Case 303: Delayed Posthypoxic Leukoencephalopathy.

HISTORY: A 54-year-old man was found by paramedics in his home face-down at his computer desk with a substantially reduced level of consciousness. He had not contacted his family for more than 50 hours. The patient lived alone and was a heavy smoker with a history of alcohol abuse. His medical history was otherwise unremarkable, and there was no history of cancer, psoriasis, or rheumatoid arthritis, nor was there a history of methotrexate administration. At presentation to the emergency department, he was mildly hypotensive and was experiencing hypercapnic respiratory failure and acute renal failure with rhabdomyolysis. His toxicology screen was mildly positive for opiates. He received naloxone (Narcan; Emergent) with minimal effect. An unenhanced CT scan of the head was obtained. Of note, this patient's presentation predated the COVID-19 pandemic. He was admitted to the intensive care unit for decreased level of consciousness and respiratory failure. The decreased level of consciousness was thought to be secondary to seizure, as he developed seizurelike movements prior to intubation, probably in the context of intoxication or alcohol withdrawal. Electroencephalography revealed moderate bilateral cerebral dysfunction and encephalopathy, with no evidence of nonconvulsive seizures. He had a short course of intermittent hemodialysis and was discharged home 8 days later with an appointment for neurology follow-up. At discharge, he was at his cognitive and functional baseline. Approximately 3 weeks later, the patient was brought back to the emergency department for progressive confusion and decrease in balance. He became apathetic with reduced psychomotor activity and was no longer able to perform basic daily activities, such as cooking or bathing. He displayed bizarre behavior, such as staring at a wall for hours, and was somnolent, irritable, and inattentive. He eventually became incontinent of urine and stool. Results of a neurologic examination of the cranial nerves, motor function, sensation, and reflexes were normal. The results of blood work-up were grossly normal, and the results of an extensive toxicology work-up were negative. Repeat head CT was performed. MRI was ordered to further investigate the patient's encephalopathic presentation.

Case 303.

History A 54-year-old man was found by paramedics in his home face-down at his computer desk with a substantially reduced level of consciousness. He had not contacted his family for more than 50 hours. The patient lived alone and was a heavy smoker with a history of alcohol abuse. His medical history was otherwise unremarkable, and there was no history of cancer, psoriasis, or rheumatoid arthritis, nor was there a history of methotrexate administration. On presentation to the emergency department, he was mildly hypotensive and was experiencing hypercapnic respiratory failure and acute renal failure with rhabdomyolysis. His toxicology screen was mildly positive for opiates. He received naloxone (Narcan; Emergent) with minimal effect. An unenhanced CT scan of the head was obtained (Fig 1A). Of note, this patient's presentation predated the COVID-19 pandemic. He was admitted to the intensive care unit for decreased level of consciousness and respiratory failure. The decreased level of consciousness was thought to be secondary to seizure, as he developed seizurelike movements prior to intubation, probably in the context of intoxication or alcohol withdrawal. Electroencephalography revealed moderate bilateral cerebral dysfunction and encephalopathy, with no evidence of nonconvulsive seizures. He had a short course of intermittent hemodialysis and was discharged home 8 days later with an appointment for neurology follow-up. At discharge, he was at his cognitive and functional baseline. Approximately 3 weeks later, the patient was brought back to the emergency department for progressive confusion and decrease in balance. He became apathetic with reduced psychomotor activity and was no longer able to perform basic daily activities, such as cooking or bathing. He displayed bizarre behavior, such as staring at a wall for hours, and was somnolent, irritable, and inattentive. He eventually became incontinent of urine and stool. Results of a neurologic examination of the cranial nerves, motor function, sensation, and reflexes were normal. The results of blood work-up were grossly normal, and the results of an extensive toxicology work-up were negative. Repeat head CT was performed (Fig 1B). MRI was ordered to further investigate the patient's encephalopathic presentation (Figs 2-3).

Preoperative Determination of Isocitrate Dehydrogenase Mutation in Gliomas Using Spectral Editing MRS: A Prospective Study.

