Meta-analytical prognostic accuracy of the Comprehensive Assessment of at Risk Mental States (CAARMS): The need for refined prediction.

Primary indicated prevention is reliant on accurate tools to predict the onset of psychosis. The gold standard assessment for detecting individuals at clinical high risk (CHR-P) for psychosis in the UK and many other countries is the Comprehensive Assessment for At Risk Mental States (CAARMS). While the prognostic accuracy of CHR-P instruments has been assessed in general, this is the first study to specifically analyse that of the CAARMS. As such, the CAARMS was used as the index test, with the reference index being psychosis onset within 2 years. Six independent studies were analysed using MIDAS (STATA 14), with a total of 1876 help-seeking subjects referred to high risk services (CHR-P+: n=892; CHR-P-: n=984). Area under the curve (AUC), summary receiver operating characteristic curves (SROC), quality assessment, likelihood ratios, and probability modified plots were computed, along with sensitivity analyses and meta-regressions. The current meta-analysis confirmed that the 2-year prognostic accuracy of the CAARMS is only acceptable (AUC=0.79 95% CI: 0.75-0.83) and not outstanding as previously reported. In particular, specificity was poor. Sensitivity of the CAARMS is inferior compared to the SIPS, while specificity is comparably low. However, due to the difficulties in performing these types of studies, power in this meta-analysis was low. These results indicate that refining and improving the prognostic accuracy of the CAARMS should be the mainstream area of research for the next era. Avenues of prediction improvement are critically discussed and presented to better benefit patients and improve outcomes of first episode psychosis.

Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk.

BACKGROUND: Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. METHOD: Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. RESULTS: Forty-four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. CONCLUSIONS: The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification.

The association between polyunsaturated fatty acid consumption and the transition to psychosis in ultra-high risk individuals.

PUFA deficiencies in cellular membranes have been observed in ultra-high risk (HR) individuals and in early schizophrenia. It is uncertain whether dietary PUFA consumption can be associated with the risk of transition to psychosis in HR individuals. The aim of the study was to assess PUFA consumption and confirm whether dietary habits are related to the risk of transition to full-threshold psychosis in HR individuals during a 12-month follow-up. PUFA consumption during the previous year was analyzed in 62 h individuals and 33 healthy controls (HC) at the beginning of the follow-up period using a validated Food-Frequency Questionnaire and the Polish Food Composition Tables. Fifteen HR individuals converted into psychosis (C-HR) during the 12-month follow-up. C-HR individuals reported significantly higher consumption of n-6 fatty acids (linoleic acid, LA and arachidonic acid, AA) in comparison with individuals who did not develop psychosis (NC-HR). The C-HR group reported a significantly higher AA/(EPA+DHA) consumption ratio than the NC-HR group. HC reported significantly higher consumption of most n-3 PUFA and lower consumption of all n-6 PUFA than both groups of HR individuals. The results suggest that dietary patterns of PUFA consumption may play a role in the conversion to psychosis of HR individuals.

Automated 3D RNA structure prediction using the RNAComposer method for riboswitches.

Understanding the numerous functions of RNAs depends critically on the knowledge of their three-dimensional (3D) structure. In contrast to the protein field, a much smaller number of RNA 3D structures have been assessed using X-ray crystallography, NMR spectroscopy, and cryomicroscopy. This has led to a great demand to obtain the RNA 3D structures using prediction methods. The 3D structure prediction, especially of large RNAs, still remains a significant challenge and there is still a great demand for high-resolution structure prediction methods. In this chapter, we describe RNAComposer, a method and server for the automated prediction of RNA 3D structures based on the knowledge of secondary structure. Its applications are supported by other automated servers: RNA FRABASE and RNApdbee, developed to search and analyze secondary and 3D structures. Another method, RNAlyzer, offers new way to analyze and visualize quality of RNA 3D models. Scope and limitations of RNAComposer in application for an automated prediction of riboswitches' 3D structure will be presented and discussed. Analysis of the cyclic di-GMP-II riboswitch from Clostridium acetobutylicum (PDB ID 3Q3Z) as an example allows for 3D structure prediction of related riboswitches from Clostridium difficile 4, Bacillus halodurans 1, and Thermus aquaticus Y5.1 of yet unknown structures.

