Cancer Incidence Trends in the Oil Shale Industrial Region in Estonia.

Large oil shale resources are found in Eastern Estonia, where the mineral resource is mined, excavated, and used for electricity generation and shale oil extraction. During industrial activities in the last 100 years, pollutants have been emitted in large amounts, some of which are toxic and carcinogenic. The current study aims to analyse time trends in cancer incidence in the oil shale industry-affected areas and compare them with overall cancer incidence rates and trends in Estonia. We analysed Estonian Cancer Registry data on selected cancer sites that have been previously indicated to have relationships with industrial activities like oil shale extraction. We included lung cancer, kidney cancer, urinary bladder cancer, leukaemia, breast cancer, and non-Hodgkin's lymphoma. A statistically significantly higher lung cancer age-standardized incidence rate (ASIR) was found during the study period (1992-2015) only in males in the oil shale areas as compared to males in Estonia overall: 133.6 and 95.5 per 100,000, respectively. However, there appeared to be a statistically significant (p < 0.05) decrease in the lung cancer ASIR in males in the oil shale areas (overall decrease 28.9%), whereas at the same time, there was a significant increase (p < 0.05) in non-oil shale areas (13.3%) and in Estonia overall (1.5%). Other cancer sites did not show higher ASIRs in the oil shale industrial areas compared to other areas in Estonia. Possible explanations could be improved environmental quality, socio-economic factors, and other morbidities.

Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first-episode psychosis patients: A 7-month follow-up study.

AIM: Second-generation antipsychotics are commonly used to treat schizophrenia, but may cause metabolic syndrome (MetS) in a subset of patients. The mechanisms of antipsychotic-related metabolic changes remain to be established, especially in first-episode psychosis (FEP) patients. METHODS: In the present study, we used a chip technology to measure metabolic (C-peptide, insulin, leptin, adiponectin and resistin) and inflammatory biomarkers (ferritin, interleukin-6, interleukin-1α, tumour necrosis factor-α and plasminogen activator inhibitor-1) in the serum samples of a population of FEP patients before and after 7 months of antipsychotic drug treatment, compared to control subjects (CS). RESULTS: The comparison of these markers in antipsychotic-naïve FEP patients (N = 38) and CS (N = 37) revealed significantly higher levels of ferritin (P = .004), and resistin (P = .03) and lower level of leptin (P = .03) among FEP patients group. Seven months of antipsychotic drug treatment in patients (N = 36) ameliorated clinical symptoms, but increased significantly body mass index (BMI; P = .002) and these changes were accompanied by increased levels of C-peptide (P = .03) and leptin (P = .02), as well as decreased level of adiponectin (P = .01). CONCLUSIONS: Seven months of antipsychotic drug treatment suppressed the clinical symptoms of psychosis whereas caused imbalance in metabolic biomarkers and increased BMI. These findings provide insight into antipsychotic-induced MetS and refer to problems in insulin processing already present in the early stage of the chronic psychotic disorder.

Residents' Self-Reported Health Effects and Annoyance in Relation to Air Pollution Exposure in an Industrial Area in Eastern-Estonia.

Eastern Estonia has large oil shale mines and industrial facilities mainly focused on electricity generation from oil shale and shale oil extraction, which produce high air pollution emissions. The "Study of the health impact of the oil shale sector-SOHOS" was aimed at identifying the impacts on residents' health and annoyance due to the industrial processing. First, a population-wide survey about health effects and annoyance was carried out. Second, the total and oil shale sectors' emitted concentrations of benzene, phenol, and PM2.5 were modelled. Third, the differences between groups were tested and relationships between health effects and environmental pollution studied using multiple regression analysis. Compared to the control groups from non-industrial areas in Tartu or Lääne-Viru, residents of Ida-Viru more frequently (p < 0.05) reported wheezing, chest tightness, shortness of breath, asthma attacks, a long-term cough, hypertension, heart diseases, myocardial infarction, stroke, and diabetes. All health effects except asthma were reported more frequently among non-Estonians. People living in regions with higher levels of PM2.5, had significantly higher odds (p < 0.05) of experiencing chest tightness (OR = 1.13, 95% CI 1.02-1.26), shortness of breath (1.16, 1.03-1.31) or an asthma attack (1.22, 1.04-1.42) during the previous year. People living in regions with higher levels of benzene had higher odds of experiencing myocardial infarction (1.98, 1.11-3.53) and with higher levels of phenol chest tightness (1.44, 1.03-2.00), long-term cough (1.48, 1.06-2.07) and myocardial infarction (2.17, 1.23-3.83). The prevalence of adverse health effects was also higher among those who had been working in the oil shale sector. Next to direct health effects, up to a quarter of the residents of Ida-Viru County were highly annoyed about air pollution. Perceived health risk from air pollution increased the odds of being annoyed. Annoyed people in Ida-Viru had significantly higher odds of experiencing respiratory symptoms during the last 12 months, e.g., wheezing (2.30, 1.31-4.04), chest tightness (2.88, 1.91-4.33 or attack of coughing (1.99, 1.34-2.95).

