Nosology, epidemiology and pathogenesis of bipolar disorder: Recent approaches

Bipolar disorder is a highly prevalent, chronic and deteriorating mental illness that requires medical, psychological and social care for life. Realizing that bipolar disorder is more common than initially thought, the associated disability and the heterogeneity in their clinical presentation, has strengthened the research on this topic. Recent advances in the field of nosology, epidemiology and pathogenesis have begun to unravel some of the complexity of this disorder and have had a marked influence on the changes in the way they are beginning to diagnose a broad spectrum of bipolar disorders according to the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5)

Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10(-16)). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a 'proxy phenotype' of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis

Effect of Genotype and Maternal Affective Disorder on Intronic Methylation of FK506 Binding Protein 5 in Cord Blood DNA

A single nucleotide polymorphism (SNP: rs1360780) in FKBP5 (FK506 Binding Protein 5) has been shown to interact with exposure to childhood adversity to promote loss of methylation and increase in gene expression in adults. We asked whether rs1360780 can influence FKBP5 intronic methylation in the context of exposure to maternal affective disorders in utero. Sixty cord blood DNA samples from the Boston Birth Cohort were genotyped at rs1360780 and studied for methylation changes as they relate to genotype and exposure to affective disorders during pregnancy. Linear regression was employed to contrast the risk (TT) genotype to the heterozygous (CT) and homozygous (CC) genotypes with adjustment for potential confounders. The recessive genotype (TT) was associated with increased methylation at multiple CpGs in the FKBP5 intron 5 region (p < 0.01). These findings were enhanced among cases exposed to maternal affective disorders (p = 0.02). A human cell line treated with cortisol showed that changes in intron 5 CpG methylation and FKBP5 expression were inversely associated. These findings suggest that rs1360780 can influence FKBP5 intronic methylation by acting in cis as a methylation quantitative locus and highlight the impact of genotypic risk on methylation in utero. Additionally, prenatal stress exposure compounded with the risk genotype may lead to a compensatory increase in methylation

SMURF: Genomic mapping of fungal secondary metabolite clusters

Fungi produce an impressive array of secondary metabolites (SMs) including mycotoxins, antibiotics and pharmaceuticals. The genes responsible for their biosynthesis, export, and transcriptional regulation are often found in contiguous gene clusters. To facilitate annotation of these clusters in sequenced fungal genomes, we developed the web-based software SMURF (www.jcvi.org/smurf/) to systematically predict clustered SM genes based on their genomic context and domain content. We applied SMURF to catalog putative clusters in 27 publicly available fungal genomes. Comparison with genetically characterized clusters from six fungal species showed that SMURF accurately recovered all clusters and detected additional potential clusters. Subsequent comparative analysis revealed the striking biosynthetic capacity and variability of the fungal SM pathways and the correlation between unicellularity and the absence of SMs. Further genetics studies are needed to experimentally confirm these clusters

Systematic review of genome-wide gene expression studies of bipolar disorder

Abstract Background Numerous genome-wide gene expression studies of bipolar disorder (BP) have been carried out. These studies are heterogeneous, underpowered and use overlapping samples. We conducted a systematic review of these studies to synthesize the current findings. Methods We identified all genome-wide gene expression studies on BP in humans. We then carried out a quantitative mega-analysis of studies done with post-mortem brain tissue. We obtained raw data from each study and used standardized procedures to process and analyze the data. We then combined the data and conducted three separate mega-analyses on samples from 1) any region of the brain (9 studies); 2) the prefrontal cortex (PFC) (6 studies); and 3) the hippocampus (2 studies). To minimize heterogeneity across studies, we focused primarily on the most numerous, recent and comprehensive studies. Results A total of 30 genome-wide gene expression studies of BP done with blood or brain tissue were identified. We included 10 studies with data on 211 microarrays on 57 unique BP cases and 229 microarrays on 60 unique controls in the quantitative mega-analysis. A total of 382 genes were identified as significantly differentially expressed by the three analyses. Eleven genes survived correction for multiple testing with a q-value &lt; 0.05 in the PFC. Among these were FKBP5 and WFS1, which have been previously implicated in mood disorders. Pathway analyses suggested a role for metallothionein proteins, MAP Kinase phosphotases, and neuropeptides. Conclusion We provided an up-to-date summary of results from gene expression studies of the brain in BP. Our analyses focused on the highest quality data available and provided results by brain region so that similarities and differences can be examined relative to disease status. The results are available for closer inspection on-line at Metamoodics [http://metamoodics.igm.jhmi.edu/], where investigators can look up any genes of interest and view the current results in their genomic context and in relation to leading findings from other genomic experiments in bipolar disorder. </jats:sec