Kinetic and molecular properties of Bacillus subtilis IBTC-3 subtilisin.

Bacillus subtilis IBTC-3 subtilisin was purified by gel filtration on Sephadex G 75 and affinity chromatography on bacitracin-CNBr-Sepharose 4B and characterized. Its molecular mass of 27 kDa was determined by SDS-PAGE, and isoelectric pH of 8.4 by chromatofocusing. FT-Raman and FT-IR spectroscopy studies revealed fragments with alpha-helix and irregular secondary structures within the polypeptide chain. The beta-sheet conformation was observed only in second-derivatives of FT-RS and FT-IR spectra, in the range of the amide II, III, and I bands. Tyr residues were shown to be hydrogen bonded and CSCH(3) groups adopted two conformations (P(H)-T and P(C)-G conformers). Kinetic properties of B. subtilis IBTC-3 subtilisin in hydrolysis of ethyl esters of amino acid derivatives were compared with that of alkaline peptidase from Bacillus alcalophilus PB92. The first enzyme displayed the highest affinity for NAc-Phe-OEt, both in hydrolysis (K(m) of 0.22 mM) and in synthesis (K(m) of 0.85 mM), whereas PB92 peptidase preferred Tyr derivatives (NAc-Tyr-OEt, K(m) of 0.043 and 0.75 mM, respectively). In contrast to the latter enzyme, B. subtilis IBTC-3 subtilisin catalyzed hydrolysis and synthesis of Bz-Arg-OEt.

Obstetric complications and Apgar score in early-onset schizophrenic patients with prominent positive and prominent negative symptoms.

UNLABELLED: The objective of the study was to find associations between obstetric complications (OCs) history and schizophrenia course and symptoms. We analysed the obstetric and psychiatric history of 50 DSM IV schizophrenic subjects who experienced their first schizophrenia episode in adolescence, and 30 healthy controls. Obstetrical data and Apgar scores were obtained from medical records and evaluated with the Lewis and Murray Scale. Based on patients' documentation [including longitudinal evaluation with Positive and Negative Syndrome Scale (PANSS)] the symptom profile and the course of schizophrenia were determined. RESULTS: we distinguished two major groups of patients: with prominent negative and prominent positive symptoms. Schizophrenics with prominent negative symptoms and a chronic schizophrenia course had significantly more definite OCs and lower Apgar scores than patients with prominent positive symptoms and controls. Subjects who had a positive OCs history were more than four times likely to develop schizophrenia in adolescence than those without such a history (OR=4.64; 95% CI=1.29-17.51) with the likelihood of developing schizophrenia with prominent negative symptoms especially high (OR=7.31; 95% CI=1.80-29.65). An Apgar score of between 0 and 3 after birth was associated with an increased risk for developing schizophrenia (OR=2.25; 95% CI=0.56-9.12), especially with prominent negative symptoms (OR=3.71; 95% CI=0.84-16.32). The findings support the hypothesis of a role of OCs in developing early-onset schizophrenia and suggest the associations of the OCs history with a specific symptoms profile (prominent negative symptoms) and a chronic course of schizophrenia.

Bacillus subtilis cells immobilised in PVA-cryogels.

Bacillus subtilis viable cells were immobilised in PVA-cryogel beads using the 'freezing-thawing' method in a two-phase (water-oil) system. Conditions providing both high thermal and mechanical stability and suitable porosity of the carrier were optimised. For monitoring and analysis of changes inside the biocatalyst beads, and for determination of diffusive properties of the carrier, an image analysis was applied. It was revealed that bacterial spores, sodium alginate and bacterial cellulose accelerated hardening of the cryogels and modified their porosity. Proteins (haemoglobin, azoalbumin, azocasein) penetrated beads of the cryogel.

