Differences in Protein Expression and Gene Amplification of Cyclins between Colon and Rectal Adenocarcinomas

Adenocarcinomas of rectum and colon may be different with regard to the cellular biological basis for cancer development. A material of 246 rectal cancers removed surgically at Akershus University Hospital in the years 1992–2000 was investigated and was compared to a material of 219 colon cancers operated on at Akershus University Hospital during the years 1988, 1990 and 1997–2000. There were highly significant differences between the rectal and the colon cancers in the protein expression of cyclin D1, cyclin D3, cyclin E, nuclear β-catenin, and c-Myc and in gene amplification of cyclin A2, cyclin B1, cyclin D1, and cyclin E. Gene amplification and protein expression in the rectal cancers correlated significantly for the cyclins B1, D3, and E. A statistically significant relation was observed between overexpression of cyclin A2 and local relapse of rectal carcinomas, as higher expression of cyclin A2 was associated with lower local recurrence rate

Multiple genetic loci for bone mineral density and fractures

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. METHODS: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). RESULTS: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. CONCLUSIONS: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis

Feasibility of ActivABLES to promote home-based exercise and physical activity of community-dwelling stroke survivors with support from caregivers : A mixed methods study

BackgroundTechnical applications can promote home-based exercise and physical activity of community-dwelling stroke survivors. Caregivers are often able and willing to assist with home-based exercise and physical activity but lack the knowledge and resources to do so. ActivABLES was established to promote home-based exercise and physical activity among community-dwelling stroke survivors, with support from their caregivers. The aim of our study is to investigate the feasibility of ActivABLES in terms of acceptability, demand, implementation and practicality.MethodsA convergent design of mixed methods research in which quantitative results were combined with personal experiences of a four-week use of ActivABLES by community-dwelling stroke survivors with support from their caregivers. Data collection before, during and after the four-week period included the Berg Balance Scale (BBS), Activities-Specific Balance Confidence Scale (ABC), Timed-Up-and-Go (TUG) and Five Times Sit to Stand Test (5xSST) and data from motion detectors. Semi-structured interviews were conducted with stroke survivors and caregivers after the four-week period. Descriptive statistics were used for quantitative data. Qualitative data was analysed with direct content analysis. Themes were identified related to the domains of feasibility: acceptability, demand, implementation and practicality. Data was integrated by examining any (dis)congruence in the quantitative and qualitative findings.ResultsTen stroke survivors aged 55-79years participated with their informal caregivers. Functional improvements were shown in BBS (+2.5), ABC (+0.9), TUG (-4.2) and 5xSST (-2.7). More physical activity was detected with motion detectors (stand up/sit down +2, number of steps +227, standing +0.3h, hours sitting/lying -0.3h). The qualitative interviews identified themes for each feasibility domain: (i) acceptability: appreciation, functional improvements, self-initiated activities and expressed potential for future stroke survivors; (2) demand: reported use, interest in further use and need for follow-up; (3) implementation: importance of feedback, variety of exercises and progression of exercises and (4) practicality: need for support and technical problems. The quantitative and qualitative findings converged well with each other and supported the feasibility of ActivABLES.ConclusionsActivABLES is feasible and can be a good asset for stroke survivors with slight or moderate disability to use in their homes. Further studies are needed with larger samples.Peer reviewe

Feasibility of ActivABLES to promote home-based exercise and physical activity of community-dwelling stroke survivors with support from caregivers: A mixed methods study

Background: Technical applications can promote home-based exercise and physical activity of community-dwelling stroke survivors. Caregivers are often able and willing to assist with home-based exercise and physical activity but lack the knowledge and resources to do so. ActivABLES was established to promote home-based exercise and physical activity among community-dwelling stroke survivors, with support from their caregivers. The aim of our study is to investigate the feasibility of ActivABLES in terms of acceptability, demand, implementation and practicality. Methods: A convergent design of mixed methods research in which quantitative results were combined with personal experiences of a four-week use of ActivABLES by community-dwelling stroke survivors with support from their caregivers. Data collection before, during and after the four-week period included the Berg Balance Scale (BBS), Activities-Specific Balance Confidence Scale (ABC), Timed-Up-and-Go (TUG) and Five Times Sit to Stand Test (5xSST) and data from motion detectors. Semi-structured interviews were conducted with stroke survivors and caregivers after the four-week period. Descriptive statistics were used for quantitative data. Qualitative data was analysed with direct content analysis. Themes were identified related to the domains of feasibility: acceptability, demand, implementation and practicality. Data was integrated by examining any (dis)congruence in the quantitative and qualitative findings. Results: Ten stroke survivors aged 55–79 years participated with their informal caregivers. Functional improvements were shown in BBS (+ 2.5), ABC (+ 0.9), TUG (− 4.2) and 5xSST (− 2.7). More physical activity was detected with motion detectors (stand up/sit down + 2, number of steps + 227, standing + 0.3 h, hours sitting/lying − 0.3 h). The qualitative interviews identified themes for each feasibility domain: (i) acceptability: appreciation, functional improvements, self-initiated activities and expressed potential for future stroke survivors; (2) demand: reported use, interest in further use and need for follow-up; (3) implementation: importance of feedback, variety of exercises and progression of exercises and (4) practicality: need for support and technical problems. The quantitative and qualitative findings converged well with each other and supported the feasibility of ActivABLES. Conclusions: ActivABLES is feasible and can be a good asset for stroke survivors with slight or moderate disability to use in their homes. Further studies are needed with larger samples

