Colchicine treatment increases the risk for fetal chromosomal aberrations-an observational study and systematic literature review.

OBJECTIVES: To examine the risk for chromosomal aberrations in fetuses of colchicine-treated patients in a large cohort, and to perform a systematic literature review on the subject. METHODS: For the observational study, a retrospective search was performed through the Ministry of Health computerized database, for all invasive tests performed due to parental colchicine treatment over the years 2003-19. The rate of aberrant karyotypes in pregnancies exposed to colchicine was compared with a local cohort of 2752 normal pregnancies, yielding six (0.2%) karyotype-detectable findings. In addition, a systematic literature search was conducted for studies examining the rate of chromosomal aberrations in pregnancies exposed to colchicine. RESULTS: The study group consisted of 755 pregnancies karyotyped due to colchicine exposure. A marked decrease due to this indication was noted over the years (i.e. 67 cases in 2003 vs 8 in 2019). Five (0.66%) chromosomal aberrations were noted: 47,XXY; 45,X0; 47,XYY; and two fetuses with trisomy 21. This rate was significantly increased compared with the control population [relative risk 2.2 (95% CI: 1.1, 4.2)]. Literature search yielded four studies encompassing 740 pregnancies. The rate of chromosomal aberrations ranged from 'none' (in three studies) up to 1.5%. Quality assessment of the evidence was defined as 'low'. CONCLUSION: The results of our observational study support the concern that colchicine treatment is associated with increased risk for fetal chromosomal aberrations; however, the absolute risk is relatively low (one in 151 pregnancies). This information should be taken into account when considering invasive testing in such pregnancies.

Relationships between cytokine (IL-6 and TGF-ß1) gene polymorphisms and chromosomal damage in hospital workers.

Cytokine gene polymorphisms have been found to be associated with a pre-disposition to a variety of diseases, including inflammatory and cancer diseases. The present study evaluated the influence of six cytokine gene polymorphisms on the level of genomic damage observed in peripheral blood lymphocytes from hospital pathologists chronically exposed to low doses of different xenobiotics. Lymphocytes from 50 pathologists and 50 control subjects were recruited and analyzed in Sister Chromatid Exchange (SCE) and Chromosomal Aberrations (CA) assays. The frequencies of six cytokine gene polymorphisms and their relationships with the cytogenetic damage levels were also evaluated. The results indicated that significant differences were found between pathologists and controls in terms of SCE frequency (p < 0.001) and RI values (p < 0.001), as well as in terms of CA and cells with aberrations (p < 0.001). No associations were found between all analyzed cytokine gene polymorphisms and CA frequency in both pathologists and control groups. Vice versa, among pathologists, homozygote individuals for the IL-6 G allele showed a significantly (p = 0.017) lower frequency of SCE with respect to heterozygote subjects. Similarly, for TGFß1 codon 10 locus, homozygote for T allele and heterozygote TC subjects showed a significantly (p = 0.021) lower frequency of SCE with respect to homozygote CC individuals. Among controls, no significant differences were found in the frequency of SCE between genotypes at all loci. Based on these results, we speculate that high circulating levels of a pro-inflammatory cytokine like IL-6 and lower levels of the immunosuppressant cytokine TGFß1 could be associated directly with a longer duration and/or greater intensity of inflammatory processes, and indirectly with significantly higher levels of genomic damage.

[CHROMOSOMAL DISORDERS IN WORKERS OF CHEMICALLY HAZARDOUS ENTERPRISES WITH THE DIFFERENT HEALTH STATUS].

