Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

The implication of ADRA2A and AVPRIB gene variants in the aetiology of stress-related bipolar disorder.

OBJECTIVE: Bipolar disorder is a complex and severe mental illness characterised by manic and depressive episodes that can be triggered and exacerbated by psychosocial, environmental, and biological stressors. Genetic variations are a risk factor for bipolar disorder. However, the identification of the exact gene variants and genotypes remains complex. This study, therefore, aims to identify the potential association between genotypes of analysed single nucleotide polymorphisms and the presence of a stressor in bipolar disorder patients. METHOD: We analysed 114 single nucleotide polymorphisms (SNPs) from bipolar and stress-related candidate genes in 550 patients with bipolar disorders (60.36 % females and 39.64 % male). We compared SNPs of patients reporting the presence (40.73 %) or absence of stressors (59.27 %) before the first episode using the Persons Chi-square test and Bayes Factor t-test. The genotyping of 114 SNPs was done using TaqMan assays. Statistical analysis was done using Statistica 13.3 software (StatSoft Poland, Krakow, Poland), R programming, and G*Power statistics. RESULT: We found significant differences in genotype distribution (p < 0.05) in 6 polymorphisms (AVPRIB/rs28536160, FKBP4/rs2968909, ADRA2A/rs3750625, 5HTR2A/rs6311, 5HTR2A/rs6313, and GLCCI1/rs37972) when comparing BD patient with and without stressor with a small effect of d = 0.2. Of these, two gene variants (ADRA2A/rs3750625/AC and AVPRIB/rs28536160/CT) with minor alleles formed an association with the presence of a stressor prior to the disease onset and favoured the alternative hypothesis using Bayes Factor Analysis t-test for hypothesis testing. CONCLUSION: This study presents a novel association of ADRA2A/rs3750625/AC and AVPR1B/rs28536160/CT gene variants in stress-related bipolar disorder with the AC genotype of ADRA2A/rs3750625 constituting a risk genotype and CT of AVPR1B/rs28536160 constituting a protective genotype. However, further functional analysis is required to fully understand their clinical and biological significance and interaction.

Optimizing miRNA transfection for screening in precision cut lung slices.

Precision cut lung slices(PCLS) are complex 3D lung tissue models, which preserve the native microenvironment, including cell diversity and cell-matrix interactions. They are an innovative ex vivo platform that allows studying disease as well as the effects of therapeutic agents or regulatory molecules(e.g. miRNA). The aim of our study was to develop a protocol to transfect PCLS with miRNA using lipid nanoparticles (LNPs) to enable higher throughput screening of miRNA, obviating the need for custom stabilization and internalization approaches. 4mm diameter PCLS were generated using agarose-filled rodent lungs and a vibratome. TYE665 labelled scrambled miRNA was used to evaluate transfection efficacy of six different commercially available LNPs. Transfection efficacy was visualised using live high content fluorescence microscopy, followed by higher resolution confocal fluorescence microscopy in fixed PCLS. Metabolic activity and cellular damage were assessed using WST-1 and lactate dehydrogenase(LDH) release. Using a live staining kit containing a cell membrane impermeant nuclear dye, RedDot2TM, we established that cellular membranes in PCLS are permeable in the initial 24 hours of slicing but diminished thereafter. Therefore, all transfection experiments occurred at least 24 hours after slicing. All six commercially available LNPs enabled transfection without inducing significant cytotoxicity or impaired metabolic function. However, RNAiMAX and INTERFERin led to increases in transfection efficacy as compared to other LNPs, with detection possible as low as 25nM. Therefore, LNP-based transfection of miRNA is possible and can be visualized in live or fixed PCLS, enabling future higher throughput studies using diverse miRNAs.

Validation of Polish-Language Questionnaires for Assessing the Quality of Life of Patients with Primary Ciliary Dyskinesia (PCD-QOL).

In recent years, questionnaires were published in English to assess the quality of life of patients with PCD (Primary Ciliary Diskinesia) for adults, adolescents aged 13-17 years, and children aged 6-12 years and their caregivers. This study aimed to prepare Polish versions of the questionnaires and validate them in specific age groups with the participation of Polish patients with PCD. The individual questionnaires were translated and discussed with the involvement of the creator of the original questionnaire in English. Patients completed the questionnaires according to their affiliation with one of the groups. Validation was based on internal consistency analysis (Cronbach's alpha coefficient and split-half reliability) and test-retest reliability (intraclass correlation coefficient-ICC). The internal consistency of all questionnaires was from moderate to very good (Cronbach's alpha 0.67-0.91, split-half reliability 0.53-0.95). The consistency of the measurements showed excellent repeatability (ICC 0.67-0.91). The surveyed Polish PCD patients rated their quality of life quite well (63-77%). QOL questionnaires for patients with PCD can be used routinely during each medical check-up as a simple tool to provide the doctor with an indication of the effectiveness of treatment and the impact of the disease on the patient's quality of life.

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.

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.

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.

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.