Possible ramifications of the identification of ovarian follicular granulosa cells as specialized endothelial-like cells: a speculative treatise.

This article presents several possible extensions and considerations stemming from the putative identification of cells of the ovarian follicular granulosa as specialized endothelial-like cells. The epithelial assignment for cells of the follicular granulosa is of limited value and potentially confusing. Phenotypic and biological evidence suggests some follicle cells may represent a 'primitive', or quasi-differentiated, cell population. Other evidence suggests that cells of the follicular granulosa produce a range of molecules whose synthesis may be affected by hypoxia; some of these molecules may play strategic roles during follicular maturation, ovulation and formation of the corpus luteum. Just as follicle cells appear capable of endothelial cell-like behaviour(s), endothelial cells appear capable of engaging in some activities essential to follicular function, including steroid hormone receptivity, hyaluronic acid synthesis and steroidogenesis. A consideration of the cells of the follicle as a specialized endothelial-like cell population may have important clinical applications with respect to the anomalies and pathologies associated with human infertility. In addition, the cells of the follicular granulosa may represent an unusual and potentially powerful model system with which to study and extend the scope of our current understanding of basic endothelial cell biology.

The vascular character of ovarian follicular granulosa cells: phenotypic and functional evidence for an endothelial-like cell population.

Ovarian follicular granulosa cells express temporally and spatially distinct functions throughout the follicle cycle. During the entire cycle, granulosa cells exhibit an unusually broad range of activities including the secretion of steroid hormones, enzymes, growth factors and cytokines. To date, the identity(ies) of these cells (lineage/cell type) remains unknown. We demonstrate expression of the Tie, Tek, cKit, Flt-1, CD-31 and vWF proteins and the ability to rapidly internalize acetylated low density lipoprotein among mural and cumulus subpopulations of human and murine follicular granulosa cells. In addition, we provide evidence that human and murine granulosa cells can engage in tube-forming activity in vitro. To the best of our knowledge, the six phenotypic and two functional markers examined during this study, as a group, are associated only with endothelial or endothelial-like cells. In total, the findings suggest that some granulosa cells may have the potential to actively participate in the vascularization of the corpus luteum, by way of an inherent capacity which is likely to be a characteristic of their unique identity and lineage. This inherent capacity of granulosa cells to behave and respond, at least to some extent, like endothelial cells may be of possible importance in the aetiology of certain follicular pathologies.

[The role of obstetric complications in the pathogenesis of schizophrenia]. / Rola komplikacji polozniczych w patogenezie schizofrenii.

The article is a review of research data on the occurrence of pregnancy and delivery complications in schizophrenic patients and their possible contribution to developing schizophrenia in adolescence or adulthood. Many studies revealed that subjects who have a positive obstetric complications history are at higher risk of developing schizophrenia. Obstetric complications, especially those resulting in asphyxia, are often mentioned as possible environmental factors that can disturb the brain developmental processes, which can be responsible for developing schizophrenia in the future. Obstetric complications can act as an environmental pathogenic factor in some cases of schizophrenia (for example not genetically conditioned ones). They can also constitute an additional factor that, acting together with other (for example genetic factors, results in schizophrenia phenotype). There are still inconsistent data and many methodological problems concerning obstetric complications studies. The problem requires further investigation with improved and unified methodological procedures applied.

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E.

A major focus in gene therapy has been the use of recombinant viruses to deliver genes in vivo. Although this approach shows much promise, there are many safety concerns associated with the use of viral materials in the treatment of human diseases. Our alternative cell-based gene therapy approach utilizes endothelial cells (Pro 175) isolated from the murine embryonic yolk sac. These endothelial cells were evaluated for their potential use in gene therapy as a gene delivery platform. As a test model, we used these cells to deliver apolipoprotein E (apoE) in the murine apoE knockout atherosclerosis model. The lack of apoE protein in these animals results in high levels of serum cholesterol and formation of severe aortic plaques and lesions at a young age. After transplantation of the apoE secreting Pro 175 endothelial cells into apoE-deficient mice, serum cholesterol levels were measured at 2 week intervals. During the 3 months after the initiation of these experiments, levels of cholesterol in the animals having received the apoE secreting endothelial cells were statistically lower compared with the levels of age-matched controls having received non-secreting endothelial cells. Concomitant with cholesterol reduction, atherosclerotic aortic plaques were noticeably reduced in the experimental apoE+ animals. These results highlight the potential of these unique endothelial cells as an efficient delivery platform for somatic gene therapy.

Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains.

This study examined the relationship between blastomere fragmentation in cultured human embryos obtained by in-vitro fertilization and the effect of fragmentation on the distribution of the following eight regulatory proteins found to be: (i) localized in the mature oocyte in subplasmalemmal, polarized domains; and (ii) unequally inherited by the blastomeres during cleavage: leptin, signal transducer and activator of transcription 3 (STAT3), Bax, Bcl-x, transforming growth factor beta 2 (TGF beta 2), vascular endothelial growth factor (VEGF), c-kit and epidermal growth factor R (EGF-R). Four basic patterns of fragmentation were observed. The severity of the impact of each type of fragmentation on the affected blastomere(s) and the developmental competence of the embryo appeared to be a function of the unique temporal and spatial features associated with the particular fragmentation pattern(s) involved in each instance. The findings demonstrate that certain patterns of fragmentation can result in the partial or near total loss of the eight regulatory proteins from specific blastomeres and that the developmental potential of the affected embryo can be particularly compromised if it occurs during the 1- or 2-cell stages. In contrast, fragmentation from portions of a fertilized egg or a blastomere(s) in a 2-cell embryo that do not contain the protein domains, or the complete loss by fragmentation of a regulatory protein domain-containing blastomere after the 4-cell stage does not necessarily preclude continued development to the blastocyst, although the normality and developmental potential of the embryo may be compromised. The possible association between fragmentation and apoptosis was examined by annexin V staining of plasma membrane phosphatidylserine and TUNEL analysis of blastomere DNA. No direct correlation between fragmentation and apoptosis was found following the analyses of fragmented embryos with these two markers. However, while we suggest that changes in cell physiology unrelated to apoptosis are the more likely causes of fragmentation, we cannot exclude the possibility that fragmentation itself may be an initiator of apoptosis if critical ratios or levels of developmentally important proteins are altered by partial or complete elimination of their polarized domains. The findings are discussed with respect to the possible developmental significance of regulatory protein polarization in human oocytes and preimplantation stage embryos.

[Clinical picture and duration of prodromal period of schizophrenia in adolescents]. / Obraz kliniczny i czas trwania objawów zwiastunowych schizofrenii u mlodziezy.

The aim of study was retrospective estimation of clinical picture and duration of prodromal period in 150 adolescents with the first episode of schizophrenia.

A novel mechanism of vascular endothelial growth factor, leptin and transforming growth factor-beta2 sequestration in a subpopulation of human ovarian follicle cells.

This study describes the occurrence of a highly specialized subpopulation of granulosa and cumulus oophorus cells that accumulate and sequester specific growth factors by a novel mechanism. These cells are characterized by multiple balloon-like processes tethered to the cell by means of a slender stalk of plasma membrane. Time-lapse analyses demonstrate that these tethered structures (TS) form in minutes and frequently detach from the cell with the bulbous portion remaining motile on the cell surface. Serial section reconstruction of transmission electron microscopic images shows a specific and stable intracellular organization in which an apparent secretory compartment composed of densely packed vacuoles, vesicles, and cisternae is separated by a thick filamentous network from a nuclear compartment containing mitochondria, polyribosomes, lipid inclusions, and rough-surfaced endoplasmic reticulum. Immunofluorescent analysis performed during the formation of these structures showed a progressive accumulation of vascular endothelial growth factor, leptin, and transforming growth factor-beta2 in the bulbous region. TS were identified in newly aspirated masses of granulosa and cumulus oophorus, and their production persists for months in culture. Observations of TS-forming cells made over several days of culture indicates that their production is episodic and factor release from these cells may be pulsatile. The findings suggest that a novel method of growth factor storage and release by an apparent apocrine-like mechanism occurs in the human ovarian follicle. The results are discussed with respect to possible roles in pre- and post-ovulatory follicular development.