UNLABELLED: OBJECTIVES. Chromosomal aberrations (CAs) are the one of the most sensitive biomarikers of biological effects from the hazardous environmental exposure. In this relation the comparison of cytogenetical indices in persons, exposed to the complex of factors of chemically hazard enterprises, with the presence of occupationally caused diseases seems to be very perspective for the understanding of the role of the contribution of genotoxical impact of occupational factors into staff morbidity. METHODS. Cytogenetical analysis was performed in 138 employees of chemically hazardous enterprises, including 84 patients, who need for establishment of the causation of diseases with the work in conditions of chemical plant and 54 persons without need for hospitalization according to results of the previous examination. Comparison group was consisted of 55 persons. There was performed the comparison of cytogenetical indices and commensuration of ratios of persons with individual high CAs levels and also carriers of exchange aberrations of chromosomal type in different groups of examined cases. RESULTS. There was shown statistically significant increase of the rate of CAs level including unexpectedly high level of dicentric and ring chromosomes in the group of 84 hospitalized patients. There was revealed statistically significant gain in the share of persons with CAs rate more then 5% (p < 0.01) and/or carriers of dicentrics and ring chronosomes (p < 0.5) in this group. CONCLUSION: It is possible to suggest that genotoxical impact plays a significant role in the mechanism of appearance of diseases etiologically related with the work on the enterprise of the high chemical risk.

Effects of Jatropha curcas oil in Lactuca sativa root tip bioassays.

Jatropha curcas L. (Euphorbiaceae) is important for biofuel production and as a feed ingredient for animal. However, the presence of phorbol esters in the oil and cake renders the seeds toxic. The toxicity of J. curcas oil is currently assessed by testing in animals, leading to their death. The identification of toxic and nontoxic improved varieties is important for the safe use of J. curcas seeds and byproducts to avoid their environmental toxicity. Hence, the aim of this study was to propose a short-term bioassay using a plant as a model to screen the toxicity of J. curcas oil without the need to sacrifice any animals. The toxicity of J. curcas oil was evident in germination, root elongation and chromosomal aberration tests in Lactuca sativa. It was demonstrated that J. curcas seeds contain natural compounds that exert phyto-, cyto- and genotoxic effects on lettuce, and that phorbol esters act as aneugenic agents, leading to the formation of sticky chromosomes and c-metaphase cells. In conclusion, the tests applied have shown reproducibility, which is important to verify the extent of detoxification and to determine toxic doses, thus reducing the numbers of animals that would be used for toxicity tests.

Sleep in ring chromosome 20 syndrome: a peculiar electroencephalographic pattern.

Ring chromosome 20 [r(20)] syndrome is a chromosomal disorder characterized by epilepsy and intellectual disability. Distinctive electroclinical features and wakefulness EEG patterns have been described. The EEG features of sleep have not yet been evaluated. We studied the pattern of sleep in six patients aged 2-59 years who underwent at least one polysomnographic recording. Their sleep pattern evolution is described as deterioration ranging from normal to destructured NREM/REM sleep. NREM sleep alterations were observed from childhood and were more evident in adulthood. EEG abnormalities detected during wakefulness persisted, with morphological changes, during sleep. During NREM sleep all the subjects presented high amplitude delta sequences with a sharply contoured or notched appearance, prevalent over frontal regions. The theta rhythm of wakefulness was seen to persist during REM sleep. Ring chromosome 20 syndrome shows sleep alterations that seem to be age-related. A potential role of cortical and thalamocortical dysfunction is discussed.

Heparin-induced thrombocytopenia associated with acute liver graft failure.

An orthotopic liver transplantation (OLT) is of a proven benefit in an acute liver failure (ALF). Heparin-induced thrombocytopenia (HIT) is strongly associated with thromboembolic complications. We present the case of a 56-year-old patient who underwent an OLT owing to an ALF of unknown aetiology. HIT type II with consecutive hepatic and portal vein thrombosis caused progressive graft failure. Total hepatectomy and porto-caval shunt were performed to reduce the toxic effects of liver cell necrosis such as multiorgan failure involving the respiratory, renal and cardiovascular systems. A suitable liver graft was allocated after an anhepatic bridging period of 56 h. Specific complications due to end-stage liver failure-such as acidosis, coagulopathy, decrease of vascular resistance, cerebral oedema, myocardial infarction and right heart failure-were treated. Following a re-OLT, the patient made a complete recovery. We present a rare case of HIT-associated early liver graft failure followed by a prolonged anhepatic phase and finally a successful re-OLT.

