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

Efficient Heralding of Photonic Qubits with Apllications to Device Independent Quantum Key Distribution

We present an efficient way of heralding photonic qubit signals using linear optics devices. First we show that one can obtain asymptotically perfect heralding and unit success probability with growing resources. Second, we show that even using finite resources, we can improve qualitatively and quantitatively over earlier heralding results. In the latte r scenario, we can obtain perfect heralded photonic qubits while maintaining a finite success probability. We demonstrate the advantage of our heralding scheme by predicting key rates for device independent quantum key distribution, taking imperfections of sources and detectors into account

Регіональні й глобальні наслідки незалежності Косово

У статті розглянуто регіональні й міжнародні аспекти проголошення незалежності Косово. Проаналізовано конфліктні аспекти косовської проблеми у регіональному й глобальному контекстах.В статье рассматриваются региональные и международные аспекты провозглашения независимости Косово. Проанализировано конфликтные аспекты косовской проблемы в региональном и глобальном контекстах.The article presents the regional and international aspects of Kosovo Independents. Special attention is to the conflict of Kosovo in the regional and global context

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

Long-term outcome after treatment of pulmonary atresia with ventricular septal defect : nationwide study of 109 patients born in 1970-2007

OBJECTIVES: Treatment of pulmonary atresia with ventricular septal defect (PA + VSD) has evolved during recent decades, but it still remains challenging. This study evaluated 41-year experience of outcome, survival and treatment of PA + VSD patients. METHODS: Patient records and angiograms of 109 patients with PA + VSD born in Finland between 1970 and 2007, and treated at the Children's Hospital, Helsinki University Central Hospital, were retrospectively analysed in this nationwide study. RESULTS: Of the 109 patients, 66 (61%) had simple PA + VSD without major aortopulmonary collateral arteries (MAPCAs). Although we observed no difference in overall survival between those with or without MAPCAs, the patients without MAPCAs had better probability to achieve repair (64 vs 28%, P <0.0003). Only 3 patients were treated by compassionate care. Overall survival was affected by the size of true central pulmonary arteries on the first angiogram (P = 0.001) and whether repair was achieved (P <0.0001). After successful repair, the survival rate was 93% at 1 year, 91% from the second year, and functional capacity as assessed by New York Heart Association (NYHA) I-II remained in 85% of patients alive at the end of follow-up. Palliated patients at 1, 5, 10 and 20 years of age had Kaplan-Meier estimated survival rates of 55, 42, 34 and 20%, respectively. Patients who underwent repair attempts but were left palliated with right ventricle (RV)-pulmonary artery connection and septal fenestration had better survival than the rest of the palliated patients (P = 0.001). Further, the McGoon index improved after implementation of a systemic-pulmonary artery shunt in the overall PA + VSD population (P <0.0001). CONCLUSIONS: These findings show that achievement of repair and initial size of true central pulmonary arteries affect survival of patients with PA + VSD. Although the overall survival of patients with MAPCAs showed no difference compared with simple PA + VSD patients, they had a higher risk of remaining palliated. However, palliative surgery may have a role in treatment of PA + VSD because the size of pulmonary arteries increased after placement of systemic-pulmonary artery shunt. In addition, subtotal repair by a RV-pulmonary artery connection and septal fenestration improved survival over extracardiac palliation.Peer reviewe

International Veterinary Epilepsy Task Force recommendations for systematic sampling and processing of brains from epileptic dogs and cats

Traditionally, histological investigations of the epileptic brain are required to identify epileptogenic brain lesions, to evaluate the impact of seizure activity, to search for mechanisms of drug-resistance and to look for comorbidities. For many instances, however, neuropathological studies fail to add substantial data on patients with complete clinical work-up. This may be due to sparse training in epilepsy pathology and or due to lack of neuropathological guidelines for companion animals. The protocols introduced herein shall facilitate systematic sampling and processing of epileptic brains and therefore increase the efficacy, reliability and reproducibility of morphological studies in animals suffering from seizures. Brain dissection protocols of two neuropathological centres with research focus in epilepsy have been optimised with regards to their diagnostic yield and accuracy, their practicability and their feasibility concerning clinical research requirements. The recommended guidelines allow for easy, standardised and ubiquitous collection of brain regions, relevant for seizure generation. Tissues harvested the prescribed way will increase the diagnostic efficacy and provide reliable material for scientific investigations

