Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera

Background: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. Results: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients. The 12 shared variants (maximum allowed minor allele frequency G (p.Phe418Leu) in ZXDC, c.1931C > G (p.Pro644Arg) in ATN1, and c.701G > A (p.Arg234Gln) in LRRC3. We also observed a rare, predicted benign germline variant c.2912C > G (p.Ala971Gly) in BCORL1 in all four patients. Somatic mutations in BCORL1 have been reported in myeloid malignancies. We further screened the variants in eight PV patients in six other Finnish families, but no other carriers were found. Conclusions: Exome sequencing provides a powerful tool for the identification of novel variants, and understanding the familial predisposition of diseases. This is the first report on Finnish familial PV cases, and we identified three novel candidate variants that may predispose to the disease.Peer reviewe

Alcohol-related Outcomes and All-cause Mortality in the Health 2000 Survey by Participation Status and Compared with the Finnish Population

Background: In the context of declining levels of participation, understanding differences between participants and non-participants in health surveys is increasingly important for reliable measurement of health-related behaviors and their social differentials. This study compared participants and non-participants of the Finnish Health 2000 survey, and participants and a representative sample of the target population, in terms of alcohol-related harms (hospitalizations and deaths) and all-cause mortality. Methods: We individually linked 6,127 survey participants and 1,040 non-participants, aged 30-79, and a register-based population sample (n = 496,079) to 12 years of subsequent administrative hospital discharge and mortality data. We estimated age-standardized rates and rate ratios for each outcome for non-participants and the population sample relative to participants with and without sampling weights by sex and educational attainment. Results: Harms and mortality were higher in non-participants, relative to participants for both men (rate ratios = 1.5 [95% confidence interval = 1.2, 1.9] for harms; 1.6 [1.3, 2.0] for mortality) and women (2.7 [1.6, 4.4] harms; 1.7 [1.4, 2.0] mortality). Non-participation bias in harms estimates in women increased with education and in all-cause mortality overall. Age-adjusted comparisons between the population sample and sampling weighted participants were inconclusive for differences by sex; however, there were some large differences by educational attainment level. Conclusions: Rates of harms and mortality in non-participants exceed those in participants. Weighted participants' rates reflected those in the population well by age and sex, but insufficiently by educational attainment. Despite relatively high participation levels (85%), social differentiating factors and levels of harm and mortality were underestimated in the participants.Peer reviewe

Psychogenic amnesia: syndromes, outcome, and patterns of retrograde amnesia

There are very few case series of patients with acute psychogenic memory loss (also known as dissociative/functional amnesia), and still fewer studies of outcome, or comparisons with neurological memory-disordered patients. Consequently, the literature on psychogenic amnesia is somewhat fragmented and offers little of prognostic value for individual patients. In the present study, we reviewed the case records and neuropsychological findings in 53 psychogenic amnesia cases (3M:1F), in comparison with 21 consecutively recruited neurological memory-disordered patients and 14 healthy controls. In particular, we examined the pattern of retrograde amnesia on an assessment of autobiographical memory (the Autobiographical Memory Interview). We found that our patients with psychogenic memory loss fell into four distinct groups, which we categorised as: (i) fugue state, (ii) fugue-to-focal retrograde amnesia, (iii) psychogenic focal retrograde amnesia following a minor neurological episode, and (iv) patients with gaps in their memories. While neurological cases were characterised by relevant neurological symptoms, a history of a past head injury was actually more common in our psychogenic cases (p=0.012), perhaps reflecting a ‘learning episode’ predisposing to later psychological amnesia. As anticipated, loss of the sense of personal identity was confined to the psychogenic group. However, clinical depression, family/relationship problems, financial/employment problems, and failure to recognise the family were also statistically more common in that group. The pattern of autobiographical memory loss differed between the psychogenic groups: fugue cases showed a severe and uniform loss of memories for both facts and events across all time-periods, whereas the two focal retrograde amnesia groups showed a ‘reversed’ temporal gradient with relative sparing of recent memories. After 3-6 months, the fugue patients had improved to normal scores for facts and near-normal scores for events. By contrast, the two focal retrograde amnesia groups showed a lesser improvement and continued to show a reversed temporal gradient. In conclusion, the outcome in psychogenic amnesia, particularly those characterised by fugue, is better than generally supposed. Findings are interpreted in terms of Markowitsch’s and Kopelman’s models of psychogenic amnesia, and with respect to Anderson’s neuroimaging findings in memory inhibition

