Işık Bökesoy

Urinary cyclophosphamide excretion and micronuclei frequencies in peripheral lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics

In this study, urinary cyclophosphamide (CP) excretion rate, as well as micronuclei (MN) in peripheral lymphocytes and in buccal epithelial cells were determined for 26 nurses handling antineoplastics and 14 referents matched for age and sex. In urine samples of 20 out of 25 exposed nurses CP excretion rate was found in a range of 0.02-9.14 microg CP/24 h. Our results of the analyses of CP in urine demonstrates that when the nurses were handling CP (and other antineoplastic drugs) this particular compound was observed in urine. The mean values (+/-SD) of MN frequencies (%) in peripheral lymphocytes from the nurses and controls were 0.61 (+/-0. 32) and 0.28 (+/-0.16), respectively (p<0.01). The mean value (+/-SD) of MN frequency (%) in buccal epithelial cells of nurses was 0.16 (+/-0.19) and also mean MN frequency in buccal epithelial cells for controls was found to be as 0.08 (+/-0.08), (p>0.05). Age, sex and smoking habits have not influenced the parameters analyzed in this study. Handling time of antineoplastics, use of protective equipment and handling frequency of drugs have no effect on urinary and cytogenetic parameters analyzed. No correlation was found between the urinary CP excretion and the cytogenetic findings in nurses. Neither could we find any relationship between two cytogenetic endpoints. Our results have identified the possible genotoxic damage of oncology nurses related to occupational exposure to at least one antineoplastic agent, which is used as a marker for drug handling. As a whole, there is concern that the present handling practices of antineoplastic drugs used in the several hospitals in Ankara will not be sufficient to prevent exposure.

Butterfly vertebra: A case report

Butterfly vertebra is a rare congenital anomaly associated with syndromes such as Pfeiffer, Jarcho-Levin, Crousen, Alagille. In the literature, only a few cases of butterfly vertebra have been reported as incidental finding. We described a 37-year-old male who had an L3 butterfly vertebra associated with an L4-L5 disc protrusion. Awareness of this anomaly is important for making correct diagnosis. Although this uncommon anomaly is considered to be usually asymptomatic, we suggest that it might increase the incidence of disc herniation, because the condition may alter the spinal biomechanics.

Molecular alterations in the TP53 gene of peripheral blood cells of patients with chronic myeloid leukemia

The TP53 gene has been extensively studied in patients with chronic myeloid leukemia (CML), both in chronic phase and in blast crisis. Mutations in the gene were found in up to 30% of the patients, especially among those in blast crisis. We report the results of an analysis of 29 blood samples from CML patients: 8 samples from chronic phase patients, 8 from patients in the accelerated phase, and 13 from patients in blast crisis. By using genomic DNA, we sequenced PCR products of the coding exons and most introns of the TP53 gene, finding genetic changes in 30% of the blast crisis samples and 12% in chronic phase. All mutations were found in introns and were previously unreported. Immunocytochemical studies revealed accumulation of TP53 in blood cells of samples both from chronic phase and blast crisis patients. Since these samples had no TP53 mutations, we believe that wild type TP53 accumulates in blood cells of CML patients. Our results, therefore, indicate that molecular changes in coding regions of the TP53 gene are rare. The significance of the abundance of intronic changes should be investigated further. Accumulation of wild type TP53 in CML cells may indicate an additional mechanism involving this gene in the pathogenesis of this disease. Genes Chromosomes Cancer 21:2–7, 1998.

Oromandibular limb hypogenesis/Hanhart's syndrome: possible drug influence on the malformation

Oromandibular limb hypogenesis/Hanharts syndrome in a female infant with an antenatal history of meclizine hydrochloride usage during gestation is reported. The genetics of the syndrome are discussed and the possibility of the drugs influence on the malformation is suggested.

Common fragile sites associated with the breakpoints of chromosomal aberrations in hematologic neoplasms.