Supplemental dietary folic acid has no effect on chromosome damage in erythrocyte progenitor cells of mice.

Folate deficiency can cause chromosome damage, which could result from reduced de novo thymidylate synthesis or DNA hypomethylation. High folic acid intake has been hypothesized to inhibit folate-dependent one-carbon metabolism, which could also lead to DNA damage. A large proportion of the general population may have high folic acid intakes. In this study, 2 experiments were conducted to examine the effects of folate on chromosome damage. First, male mice were fed folic acid-deficient (D) (0 mg folic acid/kg diet), control (C) (2 mg/kg), or folic acid-supplemented (S) (6 mg folic acid/kg diet) diets from weaning to maturity. Second, female mice were fed the D, C, or S diet throughout pregnancy, lactation, and breeding for 3 generations; male mice from the F3 generation were fed the same diet as their mothers from weaning, producing D, C, and S F3 male mice. RBC micronucleus frequencies, a measure of chromosome damage or aneuploidy, were determined for both experimental groups. In mice fed diets from weaning to maturity, erythrocyte micronucleus frequency was 24% greater in D compared with C mice. F3 mice fed diet D had 260% and 174% greater reticulocyte and erythrocyte micronucleus frequencies compared with F3 C mice, respectively. The S diets did not affect micronucleus frequency, suggesting that excess folic acid at this level does not promote or protect against chromosome damage. The results suggest that chronic exposure to folic acid at the levels similar to those achieved through fortification is unlikely to be clastogenic or aneugenic.

Risk factors for heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Heparin-induced thrombocytopenia type II (HIT II) correlates with a higher incidence of thromboembolic complications and unfavorable outcome. OBJECTIVE: To examine the risk factors and outcomes for patients with HIT II with aneurysmal subarachnoid hemorrhage. METHODS: Demographics, risk factors, treatments, and outcomes data of 600 aneurysmal subarachnoid hemorrhage patients admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively reviewed. Patients meeting the clinical criteria for HIT II were compared with those who did not develop thrombocytopenia. RESULTS: Twenty-five patients (6%) met the clinical criteria for HIT II, and 396 (94%) did not develop thrombocytopenia. Both groups were the same with respect to age, Hunt-Hess score and Fisher grade on admission, medical conditions, and social risk factors. The HIT II patients had significantly more unfavorable outcomes (modified Rankin Scale score >3), deep vein thrombosis, stroke, pulmonary embolism, and death. Development of HIT II was strongly associated with symptomatic vasospasm (odds ratio, 5.7; 95% confidence interval, 2.5-13.1; P < .001) and number of angiographic procedures (odds ratio, 1.7; 95% confidence interval, 1.3-2.2; P < .001). Forward buildup selection modeling demonstrated the latter to be the strongest predictor for HIT II development (odds ratio, 2.3; 95% confidence interval, 1.7-3.2; P = .02). CONCLUSION: Heparin-induced thrombocytopenia type II correlates with a worse outcome and higher risk of thromboembolic complications in aneurysmal subarachnoid hemorrhage patients. In addition, HIT II was strongly associated with the number of angiographic procedures performed during the same hospitalization.

The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage.

This study presents a case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred.

[Dermal necrosis as cutaneous manifestation of heparin-induced thrombocytopenia II?]. / Hautnekrose als kutane Manifestation einer heparininduzierten Thrombopenie Typ II?

Most of the rare cases of skin necrosis following heparin injections are associated with the immunologically mediated form of heparin-induced thrombocytopenia II (HIT II). We present a 62-year- old woman who developed a necrotic abdominal lesion seven days after starting daily subcutaneous injections of the low molecular heparin enoxaparin. We detected circulating antibodies against the platelet factor 4-complex but no concomitant thrombocytopenia. An isolated, antibody-mediated thrombosis of dermal vessels is the likely underlying cause of the skin necrosis in HIT II.

