Transcriptome profiling as a biological marker for bipolar disorder sub-phenotypes.

PURPOSE: Bipolar affective disorder (BP) causes major functional impairment and reduced quality of life not only for patients, but also for many close relatives. We aimed to investigate mRNA levels in BP patients to find differentially expressed genes linked to specific clinical course variants; assuming that several gene expression alterations might indicate vulnerability pathways for specific course and severity of the disease. MATERIALS: We searched for up- and down-regulated genes comparing patients with diagnosis of BP type I (BPI) vs type II (BPII), history of suicide attempts, psychotic symptoms, predominance of manic/hypomanic episodes, and history of numerous episodes and comorbidity of substance use disorders or anxiety disorders. RNA was extracted from peripheral blood mononuclear cells and analyzed with use of microarray slides. RESULTS: Differentially expressed genes (DEGs) were found in all disease characteristics compared. The lowest number of DEGs were revealed when comparing BPI and BPII patients (18 genes), and the highest number when comparing patients with and without psychotic symptoms (3223 genes). Down-regulated genes identified here with the use of the DAVID database were among others linked to cell migration, defense response, and inflammatory response. CONCLUSIONS: The most specific transcriptome profile was revealed in BP with psychotic symptoms. Differentially expressed genes in this variant include, among others, genes involved in inflammatory and immune processes. It might suggest the overlap of biological background between BP with a history of psychotic features and schizophrenia.

Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients.

RATIONALE: In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment. OBJECTIVES: We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes. RESULTS: We genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers. CONCLUSIONS: Our study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium's immunomodulatory potential.

Identification of shared disease marker genes and underlying mechanisms between major depression and rheumatoid arthritis.

Both depression and rheumatoid arthritis (RA) have a very high comorbidity rate. A bilateral association is estimated to increase the mutual risk and the common denominator is inflammation being observed in both diseases. Previous studies have mainly focused on assessing peripheral blood's inflammatory and pro-inflammatory cytokines levels. We aimed to extend insights into the molecular mechanisms of depression based on hub RA genes. To do so, we prioritized RA-related genes using in-silico tools. We then investigated whether RA-related genes undergo altered expression in patients with unipolar and bipolar depression without a concurrent RA diagnosis and any exponents of active inflammation. In addition, we selected a homogeneous group of patients treated with lithium (Li), which has immunomodulatory properties. The study was performed on patients with bipolar depression (BD, n = 45; Li, n = 20), unipolar depression (UD, n = 27), and healthy controls (HC, n = 22) of both sexes. To identify DEGs in peripheral blood mononuclear cells (PBMCs), we used the SurePrint G3 Microarray and GeneSpring software. We selected a list of 180 hub genes whose altered expression we analyzed using the expression microarray results. In the entire study group, we identified altered expression of 93 of the 180 genes, including 35 down-regulated (OPRM1 gene with highest FC > 3) and 58 up-regulated (TLR4 gene with highest FC > 3). In UD patients, we observed maximally up-regulated expression of the TEK gene (FC > 3), and in BD of the CXCL8 gene (FC > 5). On the other hand, in lithium-treated patients, the gene with the most reduced expression was the TRPV1 gene. The study proved that depression and RA are produced by a partially shared "inflammatory interactome" in which the opioid and angiogenesis pathways are important.

MRI and Pulmonary Function Tests' Results as Ventilation Inhomogeneity Markers in Children and Adolescents with Cystic Fibrosis.

