The experience with colorectal cancer screening in the Czech Republic: the detection at earlier stages and improved clinical outcomes.

OBJECTIVES: Colorectal cancer (CRC) remains a major health burden. Although screening is recommended and considered beneficial, further data on its positive effects are needed for worldwide implementation. STUDY DESIGN: The aim of our national multicentre prospective observational study was to reveal and document clinicopathological differences in CRC diagnosed by screening and presented by disease symptoms as well as assess the efficiency of the screening programme in the Czech Republic. METHODS: Between March 2013 and September 2015, a total of 265 patients were enrolled in 12 gastroenterology centres across the Czech Republic. Patients were divided into screening and symptomatic groups and compared for pathology status and clinical characteristics. Screening was defined as a primary screening colonoscopy or a colonoscopy after a positive faecal occult blood test in an average-risk population. RESULTS: The distribution of CRC stages was significantly (statistically and clinically) favourable in the screening group (predominance of stages 0, I and II) compared with the non-screening group (P < 0.001). The presence of distant and local metastases was significantly less frequent in the screening group than in the symptomatic group (P < 0.001). Patients in the screening group had a higher probability of radical surgery (R0) than those diagnosed based on symptoms (P < 0.001). Systemic palliative treatment was indicated in two patients in the screening group compared with 23 patients in the non-screening group (P = 0.018). CONCLUSION: CRC diagnosed by screening disclosed less advanced clinicopathological characteristics and results in patients with a higher probability of radical surgery (R0) than diagnoses established based on symptoms, with subsequent management differing accordingly between both groups. These results advocate the implementation of a suitable worldwide screening programme.

The Potassium Channel Kv1.5 Expression Alters During Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.

Genetic differentiation of Liparus glabrirostris (Curculionidae: Molytinae) populations from the fragmented habitats of the Alps and Carpathian Mountains.

Populations of Liparus glabrirostris (Curculionidae: Molytinae), a weevil inhabiting higher altitudes of Central Europe, were sampled from 24 localities in the Alps and Carpathian Mountains, and the geographical structuring of genetic variation was analyzed. Comparison of the concatenated mitochondrial cytochrome oxidase subunit I and subunit II sequences revealed consistent genetic divergence between the populations of L. glabrirostris from different mountain ranges. In phylogenetic analysis using maximum parsimony and median-joining networks, concatenated mitochondrial haplotypes from the Alps and Carpathians clustered as separate lineages, with high bootstrap support. Substantial genetic distances determined between the separated groups ranged from 2.6 to 3.0%, with divergence estimated to have initiated approximately 0.85-0.98 million years ago. The nuclear elongation factor 1α gene was additionally amplified and haplotype analysis showed very low evolutionary divergence (0.2%), with separate clustering as well. The observed divergence suggests that the populations have been isolated for a long time, as a consequence of environmental changes resulting in varying fragmentation of habitats in the Alps and Carpathians, interrupting genetic exchange events and altering the genetic structure of L. glabrirostris populations. On the other hand, comparison of morphological characteristics showed no differences to confirm genetically well differentiated groups of populations. A polymerase chain reaction and restriction fragment length polymorphism-based method was therefore developed to discriminate between the Alpine and Carpathian lineages.

First Report of Alder Yellows Phytoplasma Associated with Common Alder (Alnus glutinosa) in the Republic of Macedonia.

