Search

Copyright of Turkish Journal of Hematology is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

¹H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a =healthy' control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans. [ABSTRACT FROM AUTHOR]

The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P=0.0010, odds ratio=1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis.Journal of Human Genetics (2009) 54, 98–107; doi:10.1038/jhg.2008.14; published online 16 January 2009 [ABSTRACT FROM AUTHOR]

Background: Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region. Methods: We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping. Results: Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the SPRY4-FGF1 locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the TGFBI and SMAD5 genes and rs6897690 is within the SPRY4 gene. Conclusion: Our screening of 5q31-32 implicates three potential candidate genes for SZ: SMAD5, TGFBI and SPRY4. [ABSTRACT FROM AUTHOR]

A true revolution in biology and medicine has occurred as a consequence of the recent completion of sequencing the human genome. In previous years, specific biomedical problems had been studied in terms of one gene or protein at a time. We can now study the consequences of any kind of intrusion into the system in terms of simultaneous expression of the ensemble of all genes (genomics) and all proteins (proteomics) at once. As the human genome sequence is being completed, international scaled scientific projects have begun a large-scale collaboration to determine the three-dimensional structure of all proreins and other important biomolecules. These projects, mainly focused on structural genomics, proteomics and molecular design, will provide a basis for modelling how life works in molecular detail, with important applications in medicine and biotechnology. Discovering and application of genomics/ proteomics biomarkers for common diseases is an exciting opportunity for improving the health care for the patients with multi-factorial diseases. Genetic factors give individual predisposition, which plays an important role in the development of the disease, and determine a specific drug response. Revealing of responsible genes for particular disease is prerequisite for identifying of individuals at risk. This approach could be applied for individual health assessment, personalized therapy and specific prophylaxis in a particular disease and for a particular patient. The goal is to provide a technological basis and experience for the discovery of new genes/ proteins markers of common diseases and to design a target-specific computer-aided drug. The achievement of this goal requires introduction and development of new disciplines. structural genomics, clinical proteomics, computationaided methods for simulation of drug-receptor interactions, pharmacogenomics and in silico drug design techniques. The Consortium (BUCOSGIDD) is an exciting, fast-paced and multidisciplinary research unit that brings together the biggest research and educational institutions in Bulgaria. This Consortium multiplies our background and guarantees our potential to achieve the goal of the project. The major aim of the project is revealing large number of genetic markers and proteins, involved in carcinogenesis aside with developing of new tools for evaluation of protein interactions. [ABSTRACT FROM AUTHOR]

One of the best documented Indo-European civilizations that inhabited Bulgaria is the Thracians, who lasted for more than five millennia and whose origin and relationships with other past and present-day populations are debated among researchers. Here we report 25 new complete mitochondrial genomes of ancient individuals coming from three necropolises located in different regions of Bulgaria - Shekerdja mogila, Gabrova mogila and Bereketska mogila - dated to II-III millennium BC. The identified mtDNA haplogroup composition reflects the mitochondrial variability of Western Eurasia. In particular, within the ancient Eurasian genetic landscape, Thracians locate in an intermediate position between Early Neolithic farmers and Late Neolithic-Bronze Age steppe pastoralists, supporting the scenario that the Balkan region has been a link between Eastern Europe and the Mediterranean since the prehistoric time. Spatial Principal Component Analysis (sPCA) performed on Thracian and modern mtDNA sequences, confirms the pattern highlighted on ancient populations, overall indicating that the maternal gene pool of Thracians reflects their central geographical position at the gateway of Europe.

Background: The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the frequency of C9orf72 repeat expansions in a Bulgarian dementia cohort and to delineate the associated clinical features., Methods and Findings: PCR-based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples (including 82 FTD, 37 Alzheimer's disease (AD), and 16 other neurodegenerative/dementia disorder cases) were performed. We report the clinical, neuropsychological, and neuroimaging findings obtained for the C9orf72 repeat expansion carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical AD cases had a C9orf72 repeat expansion. In this cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in two subjects with C9orf72 expansions., Conclusions: This study represents the first genetic screening for C9orf72 repeat expansions in a Bulgarian dementia cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders. This report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions., Competing Interests: The authors have declared that no competing interests exist.

