Prospective longitudinal voxel-based morphometry study of major depressive disorder in young individuals at high familial risk.

BACKGROUND: Previous neuroimaging studies indicate abnormalities in cortico-limbic circuitry in mood disorder. Here we employ prospective longitudinal voxel-based morphometry to examine the trajectory of these abnormalities during early stages of illness development. METHOD: Unaffected individuals (16-25 years) at high and low familial risk of mood disorder underwent structural brain imaging on two occasions 2 years apart. Further clinical assessment was conducted 2 years after the second scan (time 3). Clinical outcome data at time 3 was used to categorize individuals: (i) healthy controls ('low risk', n = 48); (ii) high-risk individuals who remained well (HR well, n = 53); and (iii) high-risk individuals who developed a major depressive disorder (HR MDD, n = 30). Groups were compared using longitudinal voxel-based morphometry. We also examined whether progress to illness was associated with changes in other potential risk markers (personality traits, symptoms scores and baseline measures of childhood trauma), and whether any changes in brain structure could be indexed using these measures. RESULTS: Significant decreases in right amygdala grey matter were found in HR MDD v. controls (p = 0.001) and v. HR well (p = 0.005). This structural change was not related to measures of childhood trauma, symptom severity or measures of sub-diagnostic anxiety, neuroticism or extraversion, although cross-sectionally these measures significantly differentiated the groups at baseline. CONCLUSIONS: These longitudinal findings implicate structural amygdala changes in the neurobiology of mood disorder. They also provide a potential biomarker for risk stratification capturing additional information beyond clinically ascertained measures.

Childhood trauma, midbrain activation and psychotic symptoms in borderline personality disorder.

Childhood trauma is believed to contribute to the development of borderline personality disorder (BPD), however the mechanism by which childhood trauma increases risk for specific symptoms of the disorder is not well understood. Here, we explore the relationship between childhood trauma, brain activation in response to emotional stimuli and psychotic symptoms in BPD. Twenty individuals with a diagnosis of BPD and 16 healthy controls were recruited to undergo a functional MRI scan, during which they viewed images of faces expressing the emotion of fear. Participants also completed the childhood trauma questionnaire (CTQ) and a structured clinical interview. Between-group differences in brain activation to fearful faces were limited to decreased activation in the BPD group in the right cuneus. However, within the BPD group, there was a significant positive correlation between physical abuse scores on the CTQ and BOLD signal in the midbrain, pulvinar and medial frontal gyrus to fearful (versus neutral) faces. In addition there was a significant correlation between midbrain activation and reported psychotic symptoms in the BPD group (P<0.05). These results show that physical abuse in childhood is, in individuals with BPD, associated with significantly increased activation of a network of brain regions including the midbrain in response to emotional stimuli. Sustained differences in the response of the midbrain to emotional stimuli in individuals with BPD who suffered childhood physical abuse may underlie the vulnerability of these patients to developing psychotic symptoms.

Impulsivity in borderline personality disorder.

BACKGROUND: Impulsivity is a core feature of borderline personality disorder (BPD) and is most frequently measured using self-rating scales. There is a need to find objective, valid and reliable measures of impulsivity. This study aimed to examine performance of participants with BPD compared with healthy controls on delay and probabilistic discounting tasks and the stop-signal task (SST), which are objective measures of choice and motor impulsivity, respectively. METHOD: A total of 20 participants with BPD and 21 healthy control participants completed delay and probabilistic discounting tasks and the SST. They also completed the Barratt Impulsiveness Scale (BIS), a self-rating measure of impulsivity. RESULTS: Participants with BPD showed significantly greater delay discounting than controls, manifest as a greater tendency to accept the immediately available lesser reward rather than waiting longer for a greater reward. Similarly they showed significantly greater discounting of rewards by the probability of payout, which correlated with past childhood trauma. Participants with BPD were found to choose the more certain and/or immediate rewards, irrespective of the value. On the SST the BPD and control groups did not differ significantly, demonstrating no difference in motor impulsivity. There was no significant difference between groups on self-reported impulsivity as measured by the BIS. CONCLUSIONS: Measures of impulsivity show that while motor impulsivity was not significantly different in participants with BPD compared with controls, choice or reward-related impulsivity was significantly affected in those with BPD. This suggests that choice impulsivity but not motor impulsivity is a core feature of BPD.

Dysfunction of emotional brain systems in individuals at high risk of mood disorder with depression and predictive features prior to illness.