Magnetic resonance imaging (MRI) of the chest is becoming more available in the detection and monitoring of early changes in lung function and structure in patients with cystic fibrosis (CF). The aim of this study was to assess the relationship between pulmonary function tests (PFT) and perfusion deficits in CF children measured by MRI. We performed a retrospective analysis of the perfusion lung MRI scans and the results of spirometry, oscillometry, body plethysmography, single-breath carbon monoxide uptake, and multiple-breath washout technique (MBW). There were statistically significant correlations between the MRI perfusion scores and MBW parameters (2.5% LCI, M1/M0, M2/M0), spirometry parameters (FEV1, FVC, FEF25/75), reactance indices in impulse oscillometry (X5Hz, X10Hz), total lung capacity (TLC) measured in single breath carbon monoxide uptake, markers of air-trapping in body plethysmography (RV, RV/TLC), and the diffusing capacity of the lungs for carbon monoxide. We also observed significant differences in the aforementioned PFT variables between the patient groups divided based on perfusion scores. We noted a correlation between markers of functional lung deficits measured by the MRI and PFTs in CF children. MRI perfusion abnormalities were reflected sooner in the course of the disease than PFT abnormalities.

How Does the Corrected Exhalyzer Software Change the Predictive Value of LCI in Pulmonary Exacerbations in Children with Cystic Fibrosis?

Aim: Recently, the most commonly used for multiple breath washout device, the Exhalyzer D, has been shown to overestimate lung clearance index (LCI) results due to a software error. Our study aimed to compare the predictive values of LCI in the CF pulmonary exacerbations (PE) calculated with the updated (3.3.1) and the previous (3.2.1) version of the Spiroware software. Materials and Methods: The measurements were performed during 259 visits in CF pediatric patients. We used 39ΔPE pairs (PE preceded by stable visit) and 138ΔS pairs (stable visit preceded by stable visit) to compare the LCI changes during PE. The areas under the receiver operating curves (AUCROC) and odds ratios were calculated based on the differences between ΔPEs and ΔSs. The exacerbation risk was estimated using a logistic regression model with generalized estimating equations (GEE). Results: There were statistically significant differences in LCI 2.5% median values measured using the two versions of the software in the stable condition but not during PE. The AUCROC for changes between the two consecutive visits for LCI did not change significantly using the updated Spiroware software. Conclusions: Despite the lower median values, using the recalculated LCI values does not influence the diagnostic accuracy of this parameter in CF PE.

Dimensions of the Hamilton Depression Rating Scale Correlate with Impulsivity and Personality Traits among Youth Patients with Depression.

The heterogeneity of symptoms in young patients with major depression disorder makes it difficult to properly identify and diagnose. Therefore, the appropriate evaluation of mood symptoms is important in early intervention. The aim of this study was to (a) establish dimensions of the Hamilton Depression Rating Scale (HDRS-17) in adolescents and young adults and (b) perform correlations between the identified dimensions and psychological variables (impulsivity, personality traits). This study enrolled 52 young patients with major depression disorder (MDD). The severity of the depressive symptoms was established using the HDRS-17. The factor structure of the scale was studied using the principal component analysis (PCA) with varimax rotation. The patients completed the self-reported Barratt Impulsiveness Scale (BIS-11) and Temperament and Character Inventory (TCI). The three dimensions of the HDRS-17 identified as core in adolescent and young patients with MDD were (1) psychic depression/motor retardation, (2) disturbed thinking, and (3) sleep disturbances/anxiety. In our study, dimension 1 correlated with reward dependence and cooperativeness; dimension 2 correlated with non-planning impulsivity, harm avoidance, and self-directedness; and dimension 3 correlated with reward dependence. Conclusions: Our study supports the previous findings, which indicate that a certain set of clinical features (including the HDRS-17 dimensions, not only total score) may represent a vulnerability pattern that characterizes patients with depression.

Non-Coding RNAs in Pulmonary Diseases: Comparison of Different Airway-Derived Biosamples.

