and PSA mRNAs were more abundant in BPH tissue than in adjacent Ca tissue within the same specimen. The levels of PAP and PSA enzymes were analyzed immunohistochemically using a bispecific antibody having high affinity for both PAP and PSA, and the results were compared with those obtained using monoclonal anti-PAP and anti-PSA antibodies. All 3 antibodies stained only epithelial cells and BPH tissue consistently gave more intense staining than Ca tissue. Furthermore, the anti-PSA and the bispecific anti-PAP-PSA antibodies stained well or moderately differentiated Ca tissues more strongly than poorly differentiated Ca tissues. No PSA staining was detected in 3 and no PAP staining in 5 of the moderately or poorly differentiated carcinomas (grades II or III). Our results show that, in comparison with BPH tissue, prostatic Ca tissue is associated with significantly lower levels of mRNAs coding for the prostatic marker enzymes PAP and PSA, as well as with lower concentrations of these enzymes. Furthermore, dedifferentiation of prostate Ca is associated with a decrease in the level of intraprostatic PSA.     

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.