Alder yellows phytoplasma (AldYp) is classified as a member of the 16SrV-group of phytoplasmas and is closely related to Flavescence dorée (FD), a quarantined pathogen of economic importance affecting vineyards across Europe. AldYp is associated with common (Alnus glutinosa) and grey alder (A. incana), and has been reported in France, Italy, Germany, Austria, Switzerland, the Baltic region, Serbia, and Montenegro (1,2,4). For Macedonian vineyards, so far, neither infection of grapevine with 16SrV-group of phytoplasmas nor the presence of the main FD phytoplasma vector, Scaphoideus titanus, has been recorded. However, the presence of FD-related phytoplasma was detected in wild Clematis vitalba. In September and October 2013, leaves with petioles from A. glutinosa exhibiting leaf discoloration and yellowing were collected from two sites (41°23'43″ N, 22°54' E and 41°23' N, 22°53' E) in southeast Macedonia near the village of Smolare (Strumica district). Eight samples were collected from each site. Leaves of six asymptomatic alder seedlings collected from the same sites served as a control. Nucleic acids were extracted from fresh leaf midribs and petioles using a DNeasy Plant Mini Kit (Qiagen, Hilden, Germany). Initial phytoplasma identification was carried out by nested PCR assay of the 16S rRNA gene, using universal primers P1/P7 and R16F2n/R16R2 followed by RFLP with MseI endonuclease (Fermentas, Vilnius, Lithuania), as previously reported (4). Characterization of detected phytoplasmas was performed by amplifying two genetic loci specific for the members of the 16SrV group phytoplasmas; the ribosomal protein gene operon (rp) using primers rp(V)F1/rpR1 and rp(V)F1A/rp(V)R1A (3), and the non-ribosomal metionine aminopeptidase (map) gene using primer set FD9f5/MAPr1 and FD9f6/MAPr2 (1). The PCR amplicons were sequenced and deposited in NCBI GenBank database under the accession numbers KJ605448 to 52 (map) and KJ605453 to 57 (rp). The obtained sequences were compared with reference sequences of the 16SrV-group phytoplasmas (1,3) using the neighbor-joining method in MEGA5 (5). The presence of phytoplasma was detected in 14 of 16 symptomatic alder samples, while all control plants tested negative. The MseI restriction profiles were identical among all 14 samples and with the reference strains of the 16SrV group phytoplasmas (EY1 - 16SrV-A, FD-C - 16SrV-C, and FD-D - 16SrV-D). The rp-based phylogeny enabled identification of four diverse phytoplasma strains among the AldYp strains from Macedonia. Three strains clustered within the rpV-E subgroup while one belonged to rpV-L subgroup. Phylogenetic analysis of the more variable genetic locus, map, showed the presence of five diverse phytoplasma strains. Four strains belonged to the map-FD2 (FD-D, FD92) cluster, while one grouped within the map-FD1 (FD70) cluster. To our knowledge, this is the first report of 16SrV phytoplasma group occurrence on alder in Macedonia. The significant similarity between AldYp strains and FD sensu stricto indicate the risk of pathogen exchange between the wild ecosystem and the grapevine (1). Alder trees naturally infected with the FDp-related strains could therefore represent a serious risk for FD outbreak in Macedonian vineyards if local S. titanus populations developed. References: (1) G. Arnaud et al. Appl. Environ. Microbiol. 73:4001, 2007. (2) T. Cvrkovic et al. Plant Pathol. 57:773, 2008. (3) M. Martini et al. Int. J. Syst. Evol. Microbiol. 57:2037, 2007. (4) S. Radonjic et al. Plant Dis. 97:686, 2013. (5) K. Tamura et al. Mol. Biol. Evol. 28:2731, 2011.

Predicting depression with temperament and character in lung cancer patients.

Depression is highly prevalent in cancer patients. Variations in intensity and frequency of depression in cancer patients may be attributed, in part, to differences in personality dimensions. Our aim was to asses if dimensions of temperament and character could predict depression in lung cancer patients. Ninety newly diagnosed non-small cell lung cancer patients were assessed in the oncology unit with the Centre for Epidemiologic Studies Depression Scale (CES-D), pain subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the Temperament and Character Inventory (TCI). Fifty out of 90 patients (55.6%) fulfilled the cut-off criteria for depression on the CES-D scale. Logistic regression performed to assess if depression was predicted by personality dimensions, revealed dimension of temperament Harm Avoidance and pain as significant predictors of depression. Depressive reactions are highly prevalent in lung cancer patients and related to patients' personality. These findings may be helpful in planning preventive, as well as psychoeducational and treatment programmes for newly diagnosed, and depression prone patients.

Validation of a patient satisfaction questionnaire in primary health care.