Human papillomavirus (HPV) is a well-known pathogen for lower genital tract neoplasias, yet little is known regarding HPV prevalence in Bulgaria. The aim of this study was to investigate the prevalence of HPV DNA and to determine HPV types distribution among women with normal and abnormal cytology. Cervical smears with different cytological diagnoses were collected from 355 Bulgarian patients. The cohort of patients selected is the biggest ever studied in this country. Using the Roche Linear Array HPV Genotyping Test, papillomavirus DNA was found in 217 out of the 355 samples, 164 of which had only one and 53 had more than one HPV type. The distribution of the viruses tested in 355 samples was as follows: (i) the most common type was HPV 16, which was found in 61 samples; (ii) the next most frequent HPV type was HPV 33, found in 14 of the samples. A high prevalence of HPV infection was observed in this study. As HPV infection has a high correlation with cervical cancer, this study emphasizes the need for both primary prevention of cervical cancer with HPV vaccines as well as secondary prevention with screening. Currently, two HPV vaccines are included in the National immunization schedule in Bulgaria. Thus, new clinical studies will benefit from patient stratification by the presence or absence of HPV, and by designing separate clinical trials specifically for HPV associated cancers., (© 2014 Wiley Periodicals, Inc.)

Background: Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood., Methods: We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions., Results: Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders., Conclusion: Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.

Objective: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population., Methods: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples., Results: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49×10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP., Conclusion: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus.

To better define the structure and origin of the Bulgarian paternal gene pool, we have examined the Y-chromosome variation in 808 Bulgarian males. The analysis was performed by high-resolution genotyping of biallelic markers and by analyzing the STR variation within the most informative haplogroups. We found that the Y-chromosome gene pool in modern Bulgarians is primarily represented by Western Eurasian haplogroups with ∼ 40% belonging to haplogroups E-V13 and I-M423, and 20% to R-M17. Haplogroups common in the Middle East (J and G) and in South Western Asia (R-L23*) occur at frequencies of 19% and 5%, respectively. Haplogroups C, N and Q, distinctive for Altaic and Central Asian Turkic-speaking populations, occur at the negligible frequency of only 1.5%. Principal Component analyses group Bulgarians with European populations, apart from Central Asian Turkic-speaking groups and South Western Asia populations. Within the country, the genetic variation is structured in Western, Central and Eastern Bulgaria indicating that the Balkan Mountains have been permeable to human movements. The lineage analysis provided the following interesting results: (i) R-L23* is present in Eastern Bulgaria since the post glacial period; (ii) haplogroup E-V13 has a Mesolithic age in Bulgaria from where it expanded after the arrival of farming; (iii) haplogroup J-M241 probably reflects the Neolithic westward expansion of farmers from the earliest sites along the Black Sea. On the whole, in light of the most recent historical studies, which indicate a substantial proto-Bulgarian input to the contemporary Bulgarian people, our data suggest that a common paternal ancestry between the proto-Bulgarians and the Altaic and Central Asian Turkic-speaking populations either did not exist or was negligible.

To define the matrilineal relationships between Bulgarians and other European populations, we have evaluated the mitochondrial DNA (mtDNA) variation in a sample of 855 Bulgarian subjects from the mtDNA perspective. The molecular survey was performed by sequencing ∼750 bp of the control region, which resulted in 557 different haplotypes, and by a subsequent restriction fragment length polymorphism analysis to confirm haplogroup/subhaplogroup affiliation. The classification was carried out according to the most updated criteria as reported by van Oven and Kayser (Hum Mutat 30:386-394, 2009), allowing the identification of 45 mitochondrial clades. The observed pattern of mtDNA variation indicates that the Bulgarian mitochondrial pool is geographically homogeneous across the country, and that is characterized by an overall extremely high frequency of western Eurasian lineages. In the principal component analysis, Bulgarians locate in an intermediate position between Eastern European and Mediterranean populations, which is in agreement with historical events. Thus, while the Mediterranean legacy could be attributed to the Thracians, indigenous people that firstly inhabited the Balkans, the Eastern contribution is likely due to the Proto-Bulgarians originating from the Middle East and to the Slavs migrating from northeast Europe.