Gene expression patterns and environmental enrichment-induced effects in the hippocampi of mice suggest importance of Lsamp in plasticity.

Limbic system associated membrane protein (Lsamp) gene is involved in behavioral adaptation in social and anxiogenic environments and has been associated with a broad spectrum of psychiatric diseases. Here we studied the activity of alternative promoters of Lsamp gene in mice in three rearing conditions (standard housing, environmental enrichment and social isolation) and in two different genetic backgrounds (129S6/SvEv and C57BL/6). Isolation had no effect on the expression levels of Lsamp. Environmental enrichment elevated the expression levels of Lsamp 1b transcript specifically in the hippocampus in B6 mice, and the same tendency existed across both mouse lines and both transcripts. Furthermore, we showed that the density of cells exhibiting 1b promoter activity is remarkably higher in the subgranular zone of the dentate gyrus in the hippocampal formation which is a specific area of enrichment-induced neurogenesis in adult rodents. On the contrary to 1b, 1a promoter is selectively active in the pyramidal and granule cell layers. We provide evidence that Lsamp modulates enrichment-induced activation of Bdnf as the enrichment-induced elevation of Bdnf in the hippocampus is significantly diminished in Lsamp-deficient mice; furthermore, a significant correlation was found between the expression levels of Lsamp and Bdnf transcripts in the hippocampus and frontal cortex. Significant strain differences in Lsamp expression were detected in the hippocampus, frontal cortex and thalamus that could be related to the different behavioral phenotype of B6 and 129Sv mice. Our data provides further evidence that LSAMP is implicated in the hippocampal connectivity and plasticity thereby modulating adaptability in changing environments.

Variation in tryptophan hydroxylase-2 gene is not associated to male completed suicide in Estonian population.

Dysfunction of the central serotonergic system has been related to a spectrum of psychiatric disorders, including suicidal behavior. Tryptophan hydroxylase isoform 2 (TPH2) is the rate-limiting enzyme in the biosynthetic pathway of serotonin, being expressed in serotonergic neurons of raphe nuclei. We investigated genetic variation in TPH2 gene in two samples of male subjects: 288 suicide completers and 327 volunteers, in order to reveal any associations between 14 single nucleotide polymorphisms and completed suicide. No associations were revealed neither on allelic nor haplotype level. Our finding does not support the hypothesis of TPH2 being a susceptibility factor for completed suicide in males of Estonian origin.

Common variations in 4p locus are related to male completed suicide.

Suicidal behavior is a multifactorial phenomenon, with a significant genetic predisposition. To assess the contribution of genes in the 4p region to suicide risk, we genotyped 36 single nucleotide polymorphisms from a 49Mb region on the chromosome arm 4p11-16 in a total of 288 male suicide victims and 327 healthy male volunteers. The nonsynonymous variants rs1383180 in EVC gene, rs6811863 in TBC1D1 gene, rs362272 in HTT gene, and rs734312 in WFS1 gene were associated to the male completed suicide. However, only EVC polymorphism remained significant after correcting for multiple comparisons (P < .05 after 10 K permutations). The function of these genes is not clear yet. WFS1 and HTT are related to the unfolded protein response and endoplasmic reticulum stress, and TBC1D1 is a GTPase activator. EVC is a protein with transmembrane and leucine zipper domains, its function has not been elucidated yet. Further studies are required in order to reveal the role of these four polymorphisms in the pathoetiology of suicide.

Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers.

Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 +/- 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A -1019C-G, 5-HTR2A 102T-C, CCKR1 246G-A, CCKR2 -215C-A, DRD1 -94G-A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.

Association of limbic system-associated membrane protein (LSAMP) to male completed suicide.