BACKGROUND: The edited magnetic resonance spectroscopy (MRS) technique has not yet been formally evaluated for the in vivo detection of 2-hydroxyglutarate (2-HG) in patients with gliomas of various grades. PURPOSE: To evaluate the diagnostic accuracy of edited MRS in the preoperative identification of the isocitrate dehydrogenase (IDH) mutation status in patients with gliomas. STUDY TYPE: Prospective. POPULATION: Fifty-eight subjects (31 glioblastomas, 27 grade II and III gliomas). FIELD STRENGTH/SEQUENCE: Mescher-Garwood (MEGA)-PRESS and routine clinical brain tumor MR sequences were used at 3T. ASSESSMENT: Data were analyzed using an advanced method for accurate, robust, and efficient spectral fitting (AMARES) from jMRUI software. The amplitudes of the 2-HG, N-acetyl-aspartate (NAA), choline (Cho), and creatine/phosphocreatine (Cr) resonances were calculated with their associated Cramer-Rao lower bound (CRLB). The IDH1 R132H mutation status was assessed by immunohistochemistry for all patients. Patients with grades II and III gliomas with negative immunohistochemistry underwent DNA sequencing to further interrogate IDH mutation status. STATISTICAL TEST: The differences in 2-HG amplitudes, 2-HG/NAA, 2-HG/Cho, and 2-HG/Cr between IDH-mutant and IDH-wildtype gliomas were assessed using Mann-Whitney U-tests. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic accuracy of each parameter. RESULTS: The 2-HG amplitudes, 2-HG/NAA, and 2-HG/Cho were higher for IDH-mutant gliomas than IDH-wildtype gliomas (P < 0.007). Using a CRLB threshold <30%, a 2-HG cutoff greater than 0 had a sensitivity of 80% (95% confidence interval [CI]: 52-96%) and a specificity of 81% (95% CI: 54-96%) in identifying IDH-mutant gliomas. In the subset of patients with grades II and III gliomas, the sensitivity was 80% (95% CI: 52-96%) and specificity was 100% (95% CI: 40-100%). Among 2-HG ratios, the highest AUC for the identification of IDH mutant status was achieved using the 2-HG/NAA (AUC = 0.8, 95% CI 0.67-.89). DATA CONCLUSION: Preoperative edited MRS appears to be able to help identify IDH-mutant gliomas with high specificity. Level of Evidence 1 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:416-426.

Prospective comparative diagnostic accuracy evaluation of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) MR perfusion in differentiating tumor recurrence from radiation necrosis in treated high-grade gliomas.

BACKGROUND: The appearance of a new enhancing lesion after surgery and chemoradiation for high-grade glioma (HGG) presents a common diagnostic dilemma. Histopathological analysis remains the reference standard in this situation. PURPOSE: To prospectively compare the diagnostic accuracy of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) in differentiating tumor recurrence (TR) from radiation necrosis (RN). STUDY TYPE: Prospective diagnostic accuracy study. POPULATION: In all, 98 consecutive treated HGG patients with new enhancing lesion. We excluded 32 patients due to inadequate follow-up or technical limitation. FIELD STRENGTH/SEQUENCE: 3 T DCE and DSC MR. ASSESSMENT: Histogram and hot-spot analysis of cerebral blood volume (CBV), corrected CBV, Ktrans , area under the curve (AUC), and plasma volume (Vp). The reference standard of TR and/or RN was determined by histopathology in 43 surgically resected lesions or by clinical/imaging follow-up in the rest. STATISTICAL TESTS: Mann-Whitney U-tests, receiver operating characteristic (ROC) curve, and logistic regression analysis. RESULTS: A total of 68 lesions were included. There were 37 TR, 28 RN, and three lesions with equal proportions of TR and RN. TR had significantly higher CBV, corrected CBV, CBV ratio, corrected CBV ratio, AUC ratio, and Vp ratio (P < 0.05) than RN on hot-spot analysis. CBV had the highest diagnostic accuracy (AUROC 0.71). On histogram analysis, TR had higher CBV and corrected CBV maximal value compared with RN (P = 0.006, AUROC = 0.70). Only CBV on hot-spot analysis remained significant after correction for multiple comparison, with no significant improvement in diagnostic accuracy when using a combination of parameters (AUROC 0.71 vs. 0.76, P = 0.24). DATA CONCLUSION: DSC-derived CBV is the most accurate perfusion parameter in differentiating TR and RN. DSC and DCE-derived parameters reflecting the blood volume in an enhancing lesion are more accurate than the DCE-derived parameter Ktrans . Clinical practice may be best guided by blood volume measurements, rather than permeability assessment for differentiation of TR from RN. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019;50:573-582.