Due to their structural conservation and functional role in critical signalling pathways, non-coding RNA (ncRNA) is a promising biomarker and modulator of pathological conditions. Most research has focussed on the role of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules have been investigated both in a cellular and an extracellular context. Sources of ncRNAs may include organ-specific body fluids. Therefore, studies on ncRNAs in respiratory diseases include those on sputum, bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC). It is worth identifying the limitations of these biosamples in terms of ncRNA abundance, processing and diagnostic potential. This review describes the progress in the literature on the role of ncRNAs in the pathogenesis and progression of severe respiratory diseases, including cystic fibrosis, asthma and interstitial lung disease. We showed that there is a deficit of information on lncRNAs and circRNAs in selected diseases, despite attempts to functionally bind them to miRNAs. miRNAs remain the most well-studied, but only a few investigations have been conducted on the least invasive biosample material, i.e., EBC. To summarise the studies conducted to date, we also performed a preliminary in silico analysis of the reported miRNAs, demonstrating the complexity of their role and interactions in selected respiratory diseases.

Extracellular vesicles-derived miRNAs as mediators of pulmonary exacerbation in pediatric cystic fibrosis.

Children with cystic fibrosis (CF) suffer from chronic inflammation and recurrent pulmonary exacerbations (PEs). We aimed to test whether a specific miRNA could be associated with the occurrence of PE. We sequenced extracellular vesicle (EV)-derived miRNA in sputum (n= 20), exhaled breath condensate (EBC) (n= 11), and serum (n= 8) samples from pediatric patients during PE and the stable stage of CF. Four miRNAs: let-7c, miR-16, miR-25-3p and miR-146a, have been selected for validation in a larger group with reverse transcription quantitative real-time PCR (RT-qPCR) in sputum and serum, or droplet digital PCR (ddPCR) in EBC. Next-generation sequencing (NGS) differential expression analysis was done in Base Space, and the correlation between miRNAs expression and clinical data was calculated with Statistica. Functional annotation of selected miRNAs and their potential target genes was performed with miRDip and DAVID software. There were no differences in miRNA expression between stable and exacerbation in sputum and in serum. Validation of four selected miRNAs showed significant downregulation of miR-146a in serum. A panel of all four miRNAs (peripherally) was the best predictive model of exacerbation (p< 0.001, AUC = 0.96). Expression of airway miR-25-3p improved the diagnostic value of FEV1% pred and FVC% pred, while peripheral miR-146a improved the predictive model of C-reactive protein and neutrophilia.In silicoanalysis revealed a potential role for selected miRNAs in regulating processes associated with inflammation and tissue remodeling. We demonstrated that EVs contained in peripheral blood as well as local biomaterials can act as carriers for miRNAs with the diagnostic potential of predicting exacerbation in pediatric CF.

Methylation of melatonin receptors in patients with unipolar and bipolar depression.

Disturbances of melatonin secretion alter the circadian rhythm and sleep-wake cycle, which is observed among patients with depression. Melatonin acts via melatonin receptors MT1 and MT2, which are present in many tissues, including peripheral blood mononuclear cells (PBMC). We assume that disturbances of the melatonin pathway in the brain may be reflected by molecular changes in peripheral organs. The study objective was to evaluate the methylation profile of CpG island in the promoter region of melatonin receptor genes MTNR1A and MTNR1B in PBMC of patients with depression and compare it with healthy volunteers. The study group comprised 85 patients with unipolar (UP) and bipolar disorders (BP) and 83 controls. The methylation pattern of CpG island in the promoter region was analyzed using the quantitative methylation-specific real-time PCR (qMSP-PCR) method. We found that the methylation profile of the patients with depression varied in comparison to the control group. The methylation level of MTNR1A was significantly lower among depressed patients compared to controls. Additionally, melatonin concentration was negatively correlated with MTNR1B methylation level among the UP patients. The study may suggest that the methylation profile of melatonin receptors in PBMC may be used as a complementary molecular marker in depression diagnosis.

Increased expression of ORMDL3 in allergic asthma: a case control and in vitro study.