BACKGROUND: Improvement in patient satisfaction with healthcare services can be evaluated by satisfaction questionnaires of high construct validity. OBJECTIVES: To establish the dimensions and construct validity of a 20-item patient satisfaction questionnaire to assess satisfaction with general practice services. SUBJECTS: In total, 1314 adult patients of both genders, who were users of healthcare services at the General Medicine Department of Health Centre Valjevo in Serbia for two consecutive years, were included in the study. METHODS: Multidimensional scaling (MDS) was employed to identify similarities and dissimilarities among items comprising the satisfaction questionnaire. Patient satisfaction dimensions were estimated by principal component analysis for categorical data (CATAPCA). RESULTS: The MDS model configuration derived two dimensions: (1) patient satisfaction with the timeliness of healthcare service provision; and (2) patient centredness related to doctors' and nurses' commitment towards their health. In the CATAPCA model, two dimensions of patient satisfaction were found: the first dimension patient satisfaction with medical staff and the second dimension was indicative of contextual patient dissatisfaction. CONCLUSIONS: This study shows that the applied patient satisfaction questionnaire has high validity and reliability. It also has high sensitivity for longitudinal measurements, as well as good discriminatory power in measuring the different levels of patient satisfaction.

The effects of olanzapine and fluphenazine on plasma cortisol, prolactin and muscle rigidity in schizophrenic patients: a double blind study.

Pharmacotherapy of schizophrenia is associated with the stressful side effects. Muscle rigidity causes distress, discomfort and poor compliance. The aim of the study was to determine the relationship between plasma hormones (cortisol and prolactin/PRL) and muscle rigidity in female schizophrenic patients treated with olanzapine or fluphenazine. In a randomized, double-blind 22-weeks study, 12 patients were treated with olanzapine (5-20 mg/day) and 10 patients received fluphenazine (6-21 mg/day). Treatment with olanzapine moderately decreased, while treatment with fluphenazine significantly increased plasma cortisol levels and muscle rigidity. The marked and moderate increase in plasma PRL levels were found in patients treated with fluphenazine and olanzapine, respectively. The results suggested that olanzapine induced moderate neuroendocrine effects and a reduction in rigidity as compared to fluphenazine treatment.

Chronic physical illnesses in patients with schizophrenia spectrum disorders are independently associated with higher rates of psychiatric rehospitalization; a cross-sectional study in Croatia.

BACKGROUND: Increased physical morbidity in patients with schizophrenia spectrum disorders (SSDs) is well documented. However, much less is known about the association between somatic comorbidities and psychosis treatment outcomes. SUBJECTS AND METHODS: This cross-sectional study, nested within the larger frame of a prospective cohort study, was done in 2016 at Psychiatric Hospital Sveti Ivan, Zagreb, Croatia. Data were collected on a consecutive sample of 301 patients diagnosed with schizophrenia spectrum disorders who achieved a stable therapeutic dosage. Key outcome was the number of psychiatric rehospitalizations since diagnosis of the primary psychiatric illness. Predictors were number of physical and psychiatric comorbidities. By robust regression, we controlled different clinical, sociodemographic, and lifestyle confounding factors. RESULTS: The number of chronic somatic comorbidities was statistically significantly associated with a larger number of psychiatric rehospitalizations, even after the adjustment for number of psychiatric comorbidities and large number of other clinical, sociodemographic, and lifestyle variables. CONCLUSIONS: Chronic somatic comorbidities are associated with higher rates of psychiatric rehospitalization independently of psychiatric comorbidities and other clinical, sociodemographic, and lifestyle factors. Therefore, to treat psychosis effectively, it may be necessary to treat chronic somatic comorbidities promptly and adequately. Chronic somatic comorbidities should be considered equally important as the SSD, and should be brought to the forefront of psychiatric treatment and research with the SSD as one entity. The integrative approach should be the imperative in clinical practice.

Time course of schizophrenia and platelet 5-HT level.

The concentration of platelet serotonin (5-HT) and the simultaneous uptake of 5-HT into platelets have been investigated in schizophrenic patients with (A) intermittent time course of illness (complete remission), (B) chronic time course (partial remission and residual symptoms), and (C) intermittent-chronic time course (good remission at the beginning of illness with gradual progression to chronic stage). An increased platelet 5-HT concentration (i.e., hyperserotoninemia) of unknown etiology was observed, especially in the group with chronic time course of disease as compared to the normal controls. At the same time, kinetic constants Km and Vmax of 5-HT uptake into platelets were unchanged in all patients. Neuroleptic treatment did not produce any significant change either in platelet 5-HT level or in the uptake of 5-HT. These results provide further support for the possible 5-HT dysfunction in schizophrenia.

Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients.