Intradural Extramedullary Tumors and Associated Syndromes.

Most intradural tumors are located within the intradural extramedullary compartment, and the most common tumors are schwannomas and meningiomas. Other less common neoplasms include neurofibroma, solitary fibrous tumor, myxopapillary ependymoma, lymphoma, metastatic leptomeningeal disease, malignant peripheral nerve sheath tumor, and paraganglioma. Patients usually present with gait ataxia, radicular pain, and motor and sensory deficits due to chronic compressive myelopathy or radiculopathy. MRI is the modality of choice for detecting and evaluating intradural extramedullary spinal tumors. This imaging technique helps narrow the differential diagnosis and therefore decide treatment.

Evolutionary Traits and Genomic Surveillance of SARS-CoV-2 in South America.

Since the zoonotic event from which SARS-CoV-2 started infecting humans late in 2019, the virus has caused more than 5 million deaths and has infected over 500 million people around the world. The pandemic has had a severe impact on social and economic activities, with greater repercussions in low-income countries. South America, with almost 5% of the world's population, has reckoned with almost a fifth of the total people infected and more than 26% (>1/4) of the deceased. Fortunately, the full genome structure and sequence of SARS-CoV-2 have been rapidly obtained and studied thanks to all the scientific efforts and data sharing around the world. Such molecular analysis of SARS-CoV-2 dynamics showed that rates of mutation, similar to other members of the Coronaviridae family, along with natural selection forces, could result in the emergence of new variants; few of them might be of high consequence. However, this is a serious threat to controlling the pandemic and, of course, enduring the process of returning to normalization with the implicit monetary cost of such a contingency. The lack of updated knowledge in South America justifies the need to develop a structured genomic surveillance program of current and emerging SARS-CoV-2 variants. The modeling of the molecular events and microevolution of the virus will contribute to making better decisions on public health management of the pandemic and developing accurate treatments and more efficient vaccines.

Virulence Genes of Helicobacter pylori Increase the Risk of Premalignant Gastric Lesions in a Colombian Population.

Background: Genetic variability of Helicobacter pylori is associated with various gastrointestinal diseases; however, little is known about interaction with sociodemographic in the development of premalignant lesions in Colombian patients. Methods: An analytical study was conducted including cases (patients with gastric atrophy, intestinal metaplasia, and gastric dysplasia) and controls (patients with nonatrophic gastritis). Sociodemographic information was obtained using a questionnaire. Histopathological diagnosis was performed according to the Sydney System. The cagA and vacA genotypes were established using polymerase chain reaction in paraffin blocks. The effect of each variable on the study outcome (premalignant lesion) is presented as odds ratio (OR) and 95% CI. A p value of <0.05 was considered as statistically significant. Results: The vacA/s1m1 genotype increases the risk of developing premalignant lesions of the stomach (OR: 3.05, 95% IC: 1.57-5.91, p=0.001). Age and educational level showed a positive interaction with the s1m1 genotype (adjusted OR: 3.68, 95% CI: 1.73-7.82, p=0.001). The cagA genotype was not correlated to the development of premalignant lesions of the stomach (OR: 1.32, 95% CI: 0.90-1.94, p=0.151). Conclusions: The vacA genotype, age, and educational level are indicators of the risk of developing premalignant lesions of the stomach in the study population. Significance Statement. Genetic variability of H. pylori and sociodemographic information could be used to predict the risk of premalignant lesions in stomach in Colombian population.

