Bioactive glass S53P4 and tissue adhesives in the surgical treatment of chronic middle ear and mastoidal infections

The treatment of chronic middle ear infection often includes surgery, which addresses areas of the middle ear and the mastoid cavity affected by the infection. Several factors favor the filling of the opened mastoid cavity after the so-called radical mastoidectomy. Many materials with different qualities have been used over the decades as mastoid obliteration materials, either by themselves or in a combined manner. In the clinical part of this study, bioactive glass (BG) S53P4 particles were used to obliterate the mastoid cavity of 26 patients. The second and third part of this study examined the solubility and strength of fibrin glue-bioactive glass– and cyanoacrylate glue-bioactive glass –composites in vitro. Finally, a keratinocyte cell model was used to determine what kind of an effect bioactive glass S53P4 particles might have on the cells of ear cholesteatoma disease, or on the cells of normal skin of the surgical area. Based on the results of this study, bioactive glass S53P4 as a mastoid cavity obliteration material produces a dry, safe ear, and may help to achieve a more normal appearance and function of the outer ear canal. Fibrin glue seems to be a suitable addition to BG granules, as it binds to BG granules making clinical use easier, but does not have a negative influence on the solubility process of BG. Cyanoacrylate glue, on the other hand, binds BG granules into a very solid composite structure that retains its strength in spite of a 30-day water exposure. It does not seem ideal to be used with BG granules in mastoid obliteration, but it might be a candidate for fixation of rigid BG composite implants. Based on the data of the in vitro cell model using immortalized HaCaT keratinocytes, BG S53P4 seems to inhibit the growth of keratinocyte cells and appears to trigger cell apoptosis with a direct cell-BG granule –contact. As these effects are constrained, BG S53P4 could have potential to reduce the likelihood of ear cholesteatoma recurrence, while not being unnecessarily harsh to normal skin.Biolasi S53P4:n ja kudosliimojen käyttö pitkäaikaisen välikorva- ja kartiolisäketulehduksen kirurgisessa hoidossa Pitkäaikainen välikorvatulehdus edellyttää usein välikorvaan ja korvalokerostoon kohdistuvaa leikkaushoitoa. Useat seikat puoltavat leikkauksessa avatun korvalokeroston täyttämistä sopivalla materiaalilla, ja materiaaleja onkin vuosikymmenten mittaan ollut käytössä useita. Tämän tutkimuksen kliinisessä osassa 26 potilaan korvalokerosto täytettiin S53P4 biolasirakeilla. Toisessa ja kolmannessa osatyössä selvitettiin fibriinikudosliiman ja syanoakrylaattiliiman liukenemista ja lujuutta biolasirakeiden kanssa yhdessä käytettynä. Viimeisessä osatyössä tutkittiin biolasirakeiden vaikutusta kokeellisessa keratinosyyttisolumallissa, jotta syntyisi käsitys biolasin mahdollisesta vaikutuksesta kolesteatoomatautiin ja ihon keratinosyyttisoluihin. Tämän väitöskirjatutkimuksen perusteella bioaktiivinen lasi S53P4 sopii hyvin korvalokeroston täyttömateriaaliksi, ja sen avulla on mahdollista saavuttaa luotettavasti kuiva korva sekä mahdollisesti rakenteeltaan ja toiminnaltaan normaalia muistuttava korvakäytävä. Fibriiniliima soveltuu liukenemisominaisuuksiensa perusteella hyvin käytettäväksi biolasirakeiden kanssa. Syanoakrylaattiliiman huomattava lujuus ja liukenemattomuus eivät puolla kyseisen liiman yhteiskäyttöä biolasirakeiden kanssa korvalokerostossa, mutta kiinteiden biolasi-implanttien kiinnitysmenetelmänä syanoakrylaattiliima voisi tulla kyseeseen. Viimeisessä osatyössä käytetyn HaCaT keratinosyyttisolumallin perusteella biolasi S53P4 näyttää estävän keratinosyyttien kasvua ja altistavan välittömässä biolasikontaktissa olevat keratinosyyttisolut ohjelmoidulle solukuolemalle. Tämän havainnon perusteella korvalokeroston S53P4 biolasitäytöllä voisi olla rooli koleateatoomataudin uusiutumisen ehkäisemisessä, ilman merkittävää häiritsevää vaikutusta leikkausalueen ihon terveisiin keratinosyytteihin