BACKGROUND: Abnormalities of emotion-related brain circuitry, including cortico-thalamic-limbic regions underpin core symptoms of bipolar disorder (BD) and major depressive disorder (MDD). It is unclear whether these abnormalities relate to symptoms of the disorder, are present in unaffected relatives, or whether they can predict future illness. METHOD: The Bipolar Family Study (BFS) is a prospective longitudinal study that has examined individuals at familial risk of mood disorder and healthy controls on three occasions, 2 years apart. The current study concerns imaging data from the second assessment; 51 controls and 81 high-risk (HR) individuals performing an emotional memory task. The latter group was divided into 61 HR individuals who were well, and 20 who met diagnostic criteria for MDD. At the time of the third assessment a further 11 HR individuals (from the Well group) had developed MDD. The current analyses focused on (i) differences between groups based on diagnostic status at the time of the scan, and (ii) predictors of future illness, comparing the 11 HR individuals who became unwell after the second scanning assessment to those who remained well. RESULTS: All groups demonstrated typical emotional modulation of memory and associated brain activations. For analysis (i) the HR MDD group demonstrated increased thalamic activation v. HR Well. (ii) HR Well individuals who subsequently became ill showed increased activation of thalamus, insula and anterior cingulate compared to those who remained well. CONCLUSIONS: These findings suggest evidence for specific changes related to the presence of illness and evidence that changes in brain function in cortico-thalamic-limbic regions precede clinical illness.

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI.

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.

[Dissociation of Pectobacterium carotovorum subsp. carotovorumrelated to the changes in the cell wall lipopolysaccharide].

It is shown for the first time that population heterogeneity of Pectobacterium carotovorum subsp. carotovorum is applicable to a wide range of strains and therefore is a universal characteristic. Using the method of specific selection with the help of carotovoricins which are identical to the phage tails a set of population dissociants of different types was obtained, due to the fact that S-LPS is the part of the cell wall which contains their attachment sites. It was determined that changes in S-lipopolysaccharides lead to the formation of SR-, R-forms of P. carotovorum. A suggestion is made that the changes in the surface structures of dissociants have a significant impact on secretion types II and III--the main pathogenicity factor of some bacteria. The results presented are a prerequisite for studying the direction, the reasons for dissociation process and its impact on the pathogenicity of P. carotovorum.

[Polypeptide content and HPLC-chromatography of the virions of phage ZF40 mutants].

Study of the polypeptide content of erwiniophage ZF40c(5/5) and ZF40-421 virulent mutants has shown that their virions include no less than 10 structural proteins with molecular weights ranging from 16.9 to 96.5 kDa. Three polypeptides belong to a group of major proteins with molecular weights 39.2, 33.1 and 18.5 kDa. They correlate with the polypeptides of phage head, tail sheath and tail core correspondingly. It has been proven that the protein contents of these phages are identical, taking into account that the percent ratio of all polypeptides approaches 1.0. The polypeptide profile of isogenic variant of phage ZF40-421 obtained on EccRC5297 is characterized by another ratio of major proteins. These differences are reflected in the structure of procapsids, that explains low level of stability and viability of the variant. The work shows for the first time the possibility of using HPLC-chromatography for studying native phage particles and their structural components.

[Peculiarities of morphogenetical development of erwiniophage ZF40 virulent mutants ].

The distortion of morphopoiesis or tail attachment to the capsid is a characteristic feature of morphogenetical development not only of a reproductive infection but also of the lysogenic induction of the defective bacteriophage Erwinia carotovora subsp. carotovora (Ecc). A model system for studying morphogenetical development and assembling of the virion was created on the basis of the phage ZF40 and its two virulent mutants ZF40-421 and ZF40(5/5), as well as the indicator culture Ecc M2-4/50 R1 being nontraditional host for these phages. It has helped to establish that the diameter of the phage capsid is not a conservative value. The presence of capsids of two types with the average diameters 60.3 and 65.0 nm is characteristic of the virmutant ZF40c(5/5)/50RI, while in the course of morphogenesis the phage ZF40-421/50RI forms only one type of heads of 65 nm in size. These heads are probably not firmly connected to the tails since the degree of the secondary destruction of the virions of the phage Zf40-421/50RI is considerably higher, than that of the virions of the phage ZF40c(5/5)/50RI. The number of capsids being 60.3 nm in diameter prevails considerably in the latter. The both virulent mutants as a whole are essentially more stable than their isogenic partners obtained on Ecc RC5297 which helps to make a conclusion about considerable influence of specific bacterial proteins of the host-cell on morphogenesis and morphopoiesis.

[Transduction as one of the methods of obtaining genetic information in Erwinia].