Prevalence and risk factors associated with peripheral arterial disease in an adult population from Colombia.

BACKGROUND: Cardiovascular diseases (CVD) are the most important cause of mortality in Latin America, while peripheral arterial disease (PAD) is the third leading cause of atherosclerotic cardiovascular morbidity. OBJECTIVE: To establish the prevalence of PAD and the distribution of traditional CVD risk factors in a population from the Department of Cauca, Colombia. METHODS: A cross-sectional study was conducted on a total of 10,000 subjects aged ≥40 years, from 36 municipalities. An ankle-brachial index (ABI) ≤ 0.9 in either leg was used as diagnostic criterion of PAD. RESULTS: Overall PAD prevalence was 4.4% (4.7% females vs. 4.0% males), with diabetes being the most prevalent risk factor (23%). Among individuals self-reporting a history of acute myocardial infarction or stroke, PAD prevalence was 31.0% and 8.1%, respectively. After adjusting for potential confounders, PAD was significantly associated with hypertension (OR 4.6; 95% CI; 3.42-6.20), diabetes (4.3; 3.17-5.75), dyslipidaemia (3.1; 2.50-3.88), obesity (1.8; 1.37-2.30), and cigarette smoking (1.6; 1.26-1.94). Analysis for the interaction of risk factors showed that diabetes, dyslipidaemia, and obesity accounted for 13.2 times the risk for PAD (6.9-25.4), and when adding hypertension to the model, the risk effect was the highest (17.2; 8.4-35.1). CONCLUSIONS: Hypertension, diabetes, dyslipidaemia, and obesity, but not smoking were strong predictors of PAD. ABI measurement should be routinely performed as a screening test in intermediate and high-risk patients for CVD prevention. This could lead to an early intervention and follow-up on populations at risk, thus, contributing to improve strategies for reducing CVD burden.

Environmental risk factors for prevention and molecular intervention of cervical cancer.

Cervical cancer (CC) is potentially the most preventable and treatable cancer in human but it is a leading cause for cancer morbidity and mortality in women around the world. Therefore, more innovative prevention and treatment protocols need to be developed and implemented. With better understanding of the etiology of the disease, specific prevention protocols that involve life-style modifications to minimize the impact of environmental risk factors can be developed. It may be necessary to implement unique modification protocols for different countries. In addition, antiviral vaccine is a highly promising prevention approach. With respect to therapy, the development of more specific protocols that have fewer side effects is needed. With the availability of sophisticated molecular techniques, a new generation of targeted approach that has the potential to generate outstanding efficacy is being tested. Using the siRNA technology against the expression of human papillomavirus oncogenes, specific biological pathways that are essential to the growth and survival of the CC cells can be interrupted. Another promising approach is the molecular intervention of the estrogen pathway by blocking the expression of estrogen receptors. These molecular techniques may work by reactivating endogenous regulatory processes, e.g., the core apoptotic machinery, that can cause self-destruction of the CC cells, thus providing potentially effective molecular therapy. These topics are discussed in this review.

[Cardiovascular disease risk factors in people working at a Colombian health institution]. / Factores de Riesgo para Enfermedad Cardiovascular en Trabajadores de una Institución Prestadora de Servicios de Salud, Colombia.

