Chemical Imaging of Evolving Amyloid Plaque Pathology and Associated Aβ Peptide Aggregation in a Transgenic Mouse Model of Alzheimer's Disease

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid β (Aβ) plaques. While Aβ has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aβ plaque pathology manifests itself upon aggregation of distinct Aβ peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aβ aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aβ species aggregate and form plaques remains unclear. The aim of the current study was to investigate the potential of MALDI-IMS as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - MALDI imaging mass spectrometry - that allows for delineating Aβ aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long Aβ (Aβ1-42). Plaque maturation was found to be characterized by a relative increase in deposition of Aβ1-40, which was associated with the appearance of a cored morphology of the plaques. Finally, other C-terminally truncated Aβ species (Aβ1-38 and Aβ1-39) exhibited a similar aggregation pattern as Aβ1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aβ1-42; a process that is followed by plaque maturation upon deposition of Aβ1-40 as well as deposition by other C-terminally modified Aβ species

Comparison Between Nailing and Plating in the Treatment of Distal Tibial Fractures: A Meta-Analysis

Background and Aims: To evaluate evidence on the superiority of plate fixation over intramedullary nail fixation in the treatment of distal tibial fractures regarding functional outcomes and complication rates. Material and Methods: Cochrane Controlled Trials Register, Medline, Embase, CINAHL, Scopus, and Web of Science databases were searched in December 2019. The risk of systematic bias was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Results: The search resulted in 514 records, the final sample included 10 randomized controlled trials (782 patients). There were statistically significant differences in operating time (-11.2, 95% confidence interval: -16.3 to -6.1 min), time to partial weight bearing (-0.96, 95% confidence interval: -1.8 to -0.1 weeks), time to full weight bearing (-2.2, 95% confidence interval: -4.32 to -0.01 weeks), the rates of deep infections (risk ratio = 0.37, 95% confidence interval: 0.19 to 0.69), and the rates of soft-tissue complications (risk ratio = 0.52, 95% confidence interval: 0.33 to 0.82) favoring intramedullary nail. Intraoperative blood loss (127.2, 95% confidence interval: 34.7 to 219.7 mL) and postoperative knee pain and stiffness (relative risk = 5.6, 95% confidence interval: 1.4-22.6) showed significant differences favoring plate fixation. When combining all complication rates, the difference was risk ratio = 0.77 (95% confidence interval: 0.63 to 0.95) favoring intramedullary nail. No significant differences in radiation time, length of incision, length of hospital stay, time to return to work, time to union, the rates of healing complications or secondary procedures, ankle pain or stiffness, or functional scores were found. Conclusion: This meta-analysis suggests that intramedullary nail might be slightly superior in reducing postoperative complications and result in slightly faster healing when compared to plate fixation.</div

Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer was introduced several years ago.&nbsp;Despite the evidence supporting its use in clinical practice, only a minority of patients who undergo&nbsp;radical cystectomy receive preoperative chemotherapy. In addition, recommendations and methods&nbsp;to detect patients who would benefit the most from NAC are still unclear. The European Association of&nbsp;Urology (EAU) guidelines panel on muscle-invasive and metastatic bladder cancer recommends the use&nbsp;of cisplatin-based NAC for T2-T4a, cN0 M0 bladder cancer if the patient has a performance status &ge;2 and if the renal function is not impaired, but the American Urological Association, for example, does not&nbsp;have any guideline recommendations on this topic at all. In this review we describe the current literature&nbsp;supporting NAC in association with radical cystectomy in muscle-invasive urothelial carcinoma of the&nbsp;bladder. Evidence acquisition was made searching the Medline database for original articles published&nbsp;before 1st February 2014, with search terms: &ldquo;neoadjuvant chemotherapy&rdquo;, &ldquo;radical cystectomy&rdquo;, and&nbsp;&ldquo;invasive bladder cancer&rdquo;.</p

Extended spectrum penicillins reduce the risk of omphalocele : A population-based case-control study

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Challenges in context-aware mobile language learning: the MASELTOV approach