BACKGROUND: Neuroimaging studies have demonstrated volumetric abnormalities in limbic structures of suicide victims. The morphological changes might be caused by some inherited neurodevelopmental defect, such as failure to form proper axonal connections due to genetically determined dysfunction of neurite guidance molecules. Limbic system-associated membrane protein (LSAMP) is a neuronal adhesive molecule, preferentially expressed in developing limbic system neuronal dendrites and somata. Some evidence for the association between LSAMP gene and behavior has come from both animal as well as human studies but further investigation is required. In current study, polymorphic loci in human LSAMP gene were examined in order to reveal any associations between genetic variation in LSAMP and suicidal behaviour. METHODS: DNA was obtained from 288 male suicide victims and 327 healthy male volunteers. Thirty SNPs from LSAMP gene and adjacent region were selected by Tagger algorithm implemented in Haploview 3.32. Genotyping was performed using the SNPlex (Applied Biosystems) platform. Data was analyzed by Genemapper 3.7, Haploview 3.32 and SPSS 13.0. RESULTS: Chi square test revealed four allelic variants (rs2918215, rs2918213, rs9874470 and rs4821129) located in the intronic region of the gene to be associated with suicide, major alleles being overrepresented in suicide group. However, the associations did not survive multiple correction test. Defining the haplotype blocks using confidence interval algorithm implemented in Haploview 3.32, we failed to detect any associated haplotypes. CONCLUSION: Despite a considerable amount of investigation on the nature of suicidal behaviour, its aetiology and pathogenesis remain unknown. This study examined the variability in LSAMP gene in relation to completed suicide. Our results indicate that LSAMP might play a role in pathoaetiology of suicidal behaviour but further studies are needed to understand its exact contribution.

Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder.

Experimental studies on serotonin (5-HT) availability suggest a role for 5-HT synthesis rate in panicogenesis. Recently, it has been discovered that the tryptophan hydroxylase gene isoform 2 (TPH2), rather than TPH1, is preferentially expressed in the neuronal tissue and, therefore, is primarily responsible for the regulation of brain 5-HT synthesis. In the present case-control genetic association study we investigated whether panic disorder (PD) phenotypes are related to two single nucleotide polymorphisms (SNP) of TPH2, rs1386494 A/G and rs1386483 C/T. The study sample consisted of 213 (163 females and 50 males) PD patients with or without affective comorbidity and 303 (212 females and 91 males) matched healthy control subjects. The allelic and genotypic analyses in the total sample did not demonstrate significant association of PD with the studied SNPs, suggesting that these polymorphisms may not play a robust role in predisposition to PD. However, an association with rs1386494 SNP was observed in the subgroup of female patients with pure PD phenotype, indicating a possible gender-specific effect of TPH2 gene variants in PD.

Associations between serotonin-related gene polymorphisms and panic disorder.

Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD.

Litter has an effect on the behavioural changes caused by the administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine and ethanol in mice.

The aim of the work was to study the effects of litter and the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) on the behaviour of mice after acute and chronic ethanol administration and withdrawal. Male outbred NIH/S mice, from 21 litters, were distributed among experimental groups and subjected to acute and chronic ethanol administration. After acute or chronic ethanol administration, the effects of L-NOARG on the behaviour of mice in the plus-maze test were studied. Acute ethanol (1 g/kg, i.p.), L-NOARG (20 and 40 mg/kg, i.p.) and their combination induced an anxiolytic effect. Furthermore, the values for the representatives of different litters tended to be either above or below the group mean, irrespective of the drug treatment. Chronic ethanol administration (23 days by inhalation) induced an anxiolytic effect and ethanol withdrawal induced an anxiogenic effect in the plus-maze. The administration of L-NOARG (20 mg/kg, i.p.) induced an anxiolytic effect in control mice and had no effect on ethanol-intoxicated mice, but attenuated the anxiogenic effect of ethanol withdrawal in the plus-maze. However, after chronic ethanol administration and withdrawal, litter had no effect on the behaviour of mice. If the litter is a significant determinant in the behaviour of outbred mice, then the use of information about the litter origin of animals could serve for the purposes of reduction. But only if this information is available from breeders.

Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers.

Genetic regulation of the function of serotonin (5-HT) may be important for the neurobiology of panic disorder. In order to evaluate the influence of 5-HT-related gene variants on the vulnerability to panic attacks, we genotyped 32 healthy volunteers who participated in the study of the effect of 5-hydroxytryptophan on panic attacks induced with cholecystokinin tetrapeptide (CCK-4). The polymorphisms of interest included those of 5-HT transporter (5-HTTLPR) and monoamine oxidase A (MAO-A promoter region) genes. The results showed significant associations between certain genotypes and panic rate in females but not in male volunteers. Specifically, there was a significantly lower rate of CCK-4-induced panic attacks in female subjects who had MAO-A longer alleles or 5-HTTLPR short allele gene variants. These data suggest that functional genetic polymorphisms of the 5-HT system may influence the vulnerability to panic attacks and add to the growing evidence of inhibitory function of 5-HT in the neuronal circuitry of panic.