The expression of leptin and its receptors in pre-ovulatory human follicles.

The expression of leptin and its receptors was examined by reverse transcriptase-polymerase chain reaction and immunofluorescence in granulosa and cumulus cells of pre-ovulatory follicles and in meiotically mature oocytes obtained from women undergoing in-vitro fertilization. Leptin concentrations were measured in newly aspirated follicular fluids and in maternal serum before and after the administration of an ovulatory dose of human chorionic gonadotrophin. The findings demonstrate leptin expression at the mRNA and protein levels by granulosa and cumulus cells, and the presence of leptin in mature human oocytes. While an association between follicular leptin concentration and embryo development was not observed, a post-ovulatory increase in serum leptin concentration was associated with implantation potential. The results are discussed with respect to possible roles of leptin in early human development.

The developmental potential of the human oocyte is related to the dissolved oxygen content of follicular fluid: association with vascular endothelial growth factor levels and perifollicular blood flow characteristics.

Regardless of whether fertilization occurs in vivo or in vitro, a large proportion of human embryos do not develop progressively through the pre-implantation stages or arrest development after implantation. This study examined the association between the chromosomal/spindle normality of the mature human oocyte and the dissolved oxygen content, vascular endothelial growth factor concentration (VEGF) and perifollicular blood flow characteristics of the corresponding ovarian follicles. Findings from >1000 samples of follicular fluid show that developmentally significant differences in dissolved oxygen content occur in follicular fluids aspirated from follicles of equivalent size and ultrasonographic appearance. Oocytes from severely hypoxic follicles were associated with high frequencies of abnormalities in the organization of the chromosomes on the metaphase spindle that could lead to segregation disorders and catastrophic mosaicisms in the early embryo. Oocytes with cytoplasmic defects and cleavage stage embryos with multinucleated blastomeres are derived predominantly from severely hypoxic follicles. VEGF measurements of follicular fluid and colour pulsed Doppler ultrasonographic analysis of follicle-specific blood flow characteristics indicated a potentially important role for this factor both in perifollicular angiogenesis and in the regulation of intrafollicular oxygen levels. The results are discussed with respect to how severe intrafollicular hypoxia may influence the normality of chromosomal organization and segregation in the oocyte, and whether detailed pulsed Doppler analysis of individual pre-ovulatory follicles may provide an indirect indication of the 'health' of the follicle and possibly the developmental competence of the corresponding oocyte.

[Neurodevelopmental schizophrenia: the concept of developmental origins of certain forms of schizophrenia]. / Schizofrenia neurorozwojowa--koncepcja rozwojowego pochodzenia niektórych postaci schizofrenii.

This article presents the concept of neurodevelopmental schizophrenia and reviews the studies that contributed to its formulation. According to this concept some forms of schizophrenia (early onset, with predominating negative symptoms) are conditioned by distorted CNS development, probably in prenatal period. Such pathogenesis of certain forms of the disease is suggested by the following results of the studies on the CNS structure and function in schizophrenia: 1) structural abnormalities on in vivo brain imaging and postmortem studies 2) cytoarchitectural distortions in some brain regions, suggestive of disruption of cell migration during the CNS developmental processes 3) co-occurrence of the CNS congenital anomalies, minor physical anomalies and schizophrenia 4) neurological defects and psychosocial childhood dysfunction in individuals with adult onset schizophrenia. Genetical conditions, viral infections in prenatal period, obstetric complications or combination of the mentioned factors are considered as the factors disturbing the CNS developmental processes.

Oocyte influences on early development: the regulatory proteins leptin and STAT3 are polarized in mouse and human oocytes and differentially distributed within the cells of the preimplantation stage embryo.