OBJECTIVE: Establishing the prevalence of recognised biological and behavioural cardiovascular disease (CVD) risk factors in a population of workers at a health institution in Popayán, Colombia. METHODS: An observational descriptive study was conducted, 96 employees being interviewed to obtain information regarding their socio-demographic characteristics, tobacco and alcohol consumption, physical activity, eating habits and personal and family history of CVD. Each worker's standardised glycaemia, serum lipids, arterial blood pressure and body mass index were measured. RESULTS: There was 12,5% behavioural risk factor prevalence for smoking, 58,3 % for alcohol consumption, 56,3 % physical inactivity during free time and 82,3 % atherogenic diet; biological risk factor prevalence was 11,5 % hypertension, 45,8 % being overweight, 1 % diabetes, 61,5 % dyslipidaemia and 58,3 % family history of CVD. It was also found that the risk of hypertension was significantly higher in males, in individuals >40 years, in people having >25 BMI and in smokers. Regarding dyslipidaemia, the risk was higher in males and in >40 year old individuals. The risk of being overweight and obese was significantly associated with smoking and alcohol consumption. CONCLUSION: Although this is an institution having an asymptomatic and relatively young population (25-55 years), action should be taken towards modifying lifestyles to reduce CVD risk in the affected population due to the high prevalence of biological and behavioural risk factors.

Open Dataset for the Automatic Recognition of Sedentary Behaviors.

BACKGROUND: Sedentarism is associated with the development of noncommunicable diseases (NCD) such as cardiovascular diseases (CVD), type 2 diabetes, and cancer. Therefore, the identification of specific sedentary behaviors (TV viewing, sitting at work, driving, relaxing, etc.) is especially relevant for planning personalized prevention programs. OBJECTIVE: To build and evaluate a public a dataset for the automatic recognition (classification) of sedentary behaviors. RESULTS: The dataset included data from 30 subjects, who performed 23 sedentary behaviors while wearing a commercial wearable on the wrist, a smartphone on the hip and another in the thigh. Bluetooth Low Energy (BLE) beacons were used in order to improve the automatic classification of different sedentary behaviors. The study also compared six well know data mining classification techniques in order to identify the more precise method of solving the classification problem of the 23 defined behaviors. CONCLUSIONS: A better classification accuracy was obtained using the Random Forest algorithm and when data were collected from the phone on the hip. Furthermore, the use of beacons as a reference for obtaining the symbolic location of the individual improved the precision of the classification.

Exposure to wood smoke, HPV infection, and genetic susceptibility for cervical neoplasia among women in Colombia.

Cervical cancer is the second leading cause of death from cancer among women in Colombia (16/100,000). Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of high-grade squamous intraepithelial lesions (HSILs). Exposure to chemical agents may be a cofactor for tumor induction, and individual genetic differences in the metabolism of these chemical agents may affect the susceptibility of individuals towards the development of HSIL. In this case-control study, a total of 91 cases with HSIL and 92 healthy controls, frequency-matched by age and place of origin, were recruited, and their frequencies of CYP2E1, GSTM1, and GSTT1 polymorphism were determined. We then evaluated the association of these polymorphisms, by themselves and in combination with wood smoke exposure and HPV-infection status, with the risk of HSIL. The results indicate that GSTM1 and GSTT1 polymorphism were not associated with HSIL, although a small increase in risk was observed for individuals who were GSTT1 null (OR = 1.4, 95% CI = 0.57-3.44). Contrary to other investigations, the c2/c2 variant of the CYP2E1 gene was associated with a significant increase in risk after adjusting for wood smoke exposure (OR = 6.3, 95% CI = 1.10-36.38) or wood smoke exposure and HPV-infection status (OR = 10.7, 95% CI = 1.76-65.58). Wood smoke exposure also increased the risk of HSIL among CYP2E1 c2/c2 HPV-positive women (OR = 3.3, CI = 0.50-22.50); however, the increase did not achieve statistical significance. Our study provides tantalizing evidence that genetic differences in the metabolism of wood smoke carcinogens, particularly metabolism by CYP2E1, may confer susceptibility for HSIL development. Further investigations with larger populations will be needed to confirm this association, which may provide important information for improving cervical cancer prevention programs.

[Papillomavirus and factors associated with high-risk, cervical intraepithelial neoplasia in Cauca, Colombia]. / Papilomavirus y factores asociados a neoplasia intraepitelial cervical de alto grado en Cauca, Colombia.