Fragile sites are specific regions of chromosomes prone to breakage when cells are cultured under specific conditions. These sites are divided into two classes: common and rare. Common fragile sites are expressed in all individuals at different frequencies, whereas rare ones are found only in certain individuals. Common and rare fragile sites have been shown to display a number of characteristics of instability being preferential sites for chromosomal deletions, duplications, and rearrangements. Moreover, a majority of mapped oncogenes are located at or near these fragile sites. These observations have led to the suggestion that both classes of fragile sites may play a significant role in chromosomal rearrangements involved in oncogene activation or tumor supressor gene inactivation. For these reasons, involvement of common and rare fragile sites and their relevance to specific chromosome breakpoints in cancer have received much attention. In this study, which reports on the cytogenetic findings obtained from 256 patients with chronic myelocytic leukemia, 103 with acute myelocytic leukemia, 40 with acute lymphocytic leukemia, 33 with myelodysplastic syndrome, we documented the fragile sites involved in chromosomal aberrations involving oncogenes, tumor supressor genes, and other known genes important in cell cycle regulation localized at these sites.

Identification of the parental origin of polysomy in two 49,XXXXY cases

The parental origin and mechanism of formation of polysomy X were studied in two polysomic cases, using four X‐linked restriction fragment length polymorphisms, three (CA)n dinucleotide repeat sequences and one variable number tandem repeat (VNTR) locus as genetic markers. A nonradioactive technique based on the hybridization of the polymerase chain reaction (PCR) product was developed for the analysis of dinucleotide repeats. Segregation analysis using different nonradioactive approaches based on the PCR, revealed that all four X chromosomes were of maternal origin. These data provide additional evidence of an identical mechanism of successive nondisjunctions in maternal meiosis I and II.

Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting.

Background Observations with intravascular ultrasound demonstrated that neointimal hyperplasia is the predominant factor responsible for in-stent restenosis. Experimental data suggest that angiotensin I converting enzyme (ACE) plays a role in the thickening of neointima after balloon denudation. Insertion/deletion (I/D) polymorphism of the ACE gene is significantly associated with plasma level of ACE and subjects with D/D genotype have significantly higher plasma levels of ACE than normal. Objective To investigate whether this polymorphism influences the risk of restenosis after coronary stenting. Methods We genotyped 158 patients who had undergone single-vessel coronary stenting for the ACE I/D polymorphism. Results Of the 158 patients, 56 (35%) had the D/D genotype, 71 (45%) had the I/D genotype and 31(20%) had the I/I genotype. Prevalences of genotypes were compatible with Hardy-Weinberg equilibrium and distributions of ACE genotype among patients and 132 healthy controls from the same geographic area did not differ. At follow-up (after a median duration of 5.4 months), overall rates of angiographic restenosis and of revascularization of target lesion (RTL) were 32.3 and 22.8%, respectively. Of 51 patients with angiographic restenosis, 31 (60.8%) had focal and 20 (39.2%) had diffuse patterns of restenosis. Diffuse in-stent restenosis was significantly more prevalent among patients with D/D genotype (P= 0.016). Multiple stepwise logistic regression analysis identified ACE I/D polymorphism as the independent predictor of angiographic restenosis and RTL. Relative risk of angiographic restenosis was 6.29 [95% confidence interval (CI), 1.80–22.05, P= 0.0004] for D/D genotype and 3.88 (95% CI 1.11–13.12, P= 0.029) for I/D genotype, whereas relative risk of RTL was 7.44 (95% CI 1.60–34.58, P= 0.01) for D/D genotype and 3.88 (95% CI 0.083–18.15, P= 0.085) for I/D genotype. Conclusions The ACE I/D polymorphism is significantly associated with risk of angiographic and clinical restenosis after coronary stenting. Angiographic pattern of restenosis is also significantly associated with I/D polymorphism, diffuse type being more prevalent among subjects with D/D genotype.

