Genetic basis of susceptibility to melanoma

The search for candidate genes involved in the genesis of common cancers has traditionally been hampered by ambiguities in the process of determining by reliable, clinical criteria which persons harbor the genetic lesion that confers malignant susceptibility. In the case of cutaneous melanoma, the existence of genetic susceptibility has long been evident from its tendency to cluster in families, but it has been unclear until recently whether the genetic basis of familial melanoma derives from the concerted interaction of multiple genes or from a major locus with properties of a tumor suppressor gene. The original strategy used to circumvent difficulties in identifying those who harbor the genetic defect exploited a proposed melanoma precursor lesion, the dysplastic nevus, as the phenotypic marker from which the presence of the melanoma-associated genotype was inferred. That strategy in genetic linkage studies provided the first indication of a major gene for melanoma and assigned the locus to the short arm of chromosome 1. In part because the criteria for the dysplastic nevus have been neither well-defined nor generally agreed upon, multiple independent attempts to confirm the assignment of a gene to that location have failed. The probable map position of a major gene became clear when the most frequently deleted region of the human genome in melanoma tumors was localized to chromosome 9p. The significance of this assignment was established when genetic linkage studies of multiple melanoma kindreds subsequently evaluated the correlated inheritance between melanoma gene carriers, as assigned by a history of melanoma, and molecular markers for DNA polymorphisms near the 9p candidate region; this analysis provided strong statistical evidence of linkage to a melanoma susceptibility locus. Once this candidate tumor suppressor gene) as well as other relevant suppressor loci that may exist is actually cloned and characterized, rapid advances can be expected in our understanding of the pathophysiologic basis for development of melanoma. This will provide opportunities for exploring the mechanisms underlying defects in the gene and the molecular consequences of its loss of function. It will then be possible to identify precisely those persons with a genetic risk for melanoma; as a result, surveillance efforts can be more appropriately focused than has heretofore been possible.     

Empirical-Bayes and semi-Bayes approaches to occupational and environmental hazard surveillance

Depression, a complex psychobiological syndrome, has been found to be prevalent among individuals with chronic pain problems. It has been repeatedly recommended that chronic pain patients be routinely screened for depression. Many self-report questionnaires have been used to screen for depression although few have addressed potential limitations of using a self-report questionnaire to identify depressed chronic pain patients. Among the most serious problems is an over-diagnosis since typical neurovegetative symptoms of depression often resemble patients' medical/physical conditions. Some have suggested that the physical items should be replaced and others have suggested that a higher cut-off criteria for diagnosing depression should be used. In this study, the validity of the Center for Epidemiological Studies-Depression (CES-D) scale was examined to determine (a) its sensitivity, specificity, and positive, and negative predictive value with chronic pain patients, (b) the biasing effect of somatic items, and (c) the optimal cut-off score for diagnosing depression. The results support the predictive validity of the CES-D and suggest that a cut-off score of 19 should be used for diagnosing depression in chronic pain patients rather than the standard cut-off point of 16. Interestingly, the removal of the somatic items did not enhance the effectiveness of the CES-D. The discriminatory ability of somatic items with the total assessment of depression is discussed.     

Genetic polymorphisms in xenobiotic metabolizing enzymes as a determinant of susceptibility to environmental mutagens and carcinogens in humans

Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility.     

Genetic susceptibility to visceral obesity and related clinical implications

This paper reviews evidence supporting the notion that genetic factors may have an influence on the determination of body fat distribution, particularly emphasizing the genetic susceptibility of visceral adipose tissue (AT) accumulation. The potential contribution of genetic susceptibility to the development of metabolic alterations in visceral obese individuals will also be reviewed. The contribution of genetic factors to the variation in body fat distribution is supported by studies in which racial differences in body fat distribution were reported. These ethnic differences suggest that body fat distribution may be influenced by some components of the genetic background which are shared among individuals of a given race. Furthermore, the familial aggregation and the resemblance between monozygotic twins that have been observed for anthropometric measurements of body fat distribution and for visceral AT accumulation measured by computed tomography, also suggest that genetic factors are involved in the determination of body fat distribution. Genetic susceptibility may also influence the relationship between visceral AT accumulation and the development of metabolic alterations. In this regard, it has been reported that the polymorphism of some genes (for example, the apolipoprotein (apo) E, apo B100 and lipoprotein lipase genes) is altering the relationship between visceral obesity and plasma lipoprotein-lipid levels. In conclusion, results presented in this paper suggest that genetic factors seem to have a significant influence on the propensity to accumulate AT in the visceral depot and that genetic factors also seem to affect the associations commonly reported between visceral obesity and the development of metabolic alterations.     

Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons

Epidemiologic evidence on the relationship between polycyclic aromatic hydrocarbons (PAH) and cancer is reviewed. High occupational exposure to PAHs occurs in several industries and occupations. Covered here are aluminum production, coal gasification, coke production, iron and steel foundries, tar distillation, shale oil extraction, wood impregnation, roofing, road paving, carbon black production, carbon electrode production, chimney sweeping, and calcium carbide production. In addition, workers exposed to diesel engine exhaust in the transport industry and in related occupations are exposed to PAHs and nitro-PAHs. Heavy exposure to PAHs entails a substantial risk of lung, skin, and bladder cancer, which is not likely to be due to other carcinogenic exposures present in the same industries. The lung seems to be the major target organ of PAH carcinogenicity and increased risk is present in most of the industries and occupations listed above. An increased risk of skin cancer follows high dermal exposure. An increase in bladder cancer risk is found mainly in industries with high exposure to PAHs from coal tars and pitches. Increased risks have been reported for other organs, namely the larynx and the kidney; the available evidence, however, is inconclusive. The results of studies addressing environmental PAH exposure are consistent with these conclusions.     

Genetic instabilities in human cancers

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.     

Genetic epidemiology of breast and ovarian cancers

Most civilian and military air traffic control facilities in the United States use rapid rotation shift schedules. These schedules have generally been chosen for social reasons. Safety concerns have been raised because the air traffic controllers (ATCs) often carry an acute sleep debt onto the night-shift where they have little active work to do as they sit in the dark at the nadir of their circadian rhythms. This paper reviews advancing and delaying rapid shiftwork schedules, ATC workload factors as they relate to error rates and safety, and potential countermeasures. Recent studies indicate that ATC performance declines on the night-shift and that ATCs may be falling asleep while on-duty. There is indirect evidence that ATC error rates are highest on the night-shift. There are only limited studies which have evaluated potential countermeasures. The operational significance of the problems associated with ATC shiftwork is not yet clear. Further study is needed.     

Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to lung cancer--relevance to smoking

Lung cancer has been associated with smoking and many carcinogenic compounds are thought to contribute to the origin of lung cancer. Most of these carcinogens exert their carcinogenicity after conversion to more potent forms through reactions mediated by drug-metabolizing enzymes, such as cytochrome P450s (CYPs). Carcinogens in the human body are then detoxified by enzymes such as glutathione S-transferase (GST) and excreted. The genetic differences, or polymorphisms, of these enzymes may affect genetically-determined susceptibility to lung cancer. Recently, a variety of polymorphisms have been found for drug-metabolizing enzymes in humans, such as CYP2E1, CYP1A1, CYP2D6, and GST. These polymorphisms have been related to susceptibility to lung cancer by some researchers. Their relevance with the dose of tobacco smoke has also been investigated.     

Effective outcomes management in occupational and environmental health

In the final analysis, outcomes management is about changing behavior, specifically in the occupational and environmental health practitioner's communication process and practice patterns and in the workers' prevention and compliance behavior. Outcomes management is also about quantifying results, establishing occupational and environmental health performance benchmarks, developing a best practices model and asking even more questions. As health care embraces the use of outcomes in evaluating its effectiveness, similar developments can be anticipated in occupational and environmental health. While occupational and environmental health outcomes management is still in its infancy, nurses in the workplace are well positioned to "shape it" into a useful tool that meets the needs of all the various practice settings. As nurses in the workplace begin to evaluate, report, and benchmark results, measurement tools will be refined, data bases will grow and new, useful benchmarks will be established. Because occupational and environmental health programs usually operate as part of a larger business unit, nurses in the workplace are continually faced with the challenge of ensuring that corporate programs including workers' compensation, health and disability benefit programs, vaccination programs, injury prevention, and health promotion or wellness programs are delivered in an efficient and cost-effective manner and that the expected outcomes are achieved. Effective outcomes management programs are the vehicles to effective goal achievement.     