The effect of fibrin sealant on bioactive glass S53P4 particles – pH impact and dissolution characteristics in vitro

Fibrin glue, a two-component tissue adhesive, has a range of clinical indications. Bioactive glass (BG) S53P4 has been approved for clinical use in several craniomaxillofacial and orthopedic applications. Although sometimes used simultaneously, there is no data available regarding the possible interaction of these two biocompatible substances. In this in vitro study, using a BG particle concentration of 4 mg/ml, a 0.4 unit pH increment (p<0.001) was observed in simulated body fluid (SBF) after a 7-day incubation period. The addition of fibrin glue (0.13 g, SD 0.04; or 3.7 mg/ml) on top of the BG particles raised further the pH by 0.5 units (p<0.001). The difference between these groups was statistically significant (p=0.008). With a BG concentration of 25 mg/ml and a fibrin glue concentration of 18 mg/ml during a 14-day incubation period, a pH increment of 0.6 units and SBF ion concentration change of Ca, K, Mg, Na, P and Si ions was seen. Moreover, a penetration depth between 4 and 6 mm was observed when fibrin glue was applied on top of a bed of BG particles. Conclusions: Fibrin glue is not likely to have a distracting effect on BG-induced pH increase of the SBF although it might delay early BG surface reactions based on ion concentration measurements. Fibrin glue penetrated to the interparticle space to some extent, binding the particles together for easy clinical use of BG. </p

Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression

Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals. Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes (XRCC4 and MTHFD2L) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study. Availability and implementation: R-code freely available for download at http://users.ics.aalto.fi/pemartti/gene_metabolome/. Contact: [email protected]; [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 x 10(-8), odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r(2) = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) <0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.Peer reviewe

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P = 0.033), 1.59 (95% CI: 1.08-2.34, P = 0.019) and 1.07 (95% CI: 1.03-1.13, P = 0.018), respectively. There was no evidence for association between birth weight and CRC (OR = 1.22, 95% CI: 0.89-1.67, P = 0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P = 7.7 x 10(-4)) and 1.40 (95% CI: 1.14-1.72, P = 1.2 x 10(-3)), respectively. Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.Peer reviewe

The effect of fibrin sealant on bioactive glass S53P4 particles – pH impact and dissolution characteristics in vitro

Fibrin glue, a two-component tissue adhesive, has a range of clinical indications. Bioactive glass (BG) S53P4 has been approved for clinical use in several craniomaxillofacial and orthopedic applications. Although sometimes used simultaneously, there is no data available regarding the possible interaction of these two biocompatible substances. In this in vitro study, using a BG particle concentration of 4 mg/ml, a 0.4 unit pH increment (p < 0.001) was observed in simulated body fluid (SBF) after a 7-day incubation period. The addition of fibrin glue (0.13 g, SD 0.04; or 3.7 mg/ml) on top of the BG particles raised further the pH by 0.5 units (p < 0.001). The difference between these groups was statistically significant (p = 0.008). With a BG concentration of 25 mg/ml and a fibrin glue concentration of 18 mg/ml during a 14-day incubation period, a pH increment of 0.6 units and SBF ion concentration change of Ca, K, Mg, Na, P and Si ions was seen. Moreover, a penetration depth between 4 and 6 mm was observed when fibrin glue was applied on top of a bed of BG particles. Conclusions: Fibrin glue is not likely to have a distracting effect on BG-induced pH increase of the SBF although it might delay early BG surface reactions based on ion concentration measurements. Fibrin glue penetrated to the interparticle space to some extent, binding the particles together for easy clinical use of BG