Transduction is one of the key processes of horizontal transfer of genes in bacteria. It is known that it is involved in distribution of the main factors of pathogenicity among numerous enterobacteria. It is shown that clear mutants and some variants of the temperate bacteriophage ZF40 Erwinia carotovora subsp. carotovora can perform general transduction of chromosome and plasmid genes of the bacterium E. carotovora. The indicators of chromosome transduction frequencies of the markers--arg+, met+, trp+, ura+ have a broad range of values: 7.10-10(-8) - 1.1-10(-1). The authors have succeeded in increasing the transduction efficiency due to infecting the recipient bacteria on the solid medium LB. Such approach is important for the phages similar to ZF40 in which adsorption is accompanied by re-adsorption of phage particles. The mechanism of transfer of bacterial genes by the type of general transduction is connected with cyclic permutation of phage DNA.

Hippocampal function in schizophrenia and bipolar disorder.

BACKGROUND: The hippocampus plays a central role in memory formation. There is considerable evidence of abnormalities in hippocampal structure and function in schizophrenia, which may differentiate it from bipolar disorder. However, no previous studies have compared hippocampal activation in schizophrenia and bipolar disorder directly. METHOD: Fifteen patients with schizophrenia, 14 patients with bipolar disorder and 14 healthy comparison subjects took part in the study. Subjects performed a face-name pair memory task during functional magnetic resonance imaging (fMRI). Differences in blood oxygen level-dependent (BOLD) activity were determined during encoding and retrieval of the face-name pairs. RESULTS: The patient groups showed significant differences in hippocampal and prefrontal cortex (PFC) activation during face-name pair learning. During encoding, patients with schizophrenia showed decreased anterior hippocampal activation relative to subjects with bipolar disorder, whereas patients with bipolar disorder showed decreased dorsal PFC activation relative to patients with schizophrenia. During retrieval, patients with schizophrenia showed greater activation of the dorsal PFC than patients with bipolar disorder. Patients with schizophrenia also differed from healthy control subjects in the activation of several brain regions, showing impaired superior temporal cortex activation during encoding and greater dorsal PFC activation during retrieval. These effects were evident despite matched task performance. CONCLUSIONS: Patients with schizophrenia showed deficits in hippocampal activation during a memory task relative to patients with bipolar disorder. The disorders were further distinguished by differences in PFC activation. The results demonstrate that these disorders can distinguished at a group level using non-invasive neuroimaging.

[Abortive infection in Erwinia carotovora, as a source of nanoparticles of phage nature].

A possibility to obtain nanoparticles of phage nature using abortive phage infection was shown for the first time. It was found out that the nonspecific host Erwinia carotovora subsp. carotovora J2 being infected by phage ZF 40-RT80, the cells form a 100-fold surplus of capsid structures. Using the electron microscope the authors have found two types of phage capsids which differ from each other and have different modal diameters--47.5 and 71.5 nm. The found capsids pack the phage DNA which releases them under treatment of the preparations by DNAse I. A simple method of purification of capsid structures from mature virions which are formed in inconsiderable quantity in the process of abortive phage infection is proposed. The obtained results create preconditions for obtaining capsid nanoparticles as well as for studying the stages of morphogenesis and morphopoiesis of phage ZF40 without attracting special phage mutants.

Connecting the brain and new drug targets for schizophrenia.

One thing we know for certain after decades of functional imaging in schizophrenia is that it is not a disorder that can simply be attributed to circumscribed lesions in the brain. It is, in other words, a disorder of the connectivity of the brain. In this overview, we will consider the power of connectivity analyses of functional MRI (and PET) data as tools for translational neuroscience. We describe the patterns of functional and effective disconnectivity seen in schizophrenia and particular psychotic symptoms, those that appear to be attributable to genetic and/or environmental risk factors for psychosis, the potential of these disconnectivities as trait and state biomarkers, and their sensitivity to drug effects. We conclude that substantial work needs to be done on standardising connectivity analyses across laboratories and that disconnectivity studies should be an integral part of drug discovery programmes.

[Destabilization of defective lysogeny as the index of population dissociation of Erwinia carotovora].

The method of quantitative determination of bacteriocinogenicity in Erwinia carotovora dissociants has been suggested. It is based on the application of indicator bacterial mutants that are resistant to nalidixic acid. It has been revealed that population dissociation destabilizes a defective lysogeny of pectolytic Erwinia. In particular, a decrease of cell indicator survivability due to an increase of active bacteriocins yield has been found under lysogenic induction of defective prophages. The reverse dependence between the indicator cell survivability caused by dissociants bacteriocins induction and the reaction of hypersensitivity on leaves of the resistant plant Nicotiana tabacum, has been revealed. Similar dependence has been determined between dissociation and activity of pectate lyase. It has been hypothesized, that viable erwiniophages, being involved in the process of lysogenicity and induction, could play the role of 'switches' of bacterial phenotype raising adaptive phytopathogene reactions. The paper is presented in Russian. K e y w o r d s: Erwinia carotovora, defective lysogeny, population dissociation, reaction of hypersensitivity, activity of pectate lyase.