Renal effects of environmental and occupational lead exposure

Environmental and industrial lead exposures continue to pose major public health problems in children and in adults. Acute exposure to high concentrations of lead can result in proximal tubular damage with characteristic histologic features and manifested by glycosuria and aminoaciduria. Chronic occupational exposure to lead, or consumption of illicit alcohol adulterated with lead, has also been linked to a high incidence of renal dysfunction, which is characterized by glomerular and tubulointerstitial changes resulting in chronic renal failure, hypertension, hyperuricemia, and gout. A high incidence of nephropathy was reported during the early part of this century from Queensland, Australia, in persons with a history of childhood lead poisoning. No such sequela has been found in studies of three cohorts of lead-poisoned children from the United States. Studies in individuals with low-level lead exposure have shown a correlation between blood lead levels and serum creatinine or creatinine clearance. Chronic low-level exposure to lead is also associated with increased urinary excretion of low molecular weight proteins and lysosomal enzymes. The relationship between renal dysfunction detected by these sensitive tests and the future development of chronic renal disease remains uncertain. Epidemiologic studies have shown an association between blood lead levels and blood pressure, and hypertension is a cardinal feature of lead nephropathy. Evidence for increased body lead burden is a prerequisite for the diagnosis of lead nephropathy. Blood lead levels are a poor indicator of body lead burden and reflect recent exposure. The EDTA lead mobilization test has been used extensively in the past to assess body lead burden. It is now replaced by the less invasive in vivo X-ray fluorescence for determination of bone lead content.     

Exposure to polycyclic aromatic hydrocarbons in occupational versus urban environmental air

OBJECTIVES: To evaluate the balance between occupational and environmental exposure to suspended particulate matter (SPM) and polycyclic aromatic hydrocarbons (PAHs), comparison measurements were performed in a coal-fired power plant and the urban atmosphere from the town nearby. METHODS: The analysis of SPM for PAH content was done according to a high-performance liquid chromatography (HPLC)-based method. The microscopic assessment was performed using scanning electron microscopy (SEM) by silver coverage of the samples derived by air filter. RESULTS: Contrary to expectations, the results showed low levels of particle-bound PAHs in the occupational environment (< 1 ng benzo(a)pyrene/m3 air) and high levels in urban air (range 80-1250 ng benzo(a)pyrene/m3). The SPM collected from the power plant exhibited non-respirable characteristics (particles larger than 10 microm), whereas urban SPM almost exclusively contained respirable airborne particles (<3 microm). CONCLUSIONS: The PAH burden, combined with the enhanced probability of respiratory absorption, confers a much greater hazard potential to the urban SPM. Under these conditions, in areas or countries in which old technologies remain in use, occupational exposure to SPM containing PAHs might represent a severe underestimation of the total risk as it does not take into account the background air pollution.     

Beyond diathesis stress: Differential susceptibility to environmental influences.

Evolutionary-biological reasoning suggests that individuals should be differentially susceptible to environmental influences, with some people being not just more vulnerable than others to the negative effects of adversity, as the prevailing diathesis-stress view of psychopathology (and of many environmental influences) maintains, but also disproportionately susceptible to the beneficial effects of supportive and enriching experiences (or just the absence of adversity). Evidence consistent with the proposition that individuals differ in plasticity is reviewed. The authors document multiple instances in which (a) phenotypic temperamental characteristics, (b) endophenotypic attributes, and (c) specific genes function less like “vulnerability factors” and more like “plasticity factors,” thereby rendering some individuals more malleable or susceptible than others to both negative and positive environmental influences. Discussion focuses upon limits of the evidence, statistical criteria for distinguishing differential susceptibility from diathesis stress, potential mechanisms of influence, and unknowns in the differential-susceptibility equation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic susceptibility testing: ethical and social quandaries

