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C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and 80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in 80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

Abstract The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Somatic mutations have a central role in cancer, but there are also a few rare autoimmune diseases in which somatic mutations play a major role. We have recently shown that nonsynonymous somatic mutations with low allele fractions are preferentially detectable in CD8+ cells and that the STAT3 gene is a promising target for screening. Here, we analyzed somatic mutations in the STAT3 SH2 domain in peripheral blood CD8+ cells in a set of 94 multiple sclerosis (MS) patients and 99 matched controls. PCR amplicons targeting the exons 20 and 21 of STAT3 were prepared and sequenced using the Illumina MiSeq instrument with 2x300bp reads. We designed a novel variant calling method, optimized for large number of samples, high sequencing depth (>25,000x) and small target genomic area. Overall, we discovered 64 STAT3 somatic mutations in the 193 donors, of which 63 were non-synonymous and 77% have been previously reported in cancer or lymphoproliferative disease. The overall median variant allele fraction was 0.065% (range 0.007–1.2%), without significant difference between MS and controls (p = 0.82). There were 26 (28%) MS patients vs. 24 (24%) controls with mutations (p = 0.62). Two or more mutations were found in 9 MS patients vs. 2 controls (p = 0.03, pcorr = 0.12). Carriership of mutations associated with older age and lower neutrophil counts. These results demonstrate that STAT3 SH2 domain is a hotspot for somatic mutations in CD8+ cells with a prevalence of 26% among the participants. There were no significant differences in the mutation prevalences between MS patients and controls. Further research is needed to elucidate the role of antigenic stimuli in the expansion of the mutant clones. Furthermore, the high discovered prevalence of STAT3 somatic mutations makes it feasible to analyze these mutations directly in tissue-infiltrating CD8+ cells in autoimmune diseases.

Following in the footsteps of ‘New Public Management’, where quality management and quality control have become widely implemented concepts among public authorities, there is now a subsequent government demand to also be innovative. However, integrating and achieving a balance between improved quality and increased innovation is not an easy task. Previous research indicates a complex and ambiguous relation, raising questions as to how to optimally combine these two approaches organisationally, operationally, and culturally. Is there an ‘edge of chaos’ where there is maximal flexibility for innovation while maintaining sufficient order for quality? The purpose of this paper is to examine the potential integration of innovation and quality management practice within the public sector. The paper is based on a multiple case study design, confronted with existing literature, and shows that the current quality management practice is perceived as being related to standardisation, leading to a decrease in the space for innovation. Second, that there is an expectation and belief that innovation and quality management can be handled in parallel and reinforce each other instead of being mutually detrimental. [ABSTRACT FROM PUBLISHER]

Somatic mutations have a central role in cancer but their role in other diseases such as common autoimmune disorders is not clear. Previously we and others have demonstrated that especially CD8+ T cells in blood can harbor persistent somatic mutations in some patients with multiple sclerosis (MS) and rheumatoid arthritis. Here we concentrated on CD8+ cells in more detail and tested (i) how commonly somatic mutations are detectable, (ii) does the overall mutation load differ between MS patients and controls, and (iii) do the somatic mutations accumulate non-randomly in certain genes? We separated peripheral blood CD8+ cells from newly diagnosed relapsing MS patients (n = 21) as well as matched controls (n = 21) and performed next-generation sequencing of the CD8+ cells’ DNA, limiting our search to a custom panel of 2524 immunity and cancer related genes, which enabled us to obtain a median sequencing depth of over 2000x. We discovered nonsynonymous somatic mutations in all MS patients’ and controls’ CD8+ cell DNA samples, with no significant difference in number between the groups (p = 0.60), at a median allelic fraction of 0.5% (range 0.2–8.6%). The mutations showed statistically significant clustering especially to the STAT3 gene, and also enrichment to the SMARCA2, DNMT3A, SOCS1 and PPP3CA genes. Known activating STAT3 mutations were found both in MS patients and controls and overall 1/5 of the mutations were previously described cancer mutations. The detected clustering suggests a selection advantage of the mutated CD8+ clones and calls for further research on possible phenotypic effects.

BACKGROUND: Antonovsky's salutogenic concept of a sense of coherence (SOC) has proved most influential in the way that health is now perceived. AIM: To (1) describe the distribution of SOC among 40-70-year-old Alanders; (2) examine the distribution of depression in Aland, Finland, and its relationship with SOC; and (3) discuss the findings within a salutogenic framework in a societal context. DESIGN: A cross-sectional study design was adopted. Antonovsky's SOC Questionnaire (13 items) and the Beck Depression Inventory (13 items) were used. In addition, in a separate questionnaire, sociodemographic information about each participant was sought, together with a question specific to this study and designed to measure self-rated health. SETTING: Aland, an autonomous island province of Finland. RESULTS: The proportion of respondents reporting good health was high (64%). The overall mean (SD) SOC was 70.7 (11.7) points, whereas for farmers and fishermen it was 73.88 (8.8) and 74.33 (9.2) points, respectively. SOC was significantly and strongly related to the self-rated health score. The higher the SOC, the better was the health of the respondents. Furthermore, the study provided clear evidence of the potential of the SOC concept as a positive mental health indicator. CONCLUSION: The SOC seems to be a health-promoting resource that supports the development of a positive subjective state of health. [ABSTRACT FROM AUTHOR]