BACKGROUND: Asthma is the most frequent chronic disease in children. One of the most replicated genetic findings in childhood asthma is the ORMDL3 gene confirmed in several GWA studies in several pediatric populations. OBJECTIVES: The purpose of this study was to analyze ORMDL3 variants and expression in childhood asthma in the Polish population. METHODS: In the study we included 416 subject, 223 asthmatic children and 193 healthy control subjects. The analysis of two SNPs (rs3744246 and rs8076131) was performed using genotyping with TaqMan probes. The methylation of the ORMDL3 promoter was examined with Methylation Sensitive HRM (MS-HRM), covering 9 CpG sites. The expression of ORMDL3 was analyzed in PBMCs from pediatric patients diagnosed with allergic asthma and primary human bronchial epithelial cells derived from healthy subjects treated with IL-13, IL-4, or co-treatment with both cytokines to model allergic airway inflammation. RESULTS: We found that ORMDL3 expression was increased in allergic asthma both in PBMCs from asthmatic patients as well as in human bronchial epithelial cells stimulated with the current cytokines. We did not observe significant differences between cases and controls either in the genotype distribution of analyzed SNPs (rs3744246 and rs8076131) nor in the level of promoter methylation. CONCLUSIONS: Increased ORMDL3 expression is associated with pediatric allergic asthma and upregulated in the airways upon Th2-cytokines stimulation, but further functional studies are required to fully understand its role in this disease.

Differential expression profile between amygdala and blood during chronic lithium treatment in a rat model of depression - a pilot study.

Lithium is a mood stabilizer widely used in the pharmacotherapy of bipolar disorder and treatment­resistant depression. Taking into account dysregulated inflammatory activity in depression and the immunomodulatory role of lithium, we hypothesized that genes associated with inflammatory responses may be potential biomarkers of lithium action. We aimed to compare gene expression changes between the brain and the periphery after chronic lithium administration in an animal model of depression. Depressive behavior was induced by chronic mild stress protocol for 4 weeks. After 2 weeks, rats started to receive lithium (study group) or water (reference group). The control group were rats not exposed to stress. Amygdala, hippocampus, frontal cortex and peripheral blood were analyzed using whole transcriptome expression microarrays. Changes were confirmed with qPCR and ELISA assay. After 2 weeks of lithium administration, we observed significant changes in gene expression between amygdala and peripheral blood. Logistic regression analysis determined Alox15 expression as a predictor of lithium status, as its expression was tissue­specific and increased in amygdala and decreased in blood. Analysis of serum ALOX15 protein revealed its upregulation after two­week lithium administration. Our study suggests that lithium may have therapeutic potential in depressive behaviors. These results indicate immunomodulatory effect of lithium and that Alox15 may be a new potential marker of chronic lithium treatment.

Allergic inflammation in lungs and nasal epithelium of rat model is regulated by tissue-specific miRNA expression.

INTRODUCTION: Atopic asthma and allergic rhinitis are common chronic inflammatory diseases affecting lower airways and nasal mucosa, respectively. Several reports demonstrated frequent co-occurrence of these two diseases, however, the exact molecular mechanism has not been described. The present study aimed to investigate if small non-coding RNA might be responsible for the co-occurrence of asthma and allergic rhinitis in an animal model of allergic airway inflammation. MATERIALS AND METHODS: As an in vivo model of allergic airway inflammation, we used Brown Norway rats exposed intranasally to house dust mite (HDM). Histological analysis, total IgE concentration, eosinophil counts and iNOS gene expression were determined to confirm inflammatory changes. Small RNA sequencing in the lung tissue and nasal epithelium was performed with TruSeq Small RNA Library Preparation Kit and analyzed using the BaseSpace tool. Validation of sequencing results was performed using qPCR. To assess the functional role of hsa-miR-223-3p, we transfected normal human bronchial epithelial (NHBE) cells with specific LNA-inhibitor and measured phosphorylated protein level of NF-kB with ELISA. Expression analysis of NF-kB pathway-related genes was performed using qPCR with SYBR Green and analyzed in DataAssist v3.01. Statistical analysis were done with STATISTICA version 13. RESULTS: We found 9 miRNA genes differentially expressed in the lungs of allergic rats. In nasal epithelium, only rno-miR-184 was upregulated in animals exposed to HDM. Validation with qPCR confirmed increased expression only for rno-miR-223-3p in the lungs from allergic rats. The expression of this miRNA was also increased in normal bronchial epithelial ALI cell culture stimulated with IL-13, but not in cells cultured in monolayer due to the low mRNA level of IL13RA1 and IL13RA2. Transfecting NHBE cells with hsa-miR-223-3p inhibitor increased the amount of phosphorylated NF-kB protein level and expression of MUC5AC, CCL24 and TSLP genes. CONCLUSIONS: These findings suggest that miRNAs that regulate allergic inflammation in the lungs and nasal epithelium are specific for upper and lower airways. Furthermore, our study provides new insight on the role of hsa-miR-223-3p, that via targeting NF-kB signaling pathway, regulates the expression of MUC5AC, CCL24 and TSLP. Taken together, our study suggests that miR-223-3p is a regulator of allergic inflammation and could potentially be used to develop novel and targeted therapy for asthma.