Developing ActivABLES for community-dwelling stroke survivors using the Medical Research Council framework for complex interventions.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Novel technical solutions are called for to promote home-based exercise among community-dwelling stroke survivors supported by their caregivers. Lack of resources and knowledge about how to accomplish it, has been demonstrated. The objective of this study is to describe in detail the development of ActivABLES, a technical intervention to promote home-based exercise and physical activity engagement of community-dwelling stroke survivors with support from their caregivers. Methods: The technical development process of ActivABLES was guided by the Medical Research Council (MRC) framework for development and evaluation of complex interventions as well as by principles of human-centred design and co-design. The main steps included: (1) Synthesis of evidence supporting the inclusion of balance exercises, mobility and walking exercises and exercises for the upper arm; (2) Implementation of initial user studies with qualitative data collection from individual interviews with stroke survivors, and focus group interviews with caregivers and health professionals; (3) Preliminary testing of eight prototypes with seven stroke survivors and their caregivers. Results: After the preliminary testing of eight prototypes, four prototypes were not further developed whereas four prototypes were modified further. In addition, two new prototypes were developed, leaving six prototypes for further modification: 1) ActivFOAM for balance exercises, 2) WalkingSTARR to facilitate walking, 3) ActivBALL for hand exercises, 4) ActivSTICKS for upper arm exercises, and 5) ActivLAMP and 6) ActivTREE which both give visual feedback on progress of daily exercise and physical activities. ActivFOAM, ActivBALL and ActivSTICKS are all connected to a tablet where exercise instructions are given. All the exercise prototypes can be connected to ActivLAMP and ActivTREE to give feedback on how much exercise the user has done. Settings can be individualised and recommended daily time and/or repetition can easily be changed as the user progresses to higher activity levels. Conclusions: The development process of ActivABLES was guided by the principles of human-centred design, with iterative testing of future users, and by the MRC framework of complex intervention, with a repeated process of development and testing. This process resulted in six prototypes which are available for feasibility testing among a small group of community-dwelling stroke survivors. Keywords: Home-based exercise; Stroke survivors; Technical intervention.NordForsk ActivABLES project Icelandic Physiotherapy Association Icelandic Ministry of Welfar

Challenges and opportunities for falls prevention:an online survey across European healthcare professionals

PURPOSE: To explore the challenges and opportunities for the implementation of falls preventive services across Europe.METHODS: An online cross-sectional survey among healthcare professionals was initiated by the European Geriatric Medicine Society (EuGMS) Special Interest Group on Falls and Fractures containing a Likert scale and multiple-choice questions on education and knowledge, current practices, barriers, and facilitators for falls prevention. Survey participation for healthcare professionals was encouraged by the EuGMS through an email invitation, website banner, and social media. National representatives from 24 countries further promoted it via societies, local networks, and hospital channels.RESULTS: A total of 1669 multidisciplinary healthcare professionals participated from 34 European countries (median 47 years; 75% female; 40.6% physicians (73.3% geriatricians/trainees), 36% physiotherapists, 23.4% other healthcare professionals). Only 26.9% believed their undergraduate education adequately prepared them for clinical practice in this area. A total of 75.8% of respondents reported opportunistically screening older adults for fall risk often or always during consultations. Gait and balance assessment was considered the most important and was the most frequently performed component of the multifactorial fall risk assessment. The top-five barriers were staffing issues, lack of time, older adults' non-adherence to recommended strategies, workload related to falls prevention, and prioritizing other tasks. The top-five facilitators were more time, easy-to-use guidelines, sufficient resources, increased education and training on falls prevention, and increased collaboration. We observed regional and country-level variation in these top barriers and facilitators.CONCLUSION: This survey highlights the need for improved undergraduate education in falls prevention across Europe. It is essential to educate and engage governmental bodies and insurers to secure their support and prioritization of falls prevention initiatives. Furthermore, enhancing education, addressing older adults' nonadherence, interdisciplinary collaboration and providing easy-to-use guidelines seem crucial for effective implementation. The falls prevention strategy should be tailored to the local context.</p

Missense variants in FRS3 affect body mass index in populations of diverse ancestries

Obesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m2 higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m2 lower BMI per allele. We also detect three other low-frequency FRS3 missense variants that associate with BMI with smaller effects and are enriched in different ancestries. We characterize FRS3 as a BMI-associated gene, encoding an adaptor protein known to act downstream of BDNF and TrkB, which regulate appetite, food intake, and energy expenditure through unknown signaling pathways. The work presented here contributes to the biological foundation of obesity by providing a convincing downstream component of the BDNF-TrkB pathway, which could potentially be targeted for obesity treatment.</p

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Source at https://doi.org/10.1038/s42003-018-0068-9. Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

Missense variants in FRS3 affect body mass index in populations of diverse ancestries

Obesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m2 higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m2 lower BMI per allele. We also detect three other low-frequency FRS3 missense variants that associate with BMI with smaller effects and are enriched in different ancestries. We characterize FRS3 as a BMI-associated gene, encoding an adaptor protein known to act downstream of BDNF and TrkB, which regulate appetite, food intake, and energy expenditure through unknown signaling pathways. The work presented here contributes to the biological foundation of obesity by providing a convincing downstream component of the BDNF-TrkB pathway, which could potentially be targeted for obesity treatment.</p