Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.     

Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.

PURPOSE: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1alpha and HIF-2alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1alpha expression. EXPERIMENTAL DESIGN: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines. RESULTS: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1alpha, regions with simultaneous HIF-1alpha and PHD2 expression could be detected. CONCLUSIONS: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1alpha in some tumors.     

Fever following immunization

Fever is a frequent systemic adverse event following immunization, especially in infants and young children. Any fever after immunization may be caused by immunization or may coincide temporally as an indication of underlying disease, usually an infectious one. The time pattern of fever attributable to immunization has characteristic features depending on the vaccine used. Comparability of fever rates associated with different vaccines, or the same vaccines in different studies, is frequently hampered by the use of different definitions and/or assessment techniques for fever. A recent analysis by the Brighton Collaboration has provided a standardized case definition for fever, the use of which should be strongly encouraged.     

Concentration of antipneumococcal antibodies as a serological correlate of protection: an application to acute otitis media

BACKGROUND: For the licensing of new pneumococcal vaccines, it is vital to be able to predict their protective efficacy on the basis of immunogenicity. However, the serological correlates of protection have not been established for pneumococcal diseases. METHODS: A total of 1666 children were immunized with the pneumococcal conjugate vaccine. Acute otitis media (AOM) events were identified, and middle-ear fluid was cultured for pneumococci. The association between the concentration of antibodies against serotypes 6B, 19F, and 23F and the risk of AOM caused by the homologous serotypes or by the cross-reactive serotype 6A was assessed. An association model was used to predict efficacy at different geometric mean concentrations (GMCs). RESULTS: An association between antibody concentration and risk of AOM was found, but with large differences between serotypes. On the basis of the association, the predicted efficacy for 19F was negligible up to the highest GMC tested. In contrast, 6B was found to be highly efficacious (>65%) at a GMC of 0.5 microg/mL. CONCLUSIONS: The results challenge the view that a new vaccine candidate should always induce antibody concentrations that are not inferior to those produced by the licensed vaccine. Furthermore, the differences between serotypes caution against defining a common correlate of protection that is applicable to all serotypes.     

The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children

BACKGROUND: The novel pneumococcal conjugate vaccine, PncCRM, has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery. Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements. METHODS: Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area (1490 of 1662 randomized at 2 months of age) were invited to a single visit at 4-5 years of age. The children had been vaccinated at 2, 4, 6 and 12 months of age with PncCRM or hepatitis B vaccine (control). Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records. Additionally, tympanostomy tube placements of all children were verified from the hospital discharge registry. Vaccine efficacy (VE) was estimated by comparing all events of tympanostomy tube placement between vaccine groups. RESULTS: During the vaccine trial (2-24 months of age), VE (95% confidence interval) in preventing tympanostomy tube placement was only 4% (-19-23%). Altogether 756 children were enrolled for the follow-up study. After 24 months of age, the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children, giving VE of 39% (4-61%). In the hospital-based data of all children (N = 1490), VE of 44% was obtained (19-62%). CONCLUSIONS: Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4-5 years of age.     

Multiple sclerosis in western Finland: evidence for a founder effect

We have previously demonstrated that there is a high-risk focus for multiple sclerosis (MS) in the southern Ostrobothnian region of western Finland (population 376121 in 1993). Of the two southern Ostrobothnian health-care districts, Vaasa and Sein?joki, the incidence and prevalence of MS were especially high in the latter. In recent genetic studies, we identified haplotypes of the myelin basic protein (MBP) gene in a group of MS patients originating from southern Ostrobothnia, suggesting a founder effect. This finding led us to explore the population history of the southern Ostrobothnia and correlate it with MS epidemiology. Southern Ostrobothnia can be divided into three distinct regions with respect to its historical settlement: Vaasa, Sein?joki-south, and Sein?joki-north. Vaasa, the coastal region was settled by Swedes, who immigrated during the 13th century. In Vaasa, the prevalence of clinically definite MS (CDMS) in 1993 was 107/10(5) (95% CI 90-124). Sein?joki-south was populated from the 13th century onwards from southwestern Finland, a region which has been recognised as a high-risk focus of MS. In Sein?joki-south, the prevalence of CDMS in 1993 was 219/10(5) (95% CI 190-247). Sein?joki-north was inhabited rather late starting in the 16th century from eastern Finland. In Sein?joki-north the prevalence of CDMS in 1993 was 136/10(5) (95% CI 108-164). The historical settlement pattern of the southern Ostrobothnia indicates that its population is quite heterogeneous. Sein?joki-south has a very high prevalence of MS, significantly higher than its two neighbouring regions. The distinctive settlement history of Sein?joki-south, the historical link with the other southwestern high-risk foci and molecular genetic evidence, suggest that a founder effect plays an important role in the high-risk of MS in western Finland.     