Smartphones, as highly portable networked computing devices with embedded sensors including GPS receivers, are ideal platforms to support context-aware language learning. They can enable learning when the user is en-gaged in everyday activities while out and about, complementing formal language classes. A significant challenge, however, has been the practical implementation of services that can accurately identify and make use of context, particularly location, to offer meaningful language learning recommendations to users. In this paper we review a range of approaches to identifying context to support mobile language learning. We consider how dynamically changing aspects of context may influence the quality of recommendations presented to a user. We introduce the MASELTOV project’s use of context awareness combined with a rules-based recommendation engine to present suitable learning content to recent immigrants in urban areas; a group that may benefit from contextual support and can use the city as a learning environment

A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts

© 2018, The Author(s). Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1–10). Fisher’s exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects

Omphalocele in Finland from 1993 to 2014: Trends, Prevalence, Mortality, and Associated Malformations-A Population-Based Study

Introduction The aim of this study is to assess the changes in prevalence, mortality and termination pregnancy of omphalocele, and to identify associated anomalies.Materials and Methods A population-based nationwide register study. All cases with omphalocele were identified in the Finnish Register of Congenital Malformations and the Care Register for Health Care from 1993 to 2014 including live births, stillbirths, and terminations of pregnancy due to fetal anomalies. Associated anomalies were recorded and analyzed, and perinatal and infant mortality and prevalence were calculated.Results There were 600 cases with omphalocele including 229 live births, 39 stillbirths, and 332 (55%) abortions. Birth prevalence in Finland was 1.96 per 10,000 births with no consistent trend over time. However, total prevalence was much higher (4.71/10,000) because more than half of these families chose option for the termination of pregnancy. Omphalocele is often complicated with other anomalies; most commonly chromosomal abnormalities (9.3%), heart defects (6.3%), central nervous system anomalies (3.0%), gastrointestinal, and urogenital malformations (both 2.0%). Proportion of chromosomal and central nervous system abnormalities were even higher in terminated pregnancies. Overall infant mortality was 22%. Total 1-year survival rates for isolated omphalocele, cases with multiple anomalies and neonates with chromosomal defects were 80, 88, and 17%, respectively.Conclusion Omphalocele is a rare congenital anomaly, often associated with other malformations. Our data suggest that isolated cases may be more common than previously thought. In the absence of chromosomal defects, survival is reasonably good. Regardless, more than half of these pregnancies are often terminated.</p

Extended spectrum penicillins reduce the risk of omphalocele: A population-based case-control study

Background: Omphalocele is a major congenital anomaly associated with significant morbidity and mortality. Regardless, the influence of maternal use of prescription drugs on the risk of omphalocele has only been addressed in a handful of studies. The aim of this study was to assess the influence of maternal risk factors and prescription drugs in early pregnancy on the risk of omphalocele.Methods: We performed a nationwide register-based case-control study in Finland. The analysis is based on the Finnish Register of Congenital Malformations and Drugs and Pregnancy databases, both upheld by the Finnish Institute for Health and Welfare. All omphalocele cases were identified between Jan 1, 2004, and Dec 31, 2014. Five age-matched controls from the same geographical region were randomly selected for each case. The main outcome measures were maternal risk factors for omphalocele. Our analysis compared the maternal characteristics and the use of prescription drugs during the first trimester of pregnancy between case and control mothers.Results: Mothers of 359 omphalocele cases were compared with 1738 randomly selected age and area-matched mothers of healthy infants between 1 January 2014 and 31 December 2014. Both maternal obesity (BMI ≥30) and diabetes increased the risk for omphalocele, and their co-occurrence accumulated this risk (aOR 5.06, 95% Cl 1.19-21.4). Similarly, history of multiple miscarriages was an independent risk factor (2.51, 1.16-5.43). The oral use of extended spectrum penicillins during the first trimester of pregnancy had a significant, protective influence (0.17, 0.04-0.71). These analyses were adjusted for sex, parity, and risk factors reported above. No significant changes in risk were observed with any other medication used during the first trimester.Conclusion: In conclusion, these findings may suggest that extended spectrum penicillins in the first trimester reduces the risk of omphalocle formation. Additionally, consistent with earlier studies, previous repeated miscarriages, maternal obesity, and diabetes were significant risk factors for omphalocele.</p

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.Peer Reviewe