A dopamine receptor genetic variant enhances perceptual speed in cognitive healthy subjects

Introduction: Cognition is under strong genetic control, yet the specific genes are unknown. Methods: One hundred and fifty-three cognitive healthy European subjects from the Reference Abilities Study (RANN) were genotyped for 1,160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities (Vocabulary, Episodic Memory, Perceptual Speed, and Reasoning). Results: One hundred and fifty-nine variants nominally were found significant in the RANN cohort and re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (β = 0.23, standard error = 0.05, Pmeta = 2.3 × 10−5). Discussion Our data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals

LNCRNAKB: A COMPREHENSIVE KNOWLEDGEBASE OF LONG NON-CODING RNAS

High throughput technologies such as next-generation sequencing technologies have allowed the genomic structure to be interrogated at high resolution and scale. That includes long non-coding RNAs (lncRNAs), a class of non-protein-coding transcripts, that range from 200 nucleotides to 100 kb (approximately 10 kb on average). The number of estimated lncRNAs annotations in humans range from 20,000 to 100,000. There are several databases that exist for annotation of human lncRNAs. Most of these databases are available through web-based searchable interfaces. Our objective was to identify current and new lncRNAs databases, download and inspect their latest annotations, integrate this information into a single resource, and create the most comprehensive up- to-date knowledge base that encompasses data from all major resources. Specifically, we provide a “one- stop shop” in which users can search for lncRNAs based on any keywords for e.g. genomic locations, gene names and types. LncRNAs annotations are commonly used as references for quantifying and identifying differentially expressed genes and transcripts in RNA-seq experiments. We used the Genotype Tissue Expression (GTEx) project RNA-seq data to quantify all the lncRNAs in our knowledge base using 9,425 samples sequenced across 31 solid organ human normal tissues. We performed RNA-seq data analysis using a custom pipeline and created a comprehensive tissue- specific expression body map of human lncRNAs. The sequence-function relationship of lncRNAs is not well understood compared to protein-coding genes whose function can be deduced from primary sequence alone. In addition to understanding and improving the annotations of lncRNAs, we sought to predict and determine molecular, biological and disease functions of lncRNAs. We positionally classified and predicted the coding potential of all lncRNAs using a machine learning approach. Using whole genome sequence (WGS) genotype data from the GTEx project we also identified lncRNAs regulated by genetic variants in cis. We performed mRNA-lncRNA co-expression network analysis and identified co-expression gene modules involved in known biological processes thus, deducing the potential function of lncRNAs. Our objective was to functionally annotate and characterize lncRNAs in our knowledge base and provide a comprehensive resource to empower the research community

Relatives' experiences in connection with end-of-life care in in patientcare : A literature review

Bakgrund: För att både sjuke närstående och anhöriga ska få en god och säker vård krävs det att sjuksköterskan arbetar utifrån ett helhetsperspektiv där sjuke närstående tillsammans med deras anhöriga läggs i fokus. Det är inte alltid att anhöriga känner sig att de blir hörda under tiden de har en närstående som befinner sig i livets slutskede. Det är inte bara viktigt för sjuke närstående att kunna ha en roll inom delaktigheten när det kommer till vård vid livets slutskede, utan anhöriga har en viktig roll i detta men blir oftast bortglömda. Syfte: Syftet med denna litteraturöversikt är att beskriva anhörigas upplevelser och erfarenheter i samband med vård i livets slutskede inom slutenvården. Metod: Detta arbete utformas som en strukturerad litteraturöversikt sammanlagt inkluderades 12 vetenskapliga artiklar som publicerades mellan 2013–2023. Dessa artiklar identifierades via databaserna PubMed och CINAHL. Resultat: I resultat framkommer fyra kategorier som är: Beslutfattande, Kommunikation, och Stöd till anhöriga. Slutsats: Att vara anhöriga och ha en sjuk närstående kan vara påfrestande speciellt närde inte vet vad deras roll är. I en sådan situation är det viktigt att både vårdpersonalen och den sjukes anhöriga kan kommunicera för att skapa en trygg slutenvårds miljö, känna sig stödda och på det vis bli mer delaktiga i patientens vård.Background: For both the patient and relatives to receive good and safe care, it is required that the nurse works from a holistic perspective where the patient together with their family members is put in focus. It is not always that family members feel that they are being heard while they have a relative who is at the end of life. It is not only important for the patient to be able to have a role in participation when it comes to care at the end of life, but relatives have an important role in this but are often forgotten. Aim: Relatives interprets and experience in connection with end-of-life care in inpatient care. Method: This work is designed as a structured literature review that focuses on relatives' point of view of their role when it comes to end-of-life care. A total of 12 scientific articles published between 2013–2023 were included. These articles were identified via the databases PubMed and CINAHL. Results: The results show three categories which are: Decision-making, Communication, and Support to family members. Conclusions: Being relatives and having a sick family member can be stressful especially when they don't know what their role is. In such a situation, it is important that both the healthcare staff and the patient's relatives can communicate in order to create a safe care environment, feel supported and thus become more involved in the patient's care