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects.

Background: Craniosynostosis (CS) represents a highly heterogeneous genetic condition whose genetic background has not been yet revealed. The abnormality occurs either in isolated form or syndromic, as an element of hundreds of different inborn syndromes. Consequently, CS may often represent a challenging diagnostic issue. Methods: We investigated a three-tiered approach (karyotyping, Sanger sequencing, followed by custom gene panel/chromosomal microarray analysis, and exome sequencing), coupled with prioritization of variants based on dysmorphological assessment and description in terms of human phenotype ontology. In addition, we have also performed a statistical analysis of the obtained clinical data using the nonparametric test χ2. Results: We achieved a 43% diagnostic success rate and have demonstrated the complexity of mutations' type harbored by the patients, which were either chromosomal aberrations, copy number variations, or point mutations. The majority of pathogenic variants were found in the well-known CS genes, however, variants found in genes associated with chromatinopathies or RASopathies are of particular interest. Conclusion: We have critically summarized and then optimised a cost-effective diagnostic algorithm, which may be helpful in a daily diagnostic routine and future clinical research of various CS types. Moreover, we have pinpointed the possible underestimated co-occurrence of CS and intellectual disability, suggesting it may be overlooked when intellectual disability constitutes a primary clinical complaint. On the other hand, in any case of already detected syndromic CS and intellectual disability, the possible occurrence of clinical features suggestive for chromatinopathies or RASopathies should also be considered.

Dysregulation of miRNAs Levels in Glycogen Synthase Kinase-3ß Overexpressing Mice and the Role of miR-221-5p in Synaptic Function.

Glycogen synthase kinase-3ß (GSK-3ß) is a highly expressed kinase in the brain, where it has an important role in synaptic plasticity. Aberrant activity of GSK-3ß leads to synaptic dysfunction which results in the development of several neuropsychiatric and neurological diseases. Notably, overexpression of constitutively active form of GSK-3ß (GSK-3ß[S9A]) in mice recapitulates the cognitive and structural defects characteristic for neurological and psychiatric disorders. However, the mechanisms by which GSK-3ß regulates synaptic functions are not clearly known. Here, we investigate the effects of GSK-3ß overactivity on neuronal miRNA expression in the mouse hippocampus. We found that GSK-3ß overactivity downregulates miRNA network with a potent effect on miR-221-5p (miR-221*). Next, characterization of miR-221* function in primary hippocampal cell culture transfected by miR-221* inhibitor, showed no structural changes in dendritic spine shape and density. Using electrophysiological methods, we found that downregulation of miR-221* increases excitatory synaptic transmission in hippocampal neurons, probably via postsynaptic mechanisms. Thus, our data reveal potential mechanism by which GSK-3ß and miRNAs might regulate synaptic function and therefore also synaptic plasticity.

Predictive value of impulse oscillometry and multiple breath washout parameters in pediatric patients with cystic fibrosis pulmonary exacerbation.

