Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

[Late cardiotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma].

AIM: To evaluate the late cardiotoxicity (CT) of high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) protocol in adult patients with diffuse large B-cell lymphoma (DLBCL). SUBJECTS AND METHODS: The results of electrocardiography (ECG) and echocardiography (echoCG) were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the Hematology Research Center (HRC), Russian Academy of Medical Sciences (RAMS), in 2002 to 2009. A study group consisted of 20 men and 20 women whose age was 31 to 76 years; median age was 56.5 years at the time of their examination and the median follow-up time after therapy was 6 years. The individual cumulative dose of doxorubicin was 150-300 mg/M2. A comparison group included 19 patients receiving CHOP/R-CHOP CT in HRC, RAMS, in 2002 to 2009. Out of them, there were 8 men and 11 women whose age was 39 to 78 years median age was 70 years at the time of their examination. The individual cumulative dose of doxorubicin was 200-400 mg/M2. ECG and echoCG were carried out before and 5 years or more after CT. RESULTS: Out of the 40 patients with DLBCL, the signs of subclinical cardiomyopathy (CMP) were detected in 24 (60%) patients; no clinical manifestations of congestive heart failure (CHF) were found in any patient. In the comparison group of 19 patients receiving CHOP/R-CHOP CT, 14 (74%) patients were found to have signs of subclinical CMP and no clinical signs of CHF. The summary toxicity index significantly depended on age (p=0.03) and a history of heart disease (p=0.3); it was significantly higher after CHOP/R-CHOP CT (p=0.05). There was a statistically significant relationship of the risk of subclinical CMP to the history of heart diseases (p=0.05). CONCLUSION: Late cardiotoxicity of the mNHL-BFM-90 program does not exceed the toxicity of standard CHOP/R-CHOP therapy. Post-CT Echo-CG and ECG findings showed that the patients with the most marked subclinical signs of CMP in both groups had cardiotoxicity risk factors, such as coronary heart disease, hypertensive disease, or diabetes in their history. No clinically significant CHF was identified in any patient.

Induction of Ca2+-dependent cyclosporin A-insensitive nonspecific permeability of the inner membrane of liver mitochondria and cytochrome c release by α,ω-hexadecanedioic acid in media of varying ionic strength.

In liver mitochondria loaded with Ca2+ or Sr(2+), α,ω-hexadecanedioic acid (HDA) can induce nonspecific permeability of the inner membrane (mitochondrial pore) by the mechanism insensitive to cyclosporin A (CsA). In this work we studied the effect of ionic strength of the incubation medium on the kinetics of the processes that accompany Ca2+-dependent induction of the mitochondrial pore by fatty acid: organelle swelling, Ca2+ release from the matrix, changes in transmembrane potential (Δψ) and rate of oxygen consumption, and the release of cytochrome c from the intermembrane space. Two basic incubation media were used: sucrose medium and isotonic ionic medium containing KCl without sucrose. We found that 200 µM Ca2+ and 20 µM HDA in the presence of CsA effectively induce high-amplitude swelling of mitochondria both in the case of sucrose and in the ionic incubation medium. In the presence of CsA, mitochondria can rapidly absorb Ca2+ and retain it in the matrix for a while without reducing Δψ. Upon incubation in the ionic medium, mitochondria retain most of the added Ca2+ in the matrix for a short time without reducing the Δψ. In both cases the addition of HDA to the mitochondria 2 min after the introduction of Ca2+ leads to the rapid release of these ions from the matrix and total drop in Δψ. The mitochondrial swelling induced by Ca2+ and HDA in non-ionic medium is accompanied by almost maximal stimulation of respiration. Under the same conditions, but during incubation of mitochondria in the ionic medium, it is necessary to add cytochrome c for significant stimulation of respiration. The mitochondrial swelling induced by Ca2+ and HDA leads to the release of cytochrome c in a larger amount in the case of ionic medium than for the sucrose medium. We conclude that high ionic strength of the incubation medium determines the massive release of cytochrome c from mitochondria and liberates it from the respiratory chain, which leads to blockade of electron transport along the respiratory chain and consequently to disruption of the energy functions of the organelles.

[Development of ovarioles and nurse cells cytoskeleton in Calliphora erythrocephala Mg. (Diptera; Calliphoridae)].

We have carried out the analysis of ovariole development and morphology in Calliphora erythrocephala Mg. (Diptera: Calliphoridae). It has been shown that several regions can be distinguished in C. erythrocephala germarium. In these regions cyst morphogenesis goes on stage by stage right up to the separation of formed egg chamber. There are fusomes of different degree of branching in germarium. Two egg chambers develop in C. erythrocephala vitellarium. We have researched distribution of actin filaments and ring canals formation in the nurse cells of C. erythrocephala. Diameter of ring canals increases from 1.5 microm in germarium zone to 14.7 microm at 3 and 4 stadies oogenesis. We suggest the scheme that illustrates irregular stretching of actin rollers which are formed during middle and late oogenesis around the ring canals joining proximal, sharply increased in size nurse cells with neighboring nurse cells.