(1)H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a 'healthy' control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans.

Aims and Background: Angiogenesis is a key process in the early stages of tumor development. In this study we aimed to evaluate the expression of a panel of angiogenesis-related genes in a group of Bulgarian patients with early-stage non-small cell lung cancer (NSCLC)., Methods and Study Design: We analyzed the expression of 84 genes associated with the angiogenic process in 12 NSCLCs of two histological subtypes: 7 adenocarcinomas and 5 squamous cell carcinomas. Eight peripheral nontumorous tissues were used as controls. We performed real-time PCR on pathway-specific gene arrays (SABiosciences)., Results: Our pilot study identified upregulated genes in early-stage NSCLC including growth factors (TGFA and EFNA3), the adhesion molecule THBS2, cytokines and chemokines (MDK, CXCL9, CXCL10), and the serine protease PLAU. Several genes showed downregulation including one growth factor (FIGF), the receptors for growth factors TEK and S1PR1 as well as adhesion molecules (COL4A3 and CDH5), the cytokine IL6, the matrix protein LEP and the transcription factor NOTCH4. The study demonstrated deregulated genes specific for the two histological subtypes including the transcription factor HAND2, which was overexpressed in squamous cell carcinomas but not adenocarcinomas., Conclusions: Despite the limited number of patients, our results demonstrated the potential of angiogenesis-related genes as biomarkers in the early stages of NSCLC development.

Background: Bipolar affective disorder (BAD) is a psychiatric illness characterized by episodes of mania and depression. Although the etiology is not clear, epidemiological studies suggest it is a result of an interaction of genetic and environmental factors. Despite of enormous efforts and abundant studies conducted, none has yet been identified definitively a gene susceptible to bipolar disorder., Methods: Ninety-four Bulgarian patients diagnosed with bipolar disorder and 184 Bulgarian healthy individuals, were used for genotyping of 191 single nucleotide polymorphisms (SNPs) by TaqMan and/or Invader assays. Seventeen SNPs that revealed P value less than 0.05 in the first screening were genotyped using an additional independent set of samples, consisting of 78 BAD cases and 372 controls., Results: After applying the Bonferonni correction on genotyping results of 172 cases and 556 controls, only one SNP, rs1800883, in the HTR5A gene revealed a significant level of P value (P=0.000097; odds ratio=1.80 (95%CI, 1.27-2.54); corrected P=0.017)., Conclusions: Our findings suggest that HTR5A gene could play an important role in the pathogenesis of bipolar disorder in our population. However these findings should be viewed with caution and replication studies in other populations are necessary in support of these findings.

Background: We selected 5 oncogenes with well-established roles in carcinogenesis -- CCND1, ErbB1, ErbB2, c-myc and ZNF217 -- to investigate the coexistence of their copy imbalances in relation to the clinico-pathological characteristics of ovarian tumors., Materials and Methods: Fluorescence in situ hybridization for the 5 genes was applied to a preexisting tissue microarray. 38 ovarian tumors were successfully analyzed for copy number changes of the 5 genes., Results: At least one of these oncogenes was gained/amplified in 27 out of 38 tumors (71.1%). We report the highest frequency of c-myc genetic gain/amplification since it affected 42.1% of the ovarian tumors. We observed sequential involvement of copy number alterations of the other genes in the presence of c-myc disruption. The incidence of copy number changes of the 5 oncogenes -- both single and combinatorial -- was higher in high-grade tumors. All double aberrations in the serous group comprised c-myc and ZNF217copy number increases., Conclusions: Our results revealed a combination between copy number increases of c-myc and ZNF217, associated with serous histology. The data from this combined analysis of the 5 oncogenes could be used as a basis in considering the combined approach in molecular-based therapy of ovarian cancer., (Copyright 2009 S. Karger AG, Basel.)