OBJECTIVE: Evaluating the role of the main factors associated with high-risk cervical intraepithelial neoplasia in women from the Cauca Department in Colombia. METHODOLOGY: After signing a consent-form, women were interviewed to obtain socio-demographic and lifestyle data. A cervical biopsy was performed on each woman for histopathological diagnosis (cases) and a sample of exfoliated cells (cases and controls) to extract DNA for HPV detection by polymerase chain reaction. A total of 98 cases and 109 controls, matched by age and ethnicity, were recruited for the study. RESULTS: The study confirmed association between HPV and the risk of cervical neoplasia (OR = 19.0; 95% CI = 8.20-44.2). The data suggested that multiparity (OR = 4.1; 95% CI = 1.62-10.6) and exposure to carcinogens present in wood-smoke (OR = 7.3; 95% CI = 3.00-19.4) are important co-factors for cervical neoplasia given the presence of HPV. CONCLUSIONS: These results provide valuable information for public health institutions to develop better cervical neoplasia prevention programmes.

[Determining social factors related to pesticide poisoning among rice farmers in Colombia]. / Determinantes sociales de la intoxicación por plaguicidas entre cultivadores de arroz en Colombia.

Objective Large quantities of pesticides are used in rice crops. The aim of this study is to characterize how farmers are exposed to pesticides and subsequent poisoning. Materials and Methods A multilevel (individual and community) multi-method study, which included ethnographic and survey methods, as well as measurement of pesticides in water and human samples, was performed. Results The production process is described and the main risk factors are presented. Pesticides are considered the greatest danger at work and at their homes. Workers have poor working conditions and are not protected by the system of occupational risks. Azinphos-methyl, endosulfan, ß-BHC, bromophos-methyl, bromophos-ethyl and 2,4- DDT were found in water samples. The survey included 381 workers with mild (12.86 %), moderate (67.98 %) and severe (5.51 %) poisonings respectively. Severe cases presented lower levels of education, lower levels of health care access to the contributory regimen of the Colombian social security system and higher incidence of cardiovascular disease, diabetes, herpes or other viral infections. Conclusion There are precarious working conditions that favor exposure to pesticides correlated to the exclusion of farmers from the occupational risk system, to poverty and to poor education. It is urgent to include these workers to the system of occupational risk system and to improve their living conditions, thus reducing unsafe practices when handling pesticides.

[Pesticides use by flower companies associated with the Colombian Association of Flower Exporters]. / Descripción del uso y manejo de plaguicidas en las empresas de flores afiliadas a Asocolflores.

INTRODUCTION: In Colombia, pesticide exposure has became a public health problem, as the use of these substances continues to increase. OBJECTIVE: The current study accumulated information concerning pesticides used by flower companies in Bogotá and Rionegro (Antioquia) that were associated with Asociación Colombiana de Exportadores de Flores (Asocolflores) in Colombia. MATERIALS AND METHODS: Eighty-four companies were stratified by geographic location and size. Company and worker information was collected, and for each company, the process of pesticide application and maintenance of the cultivated flowers was carefully observed. Univariate and bivariate, and correlation analyses were applied for data analysis. RESULTS: Sex of workers was 39.4% male and 60.6% female. Pesticides were grouped into 4 toxicity classes: 14.3% were class I, 14.4% class II, 52.0% class III, and 19.2% class IV. Dithiocarbamates was the group of pesticides more commonly used (11.7%). The equipment most frequently used for pesticide application was the "bomba móvil" (92.8%), and the "lanza" (92.9%). Cholinesterase activity measured by the Michel-Aldrige method was the biological marker for exposure to pesticides used in 85.9% of the companies. Recommendations for improvements in their use and for measures to further reduce exposure of workers are made.

[Musculoskeletal pain and its association with ergonomic risk factors in administrative workers]. / Dolor músculo-esquelético y su asociación con factores de riesgo ergonómicos, en trabajadores administrativos.

