Relationships of cerebrospinal fluid Alzheimer’s disease biomarkers and COMT, DBH, and MAOB single nucleotide polymorphisms

The noradrenergic and dopaminergic systems are affected in Alzheimer's disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called -1021C/T or -970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181, p-tau199, and p-tau231), amyloid-β42 (Aβ42), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n=359). We found 80 single nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI treated patients with major depressive disorder: the MARS (n=253, P=0.0169) and GENDEP studies (n=432, P=0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TF. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

Osjećaj koherentnosti, zdravlje i kvaliteta života adolescenata tijekom srednjoškolskoga obrazovanja [Sense of Coherence, Health and Quality of Life in Adolescents During Secondary Education]

Adolescence is marked by constant adaptation to stressful situations. One of those is the beginning of secondary education and living in dormitories. The aim of the study was to analyze the relationship between sense of coherence, health and subjective well-being among adolescents living with parents and those living in dormitories during their secondary education. The study was conducted on a sample of 441 adolescents. The results did not support the hypothesis that adolescents living in dormitories have a lower sense of coherence, poorer health and a lower quality of life compared to those living with parents as well as that a sense of coherences changes during their secondary education. The hypothesis that a sense of coherence is associated with health and adolescents' quality of life during their secondary education was accepted. Furthermore, subjective quality of life, male gender and mental health singled out as the key adolescents’ sense of coherence predictor during their secondary education. Regardless of their accommodation, it is important to implement health-promoting factors into different areas of adolescent context, especially sense of coherence, so that a better quality of life and adolescents' health are promoted with salutogenic activities

Izražaj cirkulirajućih mikronaRNA (miR-125a, miR-125b, miR-126, miR-99b, miR-let7a) u bolesnika s mijelodisplastičnim sindromom [Expression of circulating microRNA (miR-125a, miR-125b, miR-126, miR-99b, miR-let7a) in myelodysplastic syndrome patients]

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematologic disorders of hematopoietic stem cells, followed by ineffective hematopoiesis of one or more cell lines with the onset of consequent cytopenia with an increased risk of progression to acute myeloid leukemia. According to the World Health Organization classification, the diagnosis of MDS is based on morphological, clinical, cytogenetic, immunophenotypic and biological criteria. In everyday clinical practice, the diagnosis of MDS is based on invasive cytomorphological analysis of peripheral blood and bone marrow cells, determination of blast percent, type and degree of dysplasia, presence of ring sideroblasts, and cytogenetic analysis of bone marrow cells. Micro Messenger Ribonucleic Acids (miRNAs) are short, non-coding molecules of 18 to 25 nucleotides in length that play an important role in regulating cell development and metabolism, their differentiation and proliferation, regulation of the cell cycle and cell death. Tumor cells release miRNAs into the circulation (plasma, serum) where they remain relatively stable. Although their discovery allowed linking of disease and miRNA gene expression, a precondition for their clinical application was the determination of gene expression by real-time quantitative polymerase chain reaction with satisfactory efficacy and specificity. In the literature, gene expression of miRNAs has been linked to the diagnosis, classification and progression of various diseases. Many studies have been conducted so far about the molecular mechanisms and epigenetic pathways in MDS and their prognostic and therapeutic significance, but few studies have analyzed the importance of miRNAs in MDS. The aim of this study was to examine the level of change of gene expression of specific mRNAs (miR-125a, miR-99b, miR-126, miR-125b, miR-let-7a) in plasma of healthy volunteers and subjects diagnosed with MDS. Gene expression of these specific mRNAs was determined in plasma samples from healthy volunteers (18) and subjects with MDS (41). This paper describes for the first time the expression of a selected miRNA cluster (125a, 125b, 99b, let-7a) in the plasma of untreated MDS patients. A significant difference was found between the study group and healthy control in miR-99b level, where at normalized values relative to miR-126, an increased level in subjects compared to control was observed 4,521 times (P = 0.004). Diagnostic and prognostic significance of miR-125a was observed and correlated negatively with erythrocyte count and hemoglobin level in the diagnosis of MDS.The results of the study suggest that gene expression of miRNA (125a, 125b, 99b, let7a) could be regulated by the same mechanism and may be clinically relevant in subjects with MDS

Anatomska podjela subtalamičke jezgre [Anatomical subdivison of the subthalamic nucleus]

Subthalamic nucleus is one of the most interesting structures of basal ganglia. Neurosurgical stimulation of STN has improved condition of many patients with levodopa resistant Parkinson’s disease. However, it also led to many unwanted side-effects due to the inconclusive delineation of STN segments’ borders. Previous studies which dealt with this topic did not produce definite answer about number and location of STN segments. In this study we analyzed the distribution of five neuronal markers in the STN: NeuN, calretinin, calbindin, parvalbumin and nNOS. All markers were positive in STN except calbindin. The largest population of neurons in STN is positive for nNOS, and the smallest population is calretinin positive. By analyzing the spatial distribution of neurons in STN we could not determine the borders between segments nor any individual segments in STN. Furthermore, we analyzed 1,5 and 3T MR images to determine STN segments. We were not able to determine any segments on these images. However, we analyzed the precision of DBS electrode location in the STN and based on these data we created “virtual” motor segment of STN. The stimulation within these “virtual segment” provided satisfactory clinical results in controlling symptoms of Parkinson’s disease

Use of pharmacogenomics in elderly patients treated for cardiovascular diseases

Older people are increasingly susceptible to adverse drug reactions (ADRs) or therapeutic failure. This could be mediated by considerable polypharmacy, which increases the possibility of drug-drug and drug-gene interactions. Precision medicine, based on individual genetic variations, enables the screening of patients at risk for ADRs and the implementation of personalized treatment regimens. It combines genetic and genomic data with environmental and clinical factors in order to tailor prevention and disease-management strategies, including pharmacotherapy. The identification of genetic factors that influence drug absorption, distribution, metabolism, excretion, and action at the drug target level allows individualized therapy. Positive pharmacogenomic findings have been reported for the majority of cardiovascular drugs (CVD), suggesting that pre-emptive testing can improve efficacy and minimize the toxicity risk. Gene variants related to drug metabolism and transport variability or pharmacodynamics of major CVD have been translated into dosing recommendations. Pharmacogenetics consortia have issued guidelines for oral anticoagulants, antiplatelet agents, statins, and some beta-blockers. Since the majority of pharmacogenetics recommendations are based on the assessment of single drug-gene interactions, it is imperative to develop tools for the prediction of multiple drug-drug-gene interactions, which are common in the elderly with comorbidity. The availability of genomic testing has grown, but its clinical application is still insufficient