Unique protein domains, concentration gradients, and asymmetric protein distributions or polarities are principle forces establishing the identity and fate of individual cells during early development in lower vertebrates and invertebrates. Here, we present evidence that these same forces exist during mammalian development in the form of two representative regulatory proteins, leptin and STAT3. Leptin, the 16 kDa cytokine product of the obese gene (ob) is involved in the activation of STAT3, a member of the signal transducer and activation of transcription family of proteins. We examined the temporal and spatial aspects of leptin and STAT3 immunofluorescence in mouse and human oocytes and preimplantation stage embryos. The findings demonstrate that both leptin and STAT3 are polarized in the oocyte and, as a consequence of their location and the position of the cleavage planes with respect to these protein domains: (i) differences in allocation of these proteins between blastomeres occur at the first cell division such that by the 8-cell stage; (ii) unique cellular domains consisting of leptin/STAT3 rich and leptin/STAT3 poor populations of cells are generated. By the morula stage, a cell-borne concentration gradient of these proteins extending along the surface of the embryo is observed. A potential role of these proteins in early development is indicated at the morula stage where the 'inner' cells consist of blastomeres that contain little, if any, leptin/STAT3 while 'outer' cells contain both leptin/STAT3 rich and poor cells. This pattern persists through the hatched blastocyst stage with little, if any, leptin/STAT3 detected in the inner cell mass and populations of leptin/STAT3 rich and poor cells forming the trophoblast. We have examined oocytes from mutant C57BL/6J ob/ob mice which are both obese and infertile (although fertility can be restored by the exogenous provision of leptin) and have found STAT3 and the mutant (truncated) leptin protein to be present and polarized, suggesting the possibility that the truncated leptin protein may still contain operational domains which are functional during oocyte development and early embryogenesis. Furthermore, analysis of leptin and STAT3 in intact ovarian follicles suggests that these proteins may be maternally derived and in particular, that a subpopulation of follicle cells may be partly responsible for the establishment of their polarized distribution in the oocyte. The results are discussed with respect to the proposition that leptin and STAT3 have critical roles in early mammalian development, and may be involved in the determination of the animal pole of the oocyte and in the establishment of the inner cell mass and trophoblast in the preimplantation stage embryo.

[Allergic reaction to products made of natural rubber]. / Reakcja alergiczna na produkty z gumy naturalnej.

In the previous few years, there has been a startling escalation in intraoperative and radiologic anaphylactic episodes, some of them lethal, that have been assigned to rubber exposure. Immediate hypersensitivity reactions to natural rubber pose a significant risk to patient with spina bifida and urogenital abnormalities, health care workers, and rubber industry workers. It has been estimated that 2% to 10% of physicians and nursing personnel are latex allergic. The clinical syndromes associated with reactions to latex may be divided into three broad categories a) contact dermatitis--limited to skin directly in contact with latex, b) contact urticaria syndrome a broad spectrum of contact reactions including not only immediate wheal and flare reactions, but also dyshidrotic vesiculation, and accelerated contact reactions including erythema, burning or pruritus occurring within 10-30 minutes after contact, c) systemic allergic reactions-including generalized urticaria or pruritus, rhinoconjunctivitis or asthma, as well as the multiple presentations of anaphylaxis. Contact dermatitis reactions are thought to be a T-cell mediated type IV reaction, systemic reactions to latex appear to be an IgE-mediated phenomenon. Contact urticaria syndrome seems to be a heterogeneous group of reactions. Diagnosis of latex allergy is made on clinical grounds, however, history alone is insufficient to recognize all patients at risk, and conscientious testing materials are not yet available. Prick tests utilizing extracts from latex gloves or from raw latex preparation can be used but the specificity of this test remains unknown. Skin prick testing must be considered experimental and should be only done by experienced physician. Serologic testing for latex allergy remains a safe alternative, although the sensitivity and specificity of this procedure is still undefined. Prophylactic regimes to avoid rubber exposure and decrease the antigen content of natural rubber products by the rubber industry should be implemented to decrease the rate of sensitization in the future and prevent allergic reactions.