[Analysis of sex chromosome homologies in representatives of the family Calliphoridae].

The distribution of sequences homologous to the Calliphora erythrocephala Mg. sex chromosome was studied in Protophormia terranovae R-D and Lucilia sp. The chromatin structure was found to be similar in regions containing homologous DNA sequences.

One-dimensional model and solutions for creeping gas flows in the approximation of uniform pressure.

A model, along with analytical and numerical solutions, is presented to describe a wide variety of one-dimensional slow flows of compressible heat-conductive fluids. The model is based on the approximation of uniform pressure valid for the flows, in which the sound propagation time is much shorter than the duration of any meaningful density variation in the system. The energy balance is described by the heat equation that is solved independently. This approach enables the explicit solution for the fluid velocity to be obtained. Interfacial and volumetric heat and mass sources as well as boundary motion are considered as possible sources of density variation in the fluid. A set of particular tasks is analyzed for different motion sources in planar, axial, and central symmetries in the quasistationary limit of heat conduction (i.e., for large Fourier number). The analytical solutions are in excellent agreement with corresponding numerical solutions of the whole system of the Navier-Stokes equations. This work deals with the ideal gas. The approach is also valid for other equations of state.

[Visualization of chromosome territories in interphase nuclei of ovarian nurse cells in Calliphora erythrocephala Mg. (Diptera: Calliphoridae)].

Analysis of localization of chromosomes 2, 3, and 6 of Calliphora erythrocephala Mg. in ovarian nurse cell nuclei with different chromatin structure has shown that the regions of DNA probe hybridization reduced with increasing chromatin compaction. Hybridization of DNA probes of chromosomes 3 and 6 to secondary reticular nuclei demonstrated that chromosomes retain their territories in the nuclei when the chromatin acquires a reticular structure. These results suggest regular organization of the chromosomal apparatus at all stages of the endomitotic cycle, including the stage of highly polyploid reticular nuclei. FISH of DNA probe of the chromosome 2 telomeric region to secondary reticular nuclei revealed a peripheral distribution of the signal. Zones of more intensive DNA probe hybridization have been distinguished. These zones probably are the regions of accumulation of telomeric and (or) centromeric chromosome regions.

Monolayers of a novel ionoselective butadienyl dye.

The novel amphiphilic benzodithia-18-crown-6 butadienyl dye (1) forms relatively stable insoluble monolayers on distilled water (collapse pressure of 41 mN/m) and on aqueous subphases containing alkali metal or heavy metal salts (collapse pressures in the range of 27-38 mN/m, respectively). The dye 1 monolayer organization depends on chromophore association and interactions (especially complex formation) with heavy and alkali metal ions as deduced from surface pressure-area and surface potential-area isotherms as well as reflection spectra and Brewster angle microscopy observations. Dye 1 undergoes specific interactions with Hg(2+) and Ag(+), respectively (formation of different complexes). Nonspecific interactions have been observed with other salts, such as KClO(4) or Pb(ClO(4))(2). Further, dye 1 monolayers on 1 mM Hg(ClO(4))(2) solution undergo reversible photoisomerization, in contrast to monolayers on water and other aqueous salt subphases.

[A study of two non-complementary H-2 mutations in mice using skin transplantation and serologic analysis]. / Izuchenie dvukh nekomplementarnykh mutatsii H-2 myshei pri pomoshchi transplantatsii kozhi i serologicheskogo analiza

Hz1 and M505 are two mutants affected the Kend of H-2 major histocompatibility system in mouse. Inability of M505 to complement Hz1 is considered as an evidence that the same gene is altered by both mutations. The gained antigens of two mutants can cross-react in vivo, and the lost antigenic determinants are not identical as revealed in skin grafting tests with presensitized recipients. The antiserum ASY-0,15, (d X a) anti-i, could differentiate between normal and mutant cells as well as between both mutants in absorption tests. These results show that some haptenic determinants are changed in the Hz1 and M505 mutations together with changes of histocompatibility determinants.

[Thrombocyte function during the performance of plasmapheresis and immunosorption in patients with familial hypercholesterolemia]. / Sostoianie trombotsitov pri provedenii plazmafereza i immunosorbtsii u bol'nykh s semeinoi giperkholesterinemiei.