Chromosome damage and cytotoxicity in oral mucosa cells after 2 months of exposure to anabolic steroids (decadurabolin and winstrol) in weight lifting.

The aim of the present study was to evaluate DNA damage (micronucleus) and cellular death (pyknosis, karyolysis and karyorrhexis) in exfoliated buccal mucosa cells from anabolic steroid users after 2 months of exposure. Two experimental groups consisting of 15 adult males who practise weight lifting and are anabolic steroid users or 15 adult males who practise weight lifting, but are non-anabolic steroid users, were recruited. In addition, 20 sedentary males, who do not practise any physical activity regularly, were matched by age with experimental groups. No significant statistical differences (p>0.05) were noticed in individuals who practise physical activity only. On the other hand, an increase of micronucleated cells (MNCs) in anabolic steroid (decadurabulin and Winstrol) users was observed. Regarding cytotoxic parameters, the same observation has occurred, that is, significant statistical differences (p<0.05) were noticed in the group exposed to anabolic steroids when compared with other controls, as depicted by high frequencies of pyknosis, karyolysis and karyorrhexis. Taken together, our results suggest that genomic instability and cytotoxicity are induced by anabolic steroid administration in oral mucosa cells as assessed by the micronucleus test.

Residential proximity to waste sites and industrial facilities and chromosomal anomalies in offspring.

A few studies have found chromosomal anomalies in offspring associated with a maternal residence near waste sites, but did not examine the effect of living near industrial facilities, and most combined specific anomalies into heterogeneous groups. With a case-control study design, we investigated whether maternal residential proximity to hazardous waste sites or industrial facilities with chemical air emissions was associated with chromosomal anomalies in births. Maternal residences of 2099 Texas births with chromosomal anomalies and 4368 control births without documented malformations were related to boundaries of hazardous waste sites and street addresses of industrial facilities through geographic information systems. With adjustment for maternal age, race/ethnicity, and education, maternal residence within 1mile of a hazardous waste site (relative to farther away) was not associated with chromosomal anomalies in offspring except for Klinefelter variants among Hispanic births (odds ratios (OR) 7.9, 95% confidence interval (CI) 1.1-42.4). Women 35 years or older who lived within 1mile of industries with emissions of heavy metals were two times more likely (95% CI 1.1-4.1) than women living farther away to have offspring with chromosomal anomalies including trisomies 13, 18, or 21 or sex chromosome abnormalities. Among women 40 years or older, maternal residence within a mile of industries with solvent emissions was associated with chromosomal anomalies in births (OR 4.8, 95% CI 1.2-42.8). Study findings suggest some relation between residential proximity to industries with emissions of solvents or heavy metals and chromosomal anomalies in births to older mothers.

[Prenatal exposure to birth control pills: risk of fetal death and congenital malformations]. / Praenatal udsaettelse for p-piller og risiko for fosterdød og medfødte misdannelser.

About 1% of pregnant women uses oral contraceptives during the first part of their pregnancy and thereby exposes their offspring to artificial estrogens. Artificial estrogens, such as oral contraceptives, accidentally used during pregnancy may have a negative impact on the fetus. This article reviews the literature on prenatal exposure to oral contraceptives and the risk of congenital malformations and fetal death. The conclusion is that prenatal exposure to oral contraceptives may be associated with a slightly elevated risk of certain specific congenital malformations.

Impact of follicular-fluid meiosis-activating sterol in an albumin-based formulation on the incidence of human pre-embryos with chromosome abnormalities.