[Physico-chemical properties of temperate bacteriophage ZF40 of Erwinia carotovora].

A method of efficient purification of the extremely instable virions of the temperate bacteriophage ZF40 of Erwinia carotovora was proposed in the work. The stage-by-stage centrifugation in mentrizamide and caesium chloride gradients permitted to obtain highly purified phage preparations which were used for studying the protein composition of the studied erwiniophage. It was established that the buoyant density of the phage ZF40 was 1.23 g/cm3, 1.49 g/cm3 and 1.27 g/cm3 in the gradients of metrizamide, caesium chloride and caesium sulphate, respectively. By the polypeptide composition of the virion the phage ZF40 has been included in the group of P2-like phages.

[Comparative study of properties of temperate erwiniophages 49 and 59]. / Sravnitel'noe izuchenie svoistv umerennykh érviniofagov 49 i 59.

Molecular-biological properties of two relative temperate erwiniophages 49 and 59 have been comparatively studied. The both phages are highly specific with respect to sensitive bacteria and lyse only inconsiderable quantity of amylovora-like strains of Erwinia horticola. It has been established that erwiniophages are distinguished by the basic parameters of a single reproduction cycle in the cells of common host E. horticola 450. Considerable differences between phages have been also found in the areas of genomes responsible for the establishment and maintenance of lysogenic state in the cells of the bacterium-host. Study of structure polypeptides has confirmed the identity of capsids and tails of phages 49 and 59. It has been shown that phage 49 has another, as compared to phage 59, basal plate, which availability destabilises the phage tail and leads to virion destruction under various physical effects. Virion DNA of phages 49 and 59 are of the same size--47.9 kbp, but differ as to GC-content. Using the restriction analysis it has been shown that genome of phage 49, as well as the genome of phage 59, is permuted, but its permutation is of discrete character. The fact of recombination interaction between erwiniophages 49 and 59 has been established. It is supposed that phage 49 is the recombination (hybrid) derivative of phage 59 and unknown phage, or prophage, genetic module. The given recombination, probably, took place under the persistence of different phages in the general polylysogenic system of E. horticola.

[Factors that affect transduction in microorganisms]. / Faktory, vliiaiushchie na transduktsiiu u mikroorganizmov.

Data from literature concerning general and specialized transduction in microorganisms are given in the paper. The process of exogenic DNA penetration to the cells of bacteria and participation of protein products of separate phage genes in this process are described. The so-called E-proteins in a set with DNA penetrate through a cell membrane. In phage P22 they are protein products of phage genes 7, 16, 20. In P22 mutants with an altered transducing frequencies (HFT and LFT) the due functions are also coded by the phage genes. It is shown that the process of DNA packing in phages P22, phi 80, lambda and others is genetically determined. The gene transfer frequency depends on UV radiation and the very nature of transducing phages itself. In virulent phages the UV radiation up to inactivation level 95-99% evokes a decrease of their "killer" ability, which is accompanied by an increase of survivability of the formed transductants and, as a result, by enhancement of the transduction transfer frequency. An important role of the transduction analysis for fine mapping of a genome of microorganisms and its significance for practice are shown. A mathematical analysis of the data on cotransduction of linkage markers is presented as such that may be used when determining the value of transduced fragment of a chromosome.

[Plasmid R68.45 and S-a transduction by the temperate bacteriophage 59 of Erwinia carotovora 268]. / Transduktsiia plazmid R68.45 i S-a umerennym bakteriofagom 59 Erwinia carotovora 268.

Temperature bacteriophage 59 of Erwinia carotovera 268 had transduced extrachromosomal DNA: plasmids of R68.45 and S-a. Before plasmid transduction experiments the suitable donor strains of indicator culture Erwinia horticola 450 harbouring R68.45 and S-a were created. The frequency of plasmid R68.45 transfer from Pseudomonas putida to E. horticola 450-8 by conjugation was equal to 5 x 10(-8) per a donor cell and in the case of S-a--from E. coli C600 for the same recipient cells--was 2 x 10(-6). Bacteriophage 59 has transduced only separate markers of plasmid R68.45, since plasmid S-a is probably transduced by the phage as an intact unit.

[Characteristics of transduction in Erwinia by phage 59]. / Osobennosti transduktsii érvinii fagom 59.

A temperate bacteriophage 59 from polylysogenic strain Erwinia carotovora 268 transduces the following genetic markers: arg+, ilv+, leu+, met+, thr+, thy+, trp+, ura+. The transduction frequencies varied from 1 x 10(-8)- to 1 x 10(-6) and dependent on the multiplicity of infection, UV-irradiation of transducing bacteriophage, the nature of phage lysates. The characteristics of single transductants have been studied. Analysis of the obtained results suggests bacteriophage 59 to perform the generalized transduction.