Background: The purpose of the study was to genotype four polymorphisms in CYP3A5 (CYP3A5*2, CYP3A5*3, CYP3A5*3B, and CYP3A5*6) for a possible association between individual genetic variations and susceptibility to colorectal cancer. Another point of interest was to conduct a comprehensive analysis in tumor and normal intestine tissue from the same patient, searching for somatic hotspots., Material and Methods: In our study, 146 Bulgarian patients with sporadic colorectal cancer and 160 healthy volunteers were enrolled. CYP3A5 polymorphisms were identified using rapid-cycle real-time amplification with allele-specific probes and subsequent melting curve analysis on a LightCycler., Results: The allele frequencies were comparable in both groups: frequency of CYP3A5*2 = 0.3% in patients vs. 0.6% in controls; frequency of CYP3A5*3 = 90.8% in patients vs. 93.1% in controls; in both groups no CYP3A5*3B and CYP3A5*6 variants were detected (p > 0.05). No difference was observed between genotype frequencies in tumor and surrounding normal tissues of 80 patients., Conclusions: The CYP3A5 variants are unlikely to have an important functional significance in patients with colorectal cancer. The studied CYP3A5 loci do not seem to be hotspots for somatic mutation. DNA from archived tumor tissues is a valid alternative to the use of leukocyte DNA for genotyping of these polymorphisms.

Background: Polymorphisms in NAD[P]H:quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs) have been reported to be associated with an increased risk for environmentally and/or occupationally induced renal and bladder cancers. Genetic factors related to chronic nephropathy and to urinary bladder or renal cancer development in Balkan endemic nephropathy (BEN) is unknown. In order to evaluate their possible role in BEN susceptibility, we determined the frequencies of NQO1 alleles *1, *2 and *3, as well as the GSTT1 and GSTM1 null genotypes in BEN patients and healthy subjects from a non-endemic region of Bulgaria., Methods: The respective genotypes of 95 unrelated Bulgarian BEN patients and of 112 healthy individuals (control group) were determined by rapid cycle polymerase chain reaction (PCR) and detected with either SYBR green I fluorescent dye or melting curve analysis using allele specific probes., Results: NQO1 genotyping showed a higher NQO1*2 allele frequency (23.68%) in BEN patients compared to controls (18.75%; p=0.219), while NQO1*3 allele frequencies were similar in both groups (2.63% in BEN patients vs. 2.23% in controls; p=0.791). The GSTT1 deficiencywas observed in 20% of BEN patients vs. 16.1% of controls (p=0.613). The GSTM1 null genotype was found in 45.3% of BEN patients vs. 51.8% of controls (p=0.674). There was no influence of NQO1 and GSTs genotypes found on BEN risk., Conclusions: Our results established that alleles NQO1*2 and NQO1*3, as well as lack of GSTT1 and GSTM1 did not influence the BEN risk. These findings provide novel information on the genetic heterogeneity in the healthy Bulgarian population.

Objective: The aim of our study was to estimate the observed heterozygosity and informativeness of 6 STR markers on chromosomes 18 and 21 in the Bulgarian population. We have evaluated the applicability of these markers used from other investigators for QF-PCR prenatal diagnosis of the most common autosomal aneuploidies in Bulgaria., Methods: DNA samples (n = 486) were extracted from different fetal tissues (amniotic fluid cells, chorionic villus samples, and fetal tissue after abortions). PCR amplifications of 4 STR markers located on chromosome 21 (D21S11, D21S1411, D21S1270, and D21S1440) and 2 on chromosome 18 (D18S535 and D18S51) were performed. They were analysed on an automated sequencer, and the allele dosage ratios were calculated., Results: The results indicate the selected markers as highly informative for our population and suitable for QF-PCR prenatal diagnosis in Bulgaria. All samples with trisomy 21 (n = 8), trisomy 18 (n = 4) and triploidy (n = 1) were correctly detected by our analysis. Thus, no false-negative results were observed., Conclusion: QF-PCR analysis could be an applicable alternative in prenatal and postnatal diagnosis in cases with a strong suspicion for particular autosomal aneuploidies (including chromosomes 21, 18, and 13) in small countries with limited resources like Bulgaria., (Copyright 2004 John Wiley & Sons, Ltd.)