BACKGROUND: Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis (CF) and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the forced expiratory volume in the first second (FEV1 ) decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE. METHODS: We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS). RESULTS: Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for lung clearance index (LCI), Sacin , R5Hz, R5-20Hz, X10Hz, AX, and Fres. The predictive values of Fres and X10Hz in IOS (AUCROC 0.71 both parameters) were higher than those of LCI (AUCROC 0.67). There was no difference in the predictive values (AUCROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs. 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV1 z-score ≥-1.64 and AUC 0.67 for LCI vs 0.69 for both ΔX10Hz zscore and Δ Fres zscore in patients with FEV1 <1.64. CONCLUSIONS: Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with PE. LCI has a similar predictive value to IOS in children with CF independently of their FEV1 value.

Studies on candidate genes for lithium prophylaxis performed at the Poznan University of Medical Sciences. / Badania genów kandydujacych profilaktyki litem przeprowadzone na Uniwersytecie Medycznym w Poznaniu.

Lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of bipolar disorder. The prophylactic efficacy of lithium can be determined by genetic factors, partially related to a predisposition to bipolar disorder. In the field of psychiatric genetics, the first decade of the 21st century was dominated by the "candidate gene" research. In this paper, the studies on candidate genes connected with lithium prophylaxis performed at the Poznan University of Medical Sciences in 2005-2018 are presented. During this time, the polymorphisms of multiple genes have been investigated, many of which are also connected with a predisposition to bipolar illness. The associations with lithium prophylactic efficacy were found for the polymorphisms in 5HTT, ACP1, ARNTL, BDNF, COMT, DRD1, FKBP5, FYN, GLCC, NR3C1, and TIM, genes, but not those in 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GRIN2B, GSK-3ß, MMP-9, and NTRK2 genes. The polymorphism of the GSK-3ß gene was found to be associated with the kidney side-effects occurring during lithium therapy. Possible roles for these genes in both the mechanism of lithium prophylactic activity and pathogenesis of bipolar mood disorder were discussed.

Nitric Oxide Synthase 2 Promoter Polymorphism Is a Risk Factor for Allergic Asthma in Children.

Background and Objectives: In paediatric population, atopic asthma is associated with increased eosinophil counts in patients, that correlate with the airway inflammation measured by the concentration of nitric oxide in exhaled air (FeNO). As the FeNO level is a biomarker of atopic asthma, we assumed that polymorphisms in nitric synthases genes may represent a risk factor for asthma development. The purpose of this study was to analyse the association of NOS genetic variants with childhood asthma in the Polish population. Materials and methods: In study we included 443 children-220 patients diagnosed with atopic asthma and 223 healthy control subjects. We have genotyped 4 single nucleotide polymorphisms (SNP) from 3 genes involved in the nitric oxide synthesis (NOS1, NOS2 and NOS3). All analyses were performed using polymerase chain reaction with restriction fragments length polymorphism (PCR-RFLP). Results: We observed significant differences between cases and controls in SNP rs10459953 in NOS2 gene, considering both genotypes (p = 0.001) and alleles (p = 0.0006). The other analyzed polymorphisms did not show association with disease. Conclusions: According to our results, 5'UTR variant within NOS2 isoform may have an impact of asthma susceptibility in the population of Polish children. Further functional studies are required to understand the role of iNOS polymorphism in NOS2 translation and to consider it as a novel risk factor in childhood asthma. The next step would be to apply this knowledge to improve diagnosis and develop novel personalized asthma therapies.

Elevated Epidermal Growth Factor (EGF) as Candidate Biomarker of Mood Disorders-Longitudinal Study in Adolescent and Young Adult Patients.