OBJECTIVE: To evaluate the effect of adding follicular-fluid meiosis-activating sterol (FF-MAS) in a novel 0.2% recombinant human albumin-based formulation to cumulus-enclosed oocytes on chromosomal status and development of pre-embryos. DESIGN: Multicenter, prospective, randomized, open (double-blind for vehicle and FF-MAS groups), four parallel groups, controlled trial. SETTING: Four public IVF clinics in Denmark. PATIENT(S): Two hundred eighteen women undergoing IVF donated 483 oocytes. INTERVENTION(S): Follicle-stimulating hormone/hCG-primed cumulus-enclosed oocytes randomized to 4 hours of exposure to medium with 1 or 10 micromol/L of FF-MAS dissolved in 0.2% recombinant human albumin, medium with 0.2% recombinant human albumin (vehicle control), or medium alone (control) before insemination. MAIN OUTCOME MEASURE(S): Primary endpoint: incidence of human pre-embryos with chromosomal abnormalities. Secondary endpoint: fertilization rate, cleavage rate, and pre-embryo quality assessed after 68 hours of culture. RESULT(S): At pre-embryo level, the overall abnormality rates in the control, vehicle control, and 1- and 10-micromol/L FF-MAS groups were 53%, 39%, 42%, 53%, respectively, and at blastomere level 49%, 44%, 44%, and 48%, respectively. After 20 and 26 hours, the fertilization rates were between 67% and 71% in all groups. No differences in the cleavage rates were observed. CONCLUSION(S): The concentrations of FF-MAS in a novel 0.2% recombinant human albumin-based formulation of FF-MAS did not increase the risk of chromosomal abnormalities in pre-embryos or blastomeres. No statistically significant differences in fertilization rate, cleavage rate, or number of good quality pre-embryos were found among the four groups.

Inhibitory effects of aqueous crude extract of Saffron (Crocus sativus L.) on chemical-induced genotoxicity in mice.

Saffron (dried stigmas of Crocus sativus L.), was evaluated in the mouse bone marrow micronucleus test for its possible protective effects against chromosomal damage induced by cisplatin (CIS), mitomycin-C (MMC) and urethane (URE). Three doses of saffron (25, 50 and 100 mg/kg body weight) were orally administered to mice for five consecutive days prior to administration of genotoxins under investigation. From the results obtained, it was evident that the administration of 50 and 100 mg saffron/kg body weight could significantly inhibit the in vivo genotoxicity of these genotoxins. However, all the three doses of saffron were effective in exerting a protective effect against urethane.

Retrospective exposure assessment and quality control in an international multi-centre case-control study.

The paper presents the exposure assessment method and quality control procedure used in an international, multi-centre case-control study within a joint Nordic and Italian cohort. This study was conducted to evaluate whether occupational exposure to carcinogens influenced the predictivity of high frequency of chromosomal aberrations (CA) in peripheral lymphocytes for increased cancer risk. Occupational hygienists assessed exposures in each participating country: Denmark, Finland, Italy, Norway and Sweden. The exposure status to a carcinogen or a clastogen was coded in the cohort according to the original CA studies at the time of CA testing, but not for the whole work life. An independent occupational hygienist coordinated harmonization of the assessment criteria and the quality control procedure. The reliability of the exposure assessments was calculated as deviation from the majority of the assessors, as Cohen's kappa and as overall proportion of the agreements. The reassessment of the exposures changed the exposure statuses significantly, when compared with the original cohort. Harmonization of the exposure criteria increased the conformity of the assessments. The prevalence of exposure was higher among the original assessors (the assessor from the same country as the subject) than the average prevalence assessed by the other four in the quality control round. The original assessors classified more job situations as exposed than the others. Several reasons for this are plausible: real country-specific differences, differences in information available to the home assessor and the others and misunderstandings or difficulties in translation of information. To ensure the consistency of exposure assessments in international retrospective case-control studies it is important to have a well-planned study protocol. Due to country-specific environments a hygienist from each participating country is necessary. A quality control study is recommended, to be performed as described, combined with round-table meetings to minimize information bias between the assessors.