Abdullah Çim

Increased Caspase-3 Immunoreactivity of Erythrocytes in STZ Diabetic Rats

Eryptosis is a term to define apoptosis of erythrocytes. Oxidative stress and hyperglycemia, both of which exist in the diabetic intravascular environment, can trigger eryptosis of erythrocytes. In this experimental study, it is presented that the majority of erythrocytes shows caspase-3 immunoreactivity in streptozocin- (STZ)-induced diabetic rats. Besides that, caspase-3 positive erythrocytes are aggregated and attached to vascular endothelium. In conclusion, these results may start a debate that eryptosis could have a role in the diabetic complications.

Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder

Vitamin D is implicated in several aspects of human physiology, and polymorphisms in the vitamin D receptor gene (VDR) are associated with a variety of neuropsychiatric disorders. The aims of this study are to determine whether VDR polymorphisms are associated with autism spectrum disorder (ASD), to examine serum 25-hydroxyvitamin D (25(OH)D) levels in ASD, and to explore whether VDR polymorphisms influence serum 25(OH)D levels. We investigated 480 subjects (237 children with ASD and 243 healthy controls) for the following VDR polymorphisms: TaqI, BsmI, FokI, ApaI, and Cdx2.Within the same samples, 25(OH)D levels were available only for 85 patients and 82 controls. The Cdx-2 variation was shown to deviate from Hardy-Weinberg equilibrium in the controls and was therefore excluded from the study. We found that the frequency of rare FokI TT, TaqI CC, and BsmI AA genotypes differed significantly between children with ASD and the controls (p=0.042, p=0.016, p=0.038, respectively). After correction for multiple testing, only the TaqI CC genotype remained significant. Further analysis using a recessive model showed that rare genotypes of these polymorphisms were significantly higher in patients compared to controls (p=0.045, p=0.005 and p=0.031, respectively). However, no significant association was found between ApaI and ASD. We found serum 25(OH)D levels to be significantly higher in children with ASD (p<0.001) and that the FokI polymorphism had an effect on serum 25(OH)D levels in children with ASD (p=0.041). Additionally, we found the haplotype GTTT (BsmI/TaqI/FokI/ApaI) conferred an increased risk for developing ASD (p=0.022; odds ratio [95% confidence interval]=2.322 [1.105-4.879]). This is the first clinical study evaluating the association between serum 25(OH)D levels and VDR polymorphisms in children with ASD. Our results demonstrated a significant association between TaqI, BsmI, and FokI polymorphisms and ASD and showed for the first time that FokI polymorphisms and haplotype GTTT (BsmI/TaqI/FokI/ApaI) are associated with an increased risk of ASD. Our findings support the hypothesis that 25(OH)D is involved in the pathophysiology of autism and that serum 25(OH)D levels may be affected by FokI polymorphisms in children with ASD. Our results should be considered as preliminary and needs confirmation by future studies.

Romano-Ward sendromunda KCNQ1 geninde bir duplikasyon mutasyonu

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life‐threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano–Ward syndrome (RWS) and the autosomal recessive Jervell and Lange‐Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher ‘peak’ QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

Serum cytokine profiles of Children with Obsessive-Compulsive Disorder shows the evidence of autoimmunity