Is SHORT syndrome another phenotypic variation of PITX2

Even though responsible genetic loci and mode of inheritance for the Rieger syndrome have been well established, the mode of inheritance and the genetic basis for SHORT syndrome are still uncertain. The purpose of this paper is to document a familial translocation of t(1;4)(q31.2;q25), in a mother and her son manifesting Rieger syndrome with polycystic ovaries and SHORT syndrome, respectively. It is suggested that these two syndromes may be different expressions of the same gene, PITX2, localized at 4q25. Our patient is the second with the association of Rieger syndrome and polycystic ovaries, and thus this may not be coincidental, moreover insulin resistance‐related phenotypes, such as lipodystrophy and polycystic ovaries, can be major component of syndromes with Rieger eye malformation.

The relationship between angiotensin converting enzyme gene I/D polymorphism and qt dispersion in patients with hypertrophic cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by disorganized myocardial architecture, and may cause ventricular arrhythmias and sudden death. The angiotensin-converting enzyme (ACE) with two deletion alleles (DD genotype) has been proposed to be associated with increased myocardial collagen content. We evaluated QT dispersion (QTd), which reflects regional differences in ventricular repolarization, in HCM patient and controls among the three different ACE genotypes. Materials and methods: Sixty-three patients with HCM and 20 healthy subjects were included in the study. QT parameters were measured from 12 lead electrocardiograms. ACE genotypes were determined from the DNA extracted from peripheral blood by a polymerase chain reaction (PCR) method. QT parameters were compared among the three ACE genotypes both in HCM patients and controls. Results: Median ages were similar in HCM and control groups. QTd and corrected QTd (QTcd) were significantly greater in the HCM group compared with the controls. The frequencies of each genotype were similar in both groups. Although QTd and QTcd did not differ among the three genotypes in the control subjects, they were significantly greater in patients with DD genotype compared with other genotypes in the HCM group. Conclusion: QTd and QTcd are increased in patients with HCM, especially in those with the DD genotype.

DNA methyltransferase expression differs with proliferation in childhood acute lymphoblastic leukemia

DNA methylation is involved in genomic imprinting, tissue and stage specific gene regulation, X chromosome inactivation and especially necessary in normal mammalian development [1]. Methylation of DNA at cytosine base occurs at most CpG islands in the mammalian genome, with exception of CpG islands of gene promoters which are usually unmethylated. Methylation of promoter CpG islands inhibits the activity of the gene by inhibiting the association of some DNA-binding factors with methylated DNA sequences or by silencing transcription via methyl-CpG binding proteins with co-repressors and chromatin modifiers [2]. Cancer is known as a genetic disease, in which epigenetic alterations play important roles. Cancer cells show global genomic hypomethylation, but the CpG islands of the promoters, especially the promoters of the tumour suppressor genes are hypermethylated [3]. Aberrant methylation of CpG islands is a major epigenetic mechanism of gene expression in human cancers. Global hypomethylation is important in tumour formation by different ways which include chromosomal and genomic instability, increased mutation rate and recombination frequency [4]. Hypermethylation of tumour suppressor genes causes gene inactivation, furthermore aberrant DNA methylation facilitates gene mutation, because deamination of 5-methylcytosine leads to the formation of thymine which is not repaired by uracil glycosylases, instead of the formation of uracil by cytosine deamination [5]. Acute lymphoblastic leukemia (ALL), is the most frequent cancer of childhood (25%). The blockage of lymhpoid cell development at any stage, leads to ALL. Chromosomal aberrations as well as epigenetic changes are important in it’s development. E-cadherin, DAP-kinase, p73 and p15 gene promoters are some of the gene promoters that are known to be hypermethylated in childhood ALL [6–8]. DNA methyltransferases (DNMT’s) are the enzymes that methylate DNA. In mammalians, there are five different DNMT’s: DNMT1, DNMT2, DNMT3A, DNMT3B and DNMT3L. All of the DNMT’s, except DNMT3L, are catalitically active. All have a catalytic carboxy terminal and a regulator amino terminal, except DNMT2. The activity of DNMTs are greatly regulated by their amino terminal domain which interacts with other molecules. DNMT2, contains only the catalytic domain and participates scarcely to the formation of DNA methylation pattern although it covalently binds to DNA [9–11]. DNMT1 targets the replication fork, methylates preferentially hemimethylated DNA, and is responsible for the Isik Bokesoy—Retired Professor.