Bipolar disorder (BD) is a chronic mental disorder that affects more than 1% of the population worldwide. Over 65% of patients experience early onset of the disease. Most cases of juvenile bipolar disorder begin with a depressed mood episode, and up to 50% of youth initially diagnosed with major depression go onto developing a BD. Our study aimed to find biomarkers of diagnosis conversion in young patients with mood disorders. We performed a two-year follow-up study on 79 adolescent patients diagnosed with MDD or BD, with a detailed clinical assessment at five visits. We monitored diagnosis change from MDD to BD. The control group consisted of 31 healthy youths. According to the neurodevelopmental and neuroimmunological hypotheses of mood disorders, we analyzed serum levels of brain-derived neurotrophic factor (BDNF), proBDNF, epidermal growth factor (EGF), migration inhibitory factor (MIF), stem cell factor (SCF), and correlations with clinical factors. We detected a significant disease-dependent increase in EGF level in MDD and BP patients at baseline exacerbation of depressive or hypomanic/manic episodes as well as in euthymic state compared to healthy controls. No potential biological predictors of disease conversion were found. Replication studies on a larger cohort of patients are needed.

Expression Biomarkers of Pharmacological Treatment Outcomes in Women with Unipolar and Bipolar Depression.

INTRODUCTION: This study aimed to find the expression biomarkers of pharmacological treatment response in a naturalistic hospital setting. Through gene expression profiling, we were able to find differentially-expressed genes (DEGs) in unipolar (UD) and bipolar (BD) depressed women. METHODS: We performed gene expression profiling in hospitalized women with unipolar (n=24) and bipolar depression (n=32) who achieved clinical improvement after pharmacological treatment (without any restriction). To identify DEGs in peripheral blood mononuclear cells (PBMCs), we used the SurePrint G3 Microarray and GeneSpring software. RESULTS: After pharmacological treatment, UD and BD varied in the number of regulated genes and ontological pathways. Also, the pathways of neurogenesis and synaptic transmission were significantly up-regulated. Our research focused on DEGs with a minimum fold change (FC) of more than 2. For both types of depression, 2 up-regulated genes, OPRM1 and CELF4 (p=0.013), were significantly associated with treatment response (defined as a 50% reduction on the Hamilton Depression Rating Scale [HDRS]). We also uncovered the SHANK3 (p=0.001) gene that is unique for UD and found that the RASGRF1 (p=0.010) gene may be a potential specific biomarker of treatment response for BD. CONCLUSION: Based on transcriptomic profiling, we identified potential expression biomarkers of treatment outcomes for UD and BD. We also proved that the Ras-GEF pathway associated with long-term memory, female stress response, and treatment response modulation in animal studies impacts treatment efficacy in patients with BD. Further studies focused on the outlined genes may help provide predictive markers of treatment outcomes in UD and BD.

30-Day spexin treatment of mice with diet-induced obesity (DIO) and type 2 diabetes (T2DM) increases insulin sensitivity, improves liver functions and metabolic status.

Spexin (SPX) is a 14 aa peptide discovered in 2007 using bioinformatics methods. SPX inhibits food intake and regulates lipid, and carbohydrate metabolism. Here, we evaluate the ability of SPX at improving metabolic control and liver function in obese and type 2 diabetic animals. The effects of 30 days SPX treatment of mice with experimentally induced obesity (DIO) or type 2 diabetes (T2DM) on serum glucose and lipid levels, insulin sensitivity and hormonal profile (insulin, glucagon, adiponectin, leptin, TNF alpha, IL-6 and IL-1ß) are characterized. In addition, alterations of hepatic lipid and glycogen contents are evaluated. We report that SPX decreases body weight in healthy and DIO mice, and reduces lipid content in all three animal groups. SPX improves insulin sensitivity in DIO and T2DM animals. In addition, SPX modulates hormonal and metabolic profile by regulating the concentration of adiponectin (concentration increase) and leptin (concentration decrease) in the serum blood of DIO and T2DM mice. Lastly, SPX decreases lipid content as well as IL-6 and TNF-α protein levels in liver of DIO and T2DM mice, and reduces IL-6 and TNF-alpha concentrations in the serum derived from T2DM mice. Based on our results, we conclude that SPX could be involved in the development of obesity and type 2 diabetes mellitus and it can be further evaluated as a potential target for therapy of DIO and T2DM.