OBJECTIVE: Establishing the frequency of musculoskeletal lesions in administrative workers and its possible association with ergonomic risk factors. METHODS: A descriptive study of 145 workers from the Universidad del Cauca in Popayán was carried out between July 2002 and June 2003. Two instruments were used for collecting the information: a format for analysing working posture and a questionnaire for analysing musculoskeletal symptoms. RESULTS: Fifty-seven percent of the administrative workers presented symptoms of pain. The most frequent lesions were found in the lower back (56.6%), upper back (53.1%) and the neck (49%). Workers who sat for most of their working day presented an OR of 3.0 for lower back lesions and workers who had to walk more during their daily activity presented an OR of 2.8. CONCLUSIONS: The results of this study reveal an association between exposure to biomechanical risk factors and the presence of musculoskeletal lesion, indicating that forced work postures signify greater risk. This type of lesion could therefore incapacitate workers carrying out their daily activities.

Development of a metabolic syndrome personal health record system.

According to the International Diabetes Federation (IDF), a quarter of the world population is affected with metabolic syndrome (MS). The paper describes the development process of a Personal Health Record System (PHR) for the management of MS. Following the recommendations of ISO 9241-210:2010, a PHR for the promotion of physical activity and healthy nutrition was implemented.

Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays.

A major barrier to understanding the role of polymorphic DNA repair genes for environmental cancer is that the functions of variant genotypes are largely unknown. Using our cytogenetic challenge assays, we conducted an investigation to address the deficiency. Using X-rays or ultraviolet (UV) light, we irradiated blood lymphocytes from 80 nonsmoking donors to challenge the cells to repair the induced DNA damage, and we analyzed expression of chromosome aberrations (CA) specific to the inducing agents. We have genotyped polymorphic DNA repair genes preferentially involved with base excision repair (BER) and nucleotide excision repair (NER) activities (XRCC1, XRCC3, APE1, XPD) corresponding to the repair of X-ray- and UV light-induced DNA damage, respectively. We expected that defects in specific DNA repair pathways due to polymorphisms would cause corresponding increases of specific CA. From our data, XRCC1 399Gln and XRCC3 241Met were associated with significant increases in chromosome deletions compared with the corresponding homozygous wild types (18.27 1.1 vs 14.79 1.2 and 18.22 0.99 vs 14.20 1.39, respectively); XPD 312Asn and XPD 751Gln were associated with significant increases in chromatid breaks compared with wild types (16.09 1.36 vs 11.41 0.98 and 16.87 1.27 vs 10.54 0.87, respectively), p < 0.05. The data indicate that XRCC1 399Gln and XRCC3 241Met are significantly defective in BER, and the XPD 312Asn and XPD 751Gln are significantly defective in NER. In addition, the variant genotypes interact significantly, with limited overlap of the two different repair pathways.

Effect of epoxide hydrolase polymorphisms on chromosome aberrations and risk for lung cancer.

Microsomal epoxide hydrolase (mEH) gene is polymorphic and its enzyme is involved in the activation and subsequent detoxification of several tobacco carcinogens, for example polycyclic aromatic hydrocarbons. Therefore, we have investigated the association of two polymorphisms at exons 3 and 4 of the mEH gene with the development of lung cancer in 110 patients and 119 matched controls. In addition, we have investigated the relationship between the different mEH alleles and the frequency of chromosome aberrations (CA), as an approach to understand the role of genetic susceptibility on cancer risk. Our results show that only the homozygous exon 4 fast genotype is significantly associated with increased risk for lung cancer (odds ratio [OR]=6.26; 95% confidence interval [CI]=1.02-38.3). When the exons 3 and 4 polymorphisms are considered together, patients carrying the high enzyme activity genotype have a significantly increased risk for lung cancer (OR=2.46; 95% CI=1.06-5.68). More importantly, the increased risk for this group is confirmed by their having the highest frequency of CA compared to any other genotype groups. In addition, genotypes with higher risk had consistently more CA than those with lower risk. Our CA data also indicates that the low activity genotype may exert a protective role in cigarette smokers, as it was associated with a significant decrease in CA compared to the high and intermediate activity genotypes. In conclusion, the CA data provides evidence to support that susceptibility mEH alleles are significantly involved with the development of lung cancer from cigarette smoking.