Tathwir mafhum idarah al-azimat al-dauliyah bi siyasiyah al-jami'ah al-'Arabiyah

Tujuan penelitian ini, pada intinya, merupakan analisis terhadap konsep perkembangan manajemen krisis internasional dalam Liga Arab berdasarkan pada penanganan krisis teluk kedua dan ketiga, dan mengkaji landasan hukum dan mekanisme yang diakui, serta sisi-sisi pengambilan keputusan di dalam Organisasi Liga Arab yang yang diakui sebagai organisasi representatif bagi sistem kerja Arab bersama di kancah hubungan internasional. Penelitian ini, ketika menganalisis berbagai variabel, bergerak menuju pada dua arah yang saling berinteraksi. Pertama, yang berhubungan dengan lembaga Liga Arab dan struktur organisasinya, serta sejarah akan kiprahnya. Sedangkan yang kedua, membahas krisis teluk kedua (tahun 1990-1991) dan krisis teluk ketiga (tahun 2003) dimana Iraq menjadi unsur utamanya. Sesungguhnya, perbandingan interaksi dua arah antara organisasi regional dan berbagai perkembangan di kancah hubungan internasional adalah suatu yang harus dalam memahami karakter wilayah arab dan krisisnya yang silih berganti. Penelitian ini mendapatkan bahwa dua krisis tersebut berdiri pada posisi tengah yang memiliki interaksi horizontal dan vertikal, yang telah didahului oleh berbagai krisis dan diikuti oleh krisis-krisis lainnya bagi Iraq dan sistem kerja Arab bersama. Kedua krisis tersebut merupakan bagian dalam krisis dunia Arab yang lebih luas, mewakili realita Arab yang mencerminkan kelemahan dan perpecaha

Relatives' experiences in connection with end-of-life care in in patientcare : A literature review

Bakgrund: För att både sjuke närstående och anhöriga ska få en god och säker vård krävs det att sjuksköterskan arbetar utifrån ett helhetsperspektiv där sjuke närstående tillsammans med deras anhöriga läggs i fokus. Det är inte alltid att anhöriga känner sig att de blir hörda under tiden de har en närstående som befinner sig i livets slutskede. Det är inte bara viktigt för sjuke närstående att kunna ha en roll inom delaktigheten när det kommer till vård vid livets slutskede, utan anhöriga har en viktig roll i detta men blir oftast bortglömda. Syfte: Syftet med denna litteraturöversikt är att beskriva anhörigas upplevelser och erfarenheter i samband med vård i livets slutskede inom slutenvården. Metod: Detta arbete utformas som en strukturerad litteraturöversikt sammanlagt inkluderades 12 vetenskapliga artiklar som publicerades mellan 2013–2023. Dessa artiklar identifierades via databaserna PubMed och CINAHL. Resultat: I resultat framkommer fyra kategorier som är: Beslutfattande, Kommunikation, och Stöd till anhöriga. Slutsats: Att vara anhöriga och ha en sjuk närstående kan vara påfrestande speciellt närde inte vet vad deras roll är. I en sådan situation är det viktigt att både vårdpersonalen och den sjukes anhöriga kan kommunicera för att skapa en trygg slutenvårds miljö, känna sig stödda och på det vis bli mer delaktiga i patientens vård.Background: For both the patient and relatives to receive good and safe care, it is required that the nurse works from a holistic perspective where the patient together with their family members is put in focus. It is not always that family members feel that they are being heard while they have a relative who is at the end of life. It is not only important for the patient to be able to have a role in participation when it comes to care at the end of life, but relatives have an important role in this but are often forgotten. Aim: Relatives interprets and experience in connection with end-of-life care in inpatient care. Method: This work is designed as a structured literature review that focuses on relatives' point of view of their role when it comes to end-of-life care. A total of 12 scientific articles published between 2013–2023 were included. These articles were identified via the databases PubMed and CINAHL. Results: The results show three categories which are: Decision-making, Communication, and Support to family members. Conclusions: Being relatives and having a sick family member can be stressful especially when they don't know what their role is. In such a situation, it is important that both the healthcare staff and the patient's relatives can communicate in order to create a safe care environment, feel supported and thus become more involved in the patient's care