The impact of plasmapheresis (PA) and immunosorption (IS) of low density lipoproteins (LDLP) on platelets was examined in patients with familial hypercholesterolemia. PA and IS sessions resulted in a decrease of platelet counts, aggregation activity in relation to TXA2 analogue, U46619, and capacity for adhesion and spreading over type-4 collagen-coated surface. All effects were of similar markedness in both procedures, i.e. they were unrelated to PA or IS specificity, but rather were due to platelet interaction with extracorporeal circulation circuit. Platelet changes seen immediately after the procedure were transitory. Platelet counts and capacity for aggregation and adhesion were recovered by the time of the next procedure (1 or 2 weeks later). Long-term (more than 6 months') use of PA or IS did not essentially affect platelet counts, aggregation and adhesion, but rather undermined platelet spreading capacity.

[Experiences using long-term (4-12 months) plasmapheresis in patients with hereditary hypercholesterolemia]. / Opyt dlitel'nogo (4-12 mes) primeneniia plazmafereza u bol'nykh s nasledstvennoi giperkholesterinemiei.

A total of 122 plasmapheresis procedures were given to 4 patients with inherited hypercholesterolemia for 4 to 12 months, with 7 to 14 days' intervals, using a cellular blood separator. The method has been shown to produce a 35 to 45% reduction in total cholesterol (CS), LDLPCS and VLDLPCS, and an 8 to 38% rise in HDLP CS, which improves general condition and working capacity of the patients, makes anginal attacks less frequent and severe and normalizes arterial BP in patients with arterial hypertension.

[Methodology of plasmapheresis in the treatment of patients with hereditary hypercholesterolemia]. / Metodika plazmafereza v lechenii bol'nykh s nasledstvennoi giperkholesterinemiei.

The plasma replacement procedure using the blood cell separator IBM-2997 provides for safe replacement of 2000-3000 ml plasma and a 35 to 45% reduction of the lipid concentration. Plasma replacement with 5% albumin solution per 50 to 70% of total volume allows to maintain normal total plasma protein levels throughout treatment. It was demonstrated that plasmapheresis with plasma ultrafiltrate return makes the procedure more tolerable for the patients, while their own electrolytes, amino acids, vitamins and some enzymes are retained. The reported technique for the discontinuation of the procedure reduces the volume of residual blood in the separation channel, preventing anemia.

[Characteristics of immunologic and neuro-hormonal status in patients with neuroses]. / Osobennosti immunnogo i neirogormonal'nogo statusa bol'nykh nevrozami.

More than 3500 neurotic patients have been examined with emphasis on their immune status and functioning of the sympathoadrenal system (SAS) (determination of adrenaline, noradrenaline, dopamine and L-DOPA excretion in terms of their daily biorhythm). The comparison of the immune and neurohormonal data of neurotic patients indicated an obvious relation between the immune status and the type of SAS functioning. The high-risk group comprises patients with the adrenaline type of SAS functioning and pronounced adrenaline and noradrenaline hypersecretion, SAS hypofunction, and imbalance between the hormone-mediated and immunologic characteristics.

[Comparative analysis of plasmapheresis and cascade plasma filtration in the management of patients with hereditary hypercholesterolemia]. / Sravnitel'nyi analiz plazmafereza i kaskadnoi plazmafil'tratsii v lechenii bol'nykh s nasledstvennoi giperkholesterinemiei.

The authors have shown that in patients with hereditary hypercholesteremia the use of plasmapheresis (PA) and cascade plasma filtration (CPF) with a cell separator 2997 (IBM, USA) and Evaflux-4A filter (Japan) makes it possible to considerably decrease the concentration of lipoprotein atherogenic classes (by 43-59%). The data obtained suggest that the use of CPF permits the return of 70-75% of the body protein, a marked decrease in the amount of substitution protein solution to minimize the risk of infection and probable allergic reactions to foreign proteins.

[Plasmosorption of low-density lipoproteins on heparin-sepharose columns]. / Plazmosorbtsiia lipoproteidov nizkoi plotnosti na kolonakh s geparin-sefarozoi.

Plasmosorption on heparin sepharose columns was shown to cause a decrease in the concentration of atherogenic lipoproteins. The results obtained suggest that plasmosorption results in the improvement of the patients' status, a decrease in the frequency and intensity of anginal attacks. Columns can be effectively used after repeated regenerations up to 30-40 times.

Oxidative C(sp3)-H bond cleavage, C-C and C=C coupling at a boron center with O2 as the oxidant mediated by platinum(II).

Dimethyl- and diphenylplatinum(II) fragments Pt(II)R2 (R = Me, Ph) enable facile and efficient oxidative C(sp(3))-H bond cleavage and stepwise C-C and C=C coupling at the boron atom of a coordinated 1,5-cyclooctanediyldi(2-pyridyl)borato ligand with O2 as the sole oxidant.