Detection of subclonal L1 transductions in colorectal cancer by long-distance inverse-PCR and Nanopore sequencing

Long interspersed nuclear elements-1 (L1s) are a large family of retrotransposons. Retrotransposons are repetitive sequences that are capable of autonomous mobility via a copy-and-paste mechanism. In most copy events, only the L1 sequence is inserted, however, they can also mobilize the flanking non-repetitive region by a process known as 3' transduction. L1 insertions can contribute to genome plasticity and cause potentially tumorigenic genomic instability. However, detecting the activity of a particular source L1 and identifying new insertions stemming from it is a challenging task with current methodological approaches. We developed a long-distance inverse PCR (LDI-PCR) based approach to monitor the mobility of active L1 elements based on their 3' transduction activity. LDI-PCR requires no prior knowledge of the insertion target region. By applying LDI-PCR in conjunction with Nanopore sequencing (Oxford Nanopore Technologies) on one L1 reported to be particularly active in human cancer genomes, we detected 14 out of 15 3' transductions previously identified by whole genome sequencing in two different colorectal tumour samples. In addition we discovered 25 novel highly subclonal insertions. Furthermore, the long sequencing reads produced by LDI-PCR/Nanopore sequencing enabled the identification of both the 5' and 3' junctions and revealed detailed insertion sequence information.Peer reviewe

3D Scaffolds of Polycaprolactone/Copper-Doped Bioactive Glass: Architecture Engineering with Additive Manufacturing and CellularAssessments in a Coculture of Bone Marrow Stem Cells and Endothelial Cells

The local delivery of Cu2+ from copper-doped bioactive glass (Cu-BaG) was combined with 3D printing of polycaprolactone (PCL) scaffolds for its potent angiogenic effect in bone tissue engineering. PCL and Cu-BaG were, respectively, dissolved and dispersed in acetone to formulate a moderately homogeneous ink. The PCL/Cu-BaG scaffolds were fabricated via direct ink writing into a cold ethanol bath. The architecture of the printed scaffolds, including strut diameter, strut spacing, and porosity, were investigated and characterized. The PCL/Cu-BaG scaffolds showed a Cu-BaG content-dependent mechanical property, as the compressive Young\u27s modulus ranged from 7 to 13 MPa at an apparent porosity of 60%. The ion dissolution behavior in simulated body fluid was evaluated, and the hydroxyapatite-like precipitation on the strut surface was confirmed. Furthermore, the cytocompatibility of the PCL/Cu-BaG scaffolds was assessed in human bone marrow stem cell (hBMSC) culture, and a dose-dependent cytotoxicity of Cu2+ was observed. Here, the PCL/BaG scaffold induced the higher expression of late osteogenic genes OSTEOCALCIN and DLX5 in comparison to the PCL scaffold. The doping of Cu2+ in BaG elicited higher expression of the early osteogenic marker gene RUNX2a but decreased the expression of late osteogenic marker genes OSTEOCALCIN and DLX5 in comparison to the PCL/BaG scaffold, demonstrating the suppressing effect of Cu2+ on osteogenic differentiation of hBMSCs. In a coculture of hBMSCs and human umbilical vein endothelial cells, both the PCL/BaG and PCL/Cu-BaG scaffolds stimulated the formation of a denser tubule network, compared to the PCL scaffold. Meanwhile, only slightly higher gene expression of vWF was observed with the PCL/Cu-BaG scaffold than with the PCL/BaG scaffold, indicating the potent angiogenic effect of the released Cu2+

Ab initio study of the surface properties of austenitic stainless steel alloys

Using ab initio calculations we investigated the surface energies of paramagnetic Fe1-c-nCrcNin random alloys within the concentration range of 0.12 <= c <= 032 and 0.04 <= n <= 0.32. These alloys crystallize mainly in the face centred cubic (fcc) structure and constitute the main building blocks of austenitic stainless steels. It is shown that all alloys have the lowest surface energies along the most close packed crystal orientation, namely the fcc (111) surfaces. The amount of Ni seems to have little effect on the surface energy, while almost all composition-driven change may be attributed to the changes in the Cr content. Within the studied compositional range, the change of the surface energy with the composition is of the order of 10%. Trends of the surface energy can be related to the magnetic structure of surfaces. Using the total energy as a function of the concentration, we determine the effective chemical potentials in bulk and at the surface, which can be used to estimate the surface segregation energies. (C) 2012 Elsevier B.V. All rights reserved

Bioavailability of riverine dissolved organic matter in three Baltic Sea estuaries and the effect of catchment land use

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