Background: Previous reports have described an association between autoimmunity and primary obsessive compulsive disorder. This study aimed to investigate any differences in the levels of T helper 1, 2, and 17 effector cell cytokines between obsessive compulsive disorder patients and the control group. Methods: The study included 34 children (23 males, 11 females), aged between 7 and 17 years, with a diagnosis of obsessive compulsive disorder prior to receiving treatment. The control group consisted of age- and gender-matched children. Study participants were assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, Children’s Yale Brown Obsession Compulsion Scale, and Children’s Depression Inventory. Cytokine serum concentrations were measured using the BD Cytometric Bead Array Human Th1/Th2/Th17 Cytokine Kit. Results: Interleukin-17A, tumor necrosis factor-α, and interleukin-2 levels were significantly higher in obsessive compulsive disorder patients, However, there was no correlation between T helper 1 and 17 cytokine profiles in the obsessive compulsive disorder group. The duration and severity of obsessive compulsive disorder symptoms were not significantly associated with interleukin-17A, interferon-gamma-γ, interleukin-10, interleukin-6, interleukin-4, and interleukin-2 levels. Interestingly, a negative correlation was found between tumor necrosis factor-α levels and Clinical Global Impression scores. Conclusions: These findings suggest, in some cases, obsessive compulsive disorder may develop on a background of autoimmunity, and interleukin-2, tumor necrosis factor-α, and interleukin-17A may play a role in these autoimmune processes. Therefore, we believe it is important to investigate for obsessive compulsive disorder symptoms in patients with autoimmune disease and, conversely, autoimmune diseases in obsessive compulsive disorder patients.

The spectrum of MEFV gene mutations and genotypes in Van province, the eastern region of Turkey, and report of a novel mutation (R361T)

Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever and abdominal pain, synovitis, and pleuritis. The aim of this study was to determine the frequency and distribution of Mediterranean fever (MEFV) gene mutations in Van province of Eastern Anatolia and to compare them with the other studies from various regions of Turkey. Therefore, we retrospectively evaluated MEFV gene mutations in 1058 pediatric patients with suspected FMF. The MEFV gene mutations were investigated using Sanger sequencing and the multiplex minisequencing technique. We identified 37 different genotypes and 16 different mutations. The four most common mutations and allelic frequencies were M694V (36.50%), E148Q (32.77%), V726A (14.09%), and M694I (4.41%). M694V was the most common mutation, and the M694I frequency was found to be higher compared to studies from other regions of Turkey. In addition, we identified a novel missense mutation (R361T, c.1082G>C) in exon 3 of the MEFV gene in a 12-year-old boy, who had a typical FMF phenotype. In conclusion, this study evaluated the distribution of MEFV gene mutations in children with FMF as the first study conducted in Van province, Eastern Anatolia.

Contribution of polymorphisms in ESR1, ESR2, FSHR, CYP19A1, SHBG, and NRIP1 genes to migraine susceptibility in Turkish population.

Migraine, a highly prevalent headache disorder, is regarded as a polygenic multifactorial disease. Single-nucleotide polymorphisms (SNPs) in the genes that involved in sex hormone metabolism may comprise risk for migraine, but the results of previous genetic association studies are conflicting. The aim of this study was to evaluate genetic variants in genes involved in oestrogen receptor and oestrogen hormone metabolism in a Turkish population. A total of 12 SNPs in the ESR1, ESR2, FSHR, CYP19A1, SHBG and NRIP1 genes were genotyped in 142 migraine cases and 141 nonmigraine controls, using a BioMark 96.96 dynamic array system. In addition, gene–gene interactions were analysed using generalized multifactor dimensionality reduction (GMDR) methods. According to GMDR analysis, our results indicated that there was a significant association between migraine and gene–gene interaction among the CYP19A1, FSHR, ESR1 and NRIP1. Single-gene variant analysis showed that a significant association was observed between the TT genotype of rs10046 and migraine susceptibility. When the analysis was performed only in women, the GG genotype of rs2229741 was different between migraineurs and controls. When the female migraine patients were divided into two groups, migraine related to menstruation (MRM) or migraine not related to menstruation (MNRM), GG genotype of rs726281 was significantly associated with MRM. These results suggested that rs10046 could play a potential role in migraine susceptibility in Turkish population. Also, the rare GG genotype of rs726281 appears to influence migraine susceptibility in a recessive manner in MRM subgroup of female patients. In addition, variant GG genotype of rs2229741 may reduce the risk of migraine in Turkish women.

Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population

Objective Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. Methods We investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. Results We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. Conclusion This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population.