Anti-PsaA and the risk of pneumococcal AOM and carriage

Pneumococcal surface adhesin A (PsaA) is one of the common protein antigens of Streptococcus pneumoniae investigated as a possible vaccine candidate on the basis of studies in experimental animal models. The relation between the serum anti-PsaA concentration collected at 6, 12 and 18 months of age and the risk of pneumococcal carriage and acute otitis media (AOM) in the following 6 months was evaluated in 329 children of the Finnish Otitis Media (FinOM) Cohort Study. A higher anti-PsaA concentration at all three time points studied was found to predict a higher risk of pneumococcal carriage 6 months later. A higher anti-PsaA concentration at 6 months also predicted a higher risk of pneumococcal AOM during the following 6 months (RR 1.51, 95% CI 1.24-1.83), whereas a higher anti-PsaA concentration at 12 or 18 months seemed to decrease the risk of pneumococcal AOM (RR 0.94 [95% CI 0.80-1.09] and RR 0.88 [95% CI 0.73-1.07], respectively). These relations remained the same when concomitant risk factors for pneumococcal AOM were included in the models. Previous pneumococcal AOM was the most important risk factor for a subsequent pneumococcal AOM (RR 5.93 [95% CI 2.87-12.3], RR 2.2 [95% CI 1.21-4.00], and RR 3.3 [95% CI 1.72-6.32] during the three periods).     

Use of psychotropics among home-dwelling nondemented and demented elderly

OBJECTIVE: To describe the use of psychotropics in the nondemented and demented elderly. PARTICIPANTS: The home-dwelling elderly (n=523) among the random sample of 700 subjects from the total population of individuals aged 75 years or more in 1998 and living in the city of Kuopio, Finland. METHODS: A trained nurse interviewed the participants about their health and current use of medicines. A geriatrician performed clinical examinations and diagnosed diseases. Dementia and depression were diagnosed according to the DSM-IV criteria. RESULTS: The demented subjects used more medicines of all kinds (p<0.01), and especially more psychotropics than the nondemented (p<0.001). One in four demented subjects, compared to one in ten nondemented ones used at least two psychotropics (p<0.01). The demented subjects used antipsychotics six times more often than the nondemented ones (p<0.001). Among the nondemented subjects, one out of two antipsychotics users was suffering from depression according to DSM-IV criteria. Three out of four persons who had dementia with Lewy bodies were using psychotropics. Persons with moderate dementia were more commonly using all kinds of psychotropic preparations especially, antipsychotics three times more commonly than persons with mild or severe dementia. CONCLUSION: Psychotropics, especially antipsychotics, are commonly used in the treatment of both nondemented and demented elderly, even without proper indication. Physicians need more training about the appropriate use of psychotropics to minimize their adverse effects.     

Expression and activation of caspase 3 following status epilepticus in the rat

It is in dispute whether caspase 3 contributes to status epilepticus (SE)-induced cell loss. We hypothesized that caspase 3-mediated cell death continues beyond the acute phase of SE. We induced SE with either kainic acid or electrical stimulation of the amygdala in Wistar and Sprague-Dawley rats. Caspase 3 immunohistochemistry, Western blot analysis and enzyme activity measurements were used to determine cellular localization and the time course of caspase 3 expression and activation. Immunohistochemistry indicated that caspase 3 protein expression increased following SE, peaking at 16-24 h. Cleavage of procaspase 3 to active fragments (p20-17) was detected 2-7 days after SE. Caspase 3 enzyme activity was elevated at 8 h and further increased up to 19.4-fold at 7 days following SE. Activation of caspase 3 after SE occurred in the hippocampus and the extrahippocampal temporal lobe but not in the thalamus. Caspase 3-immunoreactive cells represented only a minority of degenerating cells as assessed by Fluoro-Jade B and TUNEL staining. Analysis of double-labelled sections indicated that active caspase 3 was located in astrocytes rather than neurons or microglia. There was increased caspase 3 expression in both rat strains, and it was independent of the method used to induce SE. These data demonstrate that caspase 3 contributes to the cell death occurring within the first week after SE, but in only a small proportion of degenerating cells. These results suggest that, contrary to expectations, caspase 3 inhibitors would have only limited benefits in the treatment of SE.