Background: Balkan endemic nephropathy (BEN) is of great clinical importance in restricted areas of Bulgaria, Serbia, Croatia, Bosnia, Herzegovina, and Romania, since the etiology of BEN is still unknown., Methods: In urine samples from 48 patients (41 females and 7 males, aged 65.6 +/- 6.87 years) with BEN living in an endemic area of Vratza district, Bulgaria, neopterin concentrations were measured by high-pressure liquid chromatography (HPLC) and compared with other clinical and laboratory investigations, including creatinine, hemoglobin, and erythrocyte sedimentation rates (ESRs)., Results: Urinary neopterin concentrations were 263 +/- 128 (mean +/- SD; range, 78 to 786 micromol/mol creatinine), 24 (50%) of BEN patients presented with increased concentrations as compared to the established normal ranges. Average ESRs were increased (1 hour, 29.0 +/- 14.7 mm/hour) and hemoglobin was decreased (109.3 +/- 16.4 g/L). Hemoglobin correlated inversely with ESRs (rs = -0.787 and -0.780) and creatinine concentrations (r = -0.690, all P < 0.001), but not with neopterin concentrations. Neopterin concentrations also did not correlate with serum creatinine levels. There existed an age relationship of ESR, creatinine, and hemoglobin, but not of neopterin. Neopterin concentrations were slightly lower in five females with low titers of antibodies against local B1 hantavirus strain (P < 0.05)., Conclusion: The findings can support an immune-mediated inflammatory process in the pathogenesis of BEN only in a subgroup of patients.

Objectives: Cadherins play a critical role in morphogenesis and maintenance of neuronal connections in the adult brain. We examined the gene encoding a member of the non-classic seven-pass transmembrane cadherins, CELSR1 for association with schizophrenia. It maps to chromosome 22q13.31, a region in which evidence for linkage to schizophrenia has been reported. The gene has an unusually large first exon of 3544 nucleotides, which encodes the signal peptide and all nine ectodomains in the protein., Methods: We screened this exon in 24 schizophrenic patients using denaturing high-performance liquid chromatography followed by sequencing. Genotyping of amino-acid changes was performed with primer extension on a sample of 244 Bulgarian schizophrenic patients from 233 families and all their parents, as well as 180 schizophrenic patients from the UK and 157 controls., Results: Three amino-acid changes were identified and shown to be in complete linkage disequilibrium: L556 V, S664W and R1126C. There was no preferential transmission of alleles from heterozygous parents to affected offspring. In the UK population the rare alleles were even more common in controls, and this difference almost reached statistical significance for R1126C (chi2=3.63, P=0.057)., Conclusions: We conclude that variations in the nine ectodomains of CELSR1 do not increase susceptibility to schizophrenia.

Introduction: Overexpression of the receptor Her-2 leads to increased proliferative response to epidermal growth factors which plays a key role in tumor development and growth. Increased oncoprotein level, in the majority of cases, is caused by erbB-2 gene amplification. To define the frequency of amplifications of erbB-2 in bladder cancer, and to determine their association with the tumor phenotype we utilized tissue microarray (TMA) approach., Materials and Methods: We analyzed a TMA consisting of 159 transitional cell bladder carcinomas for erbB-2 gene amplification by dual-color FISH., Results: The frequency of erbB-2 amplification was 5.3% of all successfully analyzed samples (4 of 75). It increased from minimally invasive (pT1) to muscle-invasive (pT2-4) tumors, as well as with advanced tumor grade (G1 to G2 to G3). All amplifications were cluster amplifications confirming the fact that erbB-2 amplification occurs intrachromosomally in bladder cancer., Conclusions: We concluded that despite its low incidence, erbB-2 amplification is of importance for the bladder tumor invasion and progression., (Copyright 2003 S. Karger AG, Basel)