BACKGROUND: Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis activity. Abnormal response to the dexamethasone suppression test (DST) and altered platelet 5-HT concentration have been shown in some schizophrenic patients. METHODS: Platelet 5-HT and plasma cortisol concentrations were determined simultaneously in 86 male schizophrenic patients before and after DST. Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy male persons. RESULTS: Schizophrenic patients had higher plasma cortisol and platelet 5-HT concentrations than healthy persons. An abnormal escape from dexamethasone suppression was observed in 50% of patients. In these patients predexamethasone cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. CONCLUSIONS: This study demonstrates that schizophrenic patients have the HPA axis dysregulation that could be connected with a disturbance in the 5-HT system.

Seasonal influence on platelet 5-HT levels in patients with recurrent major depression and schizophrenia.

The influence of seasons on platelet serotonin (5-HT) concentration was determined in 88 unipolar depressed and 117 schizophrenic male inpatients, and 90 normal male controls. Platelet 5-HT concentrations showed moderate, but insignificant intragroup seasonal variations in healthy controls and in the groups of depressed (psychotic and nonpsychotic) and schizophrenic (positive and negative) patients. In spring, platelet 5-HT concentrations were higher in schizophrenic patients than in normal controls or in depressed patients, while in other seasons platelet 5-HT concentrations were not significantly different between the groups. Higher platelet 5-HT concentrations were detected in psychotic when compared to nonpsychotic depressed patients in summer, fall, and winter. Increased platelet 5-HT concentrations observed in schizophrenic patients with positive symptoms clearly separated these patients from patients with negative schizophrenia, especially in spring, summer, and fall. Our results indicate the necessity to match patients with regard to the season of the sampling, and to divide depressed and schizophrenic patients into subtypes.

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients.

We selected 83 patients with bipolar disorder type I or unipolar recurrent major depression and 71 healthy controls for genetic analysis of the tyrosine hydroxylase and the dopamine D4 receptor gene. No significant association was found between bipolar disorder type I and unipolar recurrent major depression and the polymorphisms located near these genes. Therefore, the hypothesis that the tyrosine hydroxylase and the dopamine D4 receptor genes may be involved in the etiology of bipolar disorder and unipolar recurrent major depression is not supported in our study.

Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.

We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes. No significant associations were found in the total patient sample. However, when the individuals were divided according to gender, trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P = 0.049 for 5-HTT) in female patients were observed. These results suggest that variations in these genes may be responsible for a minor increase in susceptibility for bipolar disorder in women.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder.

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

European Collaborative Project on Affective Disorders: interactions between genetic and psychosocial vulnerability factors.

Despite strong evidence provided by genetic epidemiology of genetic involvement in the aetiology of bipolar and unipolar affective disorders, the exact nature of the predisposing gene(s) is still being investigated through linkage and association studies. The interaction of susceptibility genes and environmental factors in these diseases is also of fundamental importance and requires proper investigation. Interesting theories have recently been proposed examining the possible role of various chromosomal regions, candidate genes and mutations in affective disorders. Reliable multicentre-based methodology is currently being employed to examine these theories, with attention given to statistical analysis and the statistical power of the sample. The present article describes the European Collaborative Project on Affective Disorders (ECPAD) 'Interactions between genetic and psychosocial vulnerability factors', involving 15 European centres. A description is given of the association and family samples collected for the project and also the methodology used to analyse interactions in the gene-psychosocial environment. This material provides a powerful tool in the search for susceptibility genes in affective disorders and takes into account non-genetic aetiological factors.

Effect of antidepressant treatment on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive patients.

Platelet 5-HT levels and scores on the 17-item Hamilton Rating Scale for Depression (HRS) were studied in patients with unipolar depression before and after antidepressant treatment. Before treatment there were no differences in platelet 5-HT values or in HRS scores between patients who showed a good and a poor therapeutic response. Repeated administration of 5-HT uptake inhibitors (amitriptyline, clovoxamine, fluvoxamine) for 28 days markedly decreased platelet 5-HT levels. Chronic treatment with trazodone or maprotiline (weak inhibitors of platelet 5-HT uptake) produced no changes in platelet 5-HT levels. No significant correlation was observed between platelet 5-HT concentrations and the HRS scores before or during treatment. The findings suggest that the changes in platelet 5-HT levels after antidepressant treatment are mainly due to the effects of antidepressants on the 5-HT uptake system.