River entry of adult Atlantic salmon Salmo salar into the River Tornionjoki, monitored during three migration seasons (1997–1999) by horizontal split-beam hydroacoustics, started early in June when water temperature was c . 9° C and when the discharge varied between 1700 and 2000 m3 s−1 . In 1997 and 1999, migration peaked during the latter half of June, 17 days after the peak flood, at water temperatures ranging from 11· 5 to 18·2° C. Few statistically significant correlations were observed between river entry and six measured environmental factors and those that were significant were not persistent over the years. The strongest correlation ( r = −0·60) was between the number of upstream migrants and seawater level, with a time lag of 1 day in 1998. In 1998 and 1999, no clear diurnal migration pattern was observed, although in 1997 the intensity of midday migration was higher than that of the midnight migration. It is concluded that environmental factors have little effect on river entry of Atlantic salmon in a large pristine river located at high latitude. [ABSTRACT FROM AUTHOR]

This article takes some preliminary steps towards an integrated analysis of dependency problems e.g., long-term tranquillizer use, alcohol dependence, problematic use of narcotics. It argues for the need to outline important theoretical, epistemological, and methodological prerequisites in the analysis of the complex dynamic developmental processes involved in dependency problems. The dynamic process leading to dependence can be studied by the aid of an artificial science neural network approach in combination with a mixed method strategy including a clarification of a combination of different epistemological positions. It is intended that the empirical output of this complex strategy will provide a starting point for a new theoretical analysis which, in turn, will lead to new and more relevant input variables in the neural network approach that will help us to extend our knowledge of the dynamic processes leading to dependency. [Translations are provided in the International Abstracts Section of this issue.] [ABSTRACT FROM AUTHOR]

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

A textile resistor implemented using conductive polymer fabric is presented. The resistor performance is verified with an equal-split textile Wilkinson power divider at L-band. Measured results show equivalent performance with a conventional chip resistor. The measured bandwidth is 565 MHz with 20 dB minimum isolation between divider output ports. Results show that it is possible to design and manufacture entirely textile feed and matching networks. [ABSTRACT FROM AUTHOR]

In patients with cleft lip and palate, bone grafting in the mixed dentition in the residual alveolar cleft has become a well-established procedure. The main advantages can be summarised as follows: stabilisation of the maxillary arch; facilitation of eruption of the canine and sometimes facilitation of the lateral incisor eruption; providing bony support to the teeth adjacent to the cleft; raising the alar base of the nose; facilitation of closure of an oro-nasal fistula; making it possible to insert a titanium fixture in the grafted site and to obtain favourable periodontal conditions of the teeth within and adjacent to the cleft. The timing of the ABG surgery take into consideration not only eruption of the canine but also that of the lateral incisor, if present. The best time for bone grafting surgery is when a thin shell of bone still covers the soon erupting lateral incisor or canine tooth close to the cleft.

UV-photoemission spectroscopy was used to measure directly the valence-band discontinuity ΔEv for both sides of a MnSe layer which was sandwiched between two ZnSe layers by the molecular beam epitaxy method. ΔEv is 0.16±0.05 eV for each interface; the valence-band edge Emaxv of the wider gap MnSe semiconductor lies within the ZnSe gap. The interface-pinning position of the Fermi level appears at 1.74 eV above Emaxv of ZnSe. It is concluded that interfacial electrostatic dipoles are small compared to the observed shift in Emaxv of MnSe, which lends a qualitative support to Tersoff’s model [Phys. Rev. Lett. 52, 465 (1984); Phys. Rev. B 30, 4874 (1984)] of heterojunction band offsets. [ABSTRACT FROM AUTHOR]

The article comments on the effect of chlorhexidine on human oral streptococci. In an experiment the authors have observed that bacteria with reduced sensitivity to chlorhexidine gluconate accumulate in saliva after long term use of 2.2 mM chlorhexidinc as a mouthwash. This indicates an effect of chlorhexidine on the cell wall of the control strains, either by releasing cell wall material and/or by causing a leakage of intracellular material. The experiments do not allow a distinction between the two possibilities, but support the indications from the azocarmine B staining experiments that chlorhexidine changes the surface properties of the microorganisms.

Intensified agricultural practices have driven biodiversity loss throughout the world, and although many actions aimed at halting and reversing these declines have been developed, their effectiveness depends greatly on the willingness of stakeholders to take part in conservation management. Knowledge of the willingness and capacity of landowners to engage with conservation can therefore be key to designing successful management strategies in agricultural land. In Iceland, agriculture is currently at a relatively low intensity but is very likely to expand in the near future. At the same time, Iceland supports internationally important breeding populations of many ground-nesting birds that could be seriously impacted by further expansion of agricultural activities. To understand the views of Icelandic farmers toward bird conservation, given the current potential for agricultural expansion, 62 farms across Iceland were visited and farmers were interviewed, using a structured questionnaire survey in which respondents indicated of a series of future actions. Most farmers intend to increase the area of cultivated land in the near future, and despite considering having rich birdlife on their land to be very important, most also report they are unlikely to specifically consider bird conservation in their management, even if financial compensation were available. However, as no agri-environment schemes are currently in place in Iceland, this concept is highly unfamiliar to Icelandic farmers. Nearly all respondents were unwilling, and thought it would be impossible, to delay harvest, but many were willing to consider sparing important patches of land and/or maintaining existing pools within fields (a key habitat feature for breeding waders). Farmers' views on the importance of having rich birdlife on their land and their willingness to participate in bird conservation provide a potential platform for the codesign of conservation management with landowners before further substantial changes in the extent of agriculture take place in this subarctic landscape.

Presents a letter to the editor about the treatment outcome in patients with complete cleft lip and palate.