Elevated levels of tissue plasminogen activator and E-selectin in male children with autism spectrum disorder

Although the etiopathology of autism spectrum disorder (ASD) is not clear, immune dysfunction has been proposed as a mechanism for the pathophysiology of ASD. The purpose of this study is to examine serum levels of tissue plasminogen activator (t‐PA) and some adhesion molecules in children with ASD that have not been investigated previously in detail. The study group included 35 male children aged from 2 to 9 diagnosed with ASD according to DSM‐V criteria. Soluble platelet endothelial adhesion molecule‐1 (sPECAM‐1), P‐selectin, E‐selectin, and t‐PA in the serum were determined with enzyme‐linked immunosorbent assay. Autism behavior check list (ABC) is used for the assessment of ASD severity. The levels of t‐PA (P = 0.025) and E‐selectin (P = 0.007) was detected significantly higher in children with ASD than control group. Serum levels of sPECAM‐1 showed statistically significant negative correlation with sensory, body and object‐use, language, social, and self‐help and total scores in the patient group (r = −0.349, P = 0.04; r = −0.411, P = 0.01; r = −0.412, P = 0.01; r = −0.417, P = 0.01, and r = −0.531, P < 0.01, respectively). Serum levels of P‐selectin levels showed statistically significant negative correlation with ABC total score in the patient group (r = −0.378, P = 0.03). It may be suggested that t‐PA, E‐selectin, P‐selectin, and sPECAM‐1 a crucial role in inflammatory conditions in children with ASD. Autism Res 2016, 9: 1241–1247.

Rhizomelic Chondrodysplasia Punctata Type 1 Caused by a Novel Mutation in the PEX7 Gene.

Peroxisomes are involved in various metabolic reactions. Rhizomelic chondrodysplasia punctata (RCDP) type 1 is one of the peroxisomal biogenesis disorders caused by mutations in the PEX7 gene and is inherited in an autosomal recessive manner. We present a nine-year-old boy with skeletal abnormalities and dysmorphic facial appearance. The patient was born to parents who were first cousins. Very-long-chain fatty acids and pristanic acid levels were in the normal range, but an elevated phytanic acid level was detected by gas chromatography/mass spectrometry. The PEX7 gene was sequenced in the patient and his parents. A novel homozygous mutation, c.192delT (p.F64Lfs*10), was identified in the patient and was present in heterozygosity in both parents. In conclusion, the clinical presentation and peroxisome profile of the patient suggest that this novel mutation leads to RCDP type 1.

Association between sequence variations of the Mediterranean fever gene and the risk of migraine: a case–control study

Migraine pathogenesis involves a complex interaction between hormones, neurotransmitters, and inflammatory pathways, which also influence the migraine phenotype. The Mediterranean fever gene (MEFV) encodes the pyrin protein. The major role of pyrin appears to be in the regulation of inflammation activity and the processing of the cytokine pro-interleukin-1β, and this cytokine plays a part in migraine pathogenesis. This study included 220 migraine patients and 228 healthy controls. Eight common missense mutations of the MEFV gene, known as M694V, M694I, M680I, V726A, R761H, K695R, P369S, and E148Q, were genotyped using real-time polymerase chain reaction with 5′ nuclease assays, which include sequence specific primers, and probes with a reporter dye. When mutations were evaluated separately among the patient and control groups, only the heterozygote E148Q carrier was found to be significantly higher in the control group than in the patient group (P=0.029, odds ratio [95% confidence interval] =0.45 [0.21–0.94]). In addition, the frequency of the homozygote and the compound heterozygote genotype carrier was found to be significantly higher in patients (n=8, 3.6%) than in the control group (n=1, 0.4%) (P=0.016, odds ratio [95% confidence interval] =8.57 [1.06–69.07]). However, there was no statistically significant difference in the allele frequencies of MEFV mutations between the patients and the healthy control group (P=0.964). In conclusion, the results of the present study suggest that biallelic mutations in the MEFV gene could be associated with a risk of migraine in the Turkish population. Moreover, MEFV mutations could be related to increased frequency and short durations of migraine attacks (P=0.043 and P=0.021, respectively). Future studies in larger groups and expression analysis of MEFV are required to clarify the role of the MEFV gene in migraine susceptibility.