Historical (1750 - 2014) anthropogenic emissions of reactive gases and aerosols from the Community Emission Data System (CEDS)

We present a new data set of annual historical (1750–2014) anthropogenic chemically reactive gases (CO, CH4, NH3, NOX, SO2, NMVOC), carbonaceous aerosols (BC and OC), and CO2 developed with the Community Emissions Database System (CEDS). We improve upon existing inventories with a more consistent and reproducible methodology applied to all emissions species, updated emission factors, and recent estimates through 2014. The data system relies on existing energy consumption data sets and regional and country-specific inventories to produce trends over recent decades. All emissions species are consistently estimated using the same activity data over all time periods. Emissions are provided on an annual basis at the level of country and sector and gridded with monthly seasonality. These estimates are comparable to, but generally slightly higher than, existing global inventories. Emissions over the most recent years are more uncertain, particularly in low- and middle-income regions where country-specific emission inventories are less available. Future work will involve refining and updating these emission estimates, estimating emissions uncertainty, and publication of the system as open source software

A Retrospective Case Series Analysis of the Relationship Between Phenylalanine: Tyrosine Ratio and Cerebral Glucose Metabolism in Classical Phenylketonuria and Hyperphenylalaninemia.

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [18F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [18F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe

Myocardial perfusion reserve compared with peripheral perfusion reserve: A [13N]ammonia PET study

INTRODUCTION: [13N]ammonia PET allows quantification of myocardial perfusion. The similarity between peripheral flow and myocardial perfusion is unclear. We compared perfusion flow in the myocardium with the upper limb during rest and adenosine stress [13N]ammonia PET to establish whether peripheral perfusion reserve (PPR) correlates with MPR. METHODS: [13N]ammonia myocardial perfusion PET-scans of 58 patients were evaluated (27 men, 31 women, age 64 ± 13 years) and were divided in four subgroups: patients with coronary artery disease (CAD, n = 15), cardiac syndrome X (SX, n = 14), idiopathic dilating cardiomyopathy (DCM, n = 16), and normal controls (NC, n = 13). Peripheral limb perfusion was measured in the muscular tissue of the proximal upper limb and quantified through a 2-tissue-compartment model and the PPR was calculated (stress/rest ratio). MPR was also calculated by a 2-tissue-compartment model. The PPR results were compared with the MPR findings. RESULTS: Mean myocardial perfusion increased significantly in all groups as evidenced by the MPR (CAD 1.99 ± 0.47; SX 1.39 ± 0.31; DCM 1.72 ± 0.69; NC 2.91 ± 0.78). Mean peripheral perfusion also increased but not significantly and accompanied with great variations within and between groups (mean PPR: CAD 1.30 ± 0.79; SX 1.36 ± 0.71; DCM 1.60 ± 1.22; NC 1.27 ± 0.63). The mean difference between PPR and MPR for all subpopulations varied widely. No significant correlations in flow reserve were found between peripheral and myocardial microcirculatory beds in any of the groups (Total group: r = -0.07, SEE = 0.70, CAD: r = 0.14, SEE = 0.48, SX: r = 0.17, SEE = 0.30, DCM: r = -0.11, SEE = 0.71, NC: r = -0.19, SEE = 0.80). CONCLUSION: No correlations between myocardial and peripheral perfusion (reserve) were found in different patient populations in the same PET session. This suggests a functional difference between peripheral and myocardial flow in the response to intravenously administered adenosine stress