We have isolated a novel human C-C chemokine, MIP-1 delta from a human fetal spleen cDNA library. The human MIP-1 delta cDNA has an unusually long 400-bp 5-prime untranslated region and a predicted 113-amino acid protein of 10 kDa. The coding sequence contains a signal peptide of 21 amino acids, indicating that the mature protein has 92 amino acids (8 kDa). Recombinant human MIP-1 delta produced by transfected human embryonic kidney 293 cells produced an 8-kDa protein, which confirmed the presence of a signal peptide. Compared with other human C-C chemokines, human MIP-1 delta shows the highest homology with human HCC-1, CK beta-8, murine C10, and CCF18 (MIP-1 gamma). The human MIP-1 delta gene is localized on chromosome 17 where most of the C-C chemokine superfamily is located. Human MIP-1 delta is expressed in T and B lymphocytes, NK cells, monocytes, and monocyte-derived dendritic cells, but not in bone marrow-derived dendritic cells. Its expression can be induced by other proinflammatory cytokines in monocytes and dendritic cells. Human MIP-1 delta is chemotactic for T cells and monocytes, but not for neutrophils, eosinophils, or B cells. Human MIP-1 delta induced calcium flux in human CCR1-transfected cells.     

Genetic and environmental influences on EEG coherence

EEG coherence measures the covariation in electrical brain activity between two locations on the scalp and is used to study connectivity between cortical regions. The aim of this study was to determine the heritability of EEG coherence. Coherence was measured in a group of 213 16-yr-old twin pairs. By including male and female twin pairs in the sample, sex differences in genetic architecture were systematically examined. The EEG was obtained during quiet supine resting. Coherence was estimated for short and long distance combinations of electrode pairs along the anterior-posterior axis within a hemisphere for four frequency bands (delta, theta, alpha and beta). Averaged over all electrode combinations about 60% of the variance was explained by genetic factors for coherence in the theta, alpha and beta bands. For the delta band, the heritability was somewhat lower. No systematic sex differences in genetic architecture were found. All environmental influences were nonshared, i.e., unique factors including measurement error. Environmental factors shared by twin siblings did not influence variation in EEG coherence. These results suggest that individual differences in coherence form a potential candidate for (molecular) genetic studies on brain function.     

Genetic analysis of susceptibility to dextran sulfate sodium-induced colitis in mice

The genetic basis for differential sensitivity of inbred mice to inflammatory bowel disease induced by dextran sulfate sodium (DSS) is unknown. Susceptible C3H/HeJ were outcrossed to partially resistant C57BL/6J mice. F2 and N2 progeny were phenotyped by evaluating histopathologic lesions in large intestine detected 16 days after a 5-day period of feeding 3.5% DSS. Screening for DSS colitis (Dssc) loci revealed quantitative trait loci (QTL) on Chr 5 (Dssc1) and Chr 2 (Dssc2). These traits contributed additively, explaining 17.5% of the variation in total colonic lesions. Additional QTL on Chr 18 and 1 that collectively explained 11% of the variation in total colon lesions were indicated. In the cecum, only a putative QTL on Chr 11 was associated with pathology (lesion severity) in the cecum. Reduced DSS susceptibility was observed in congenic stocks in which the highly susceptible NOD/Lt strain carried putative resistance alleles from either B6 on Chr 2 or from the highly resistant NON/Lt strain on Chr 9. We conclude that multiple genes control susceptibility to DSS colitis in mice. Possible Dssc candidate genes are discussed in terms of current knowledge of inflammatory bowel disease susceptibility loci in humans.     

Genetic susceptibility to head and neck cancer: interaction between nutrition and mutagen sensitivity

The development of head and neck cancer may depend not only on exposure to environmental carcinogens but also on a genetically based susceptibility to carcinogen-induced damage. This thesis presents a case-control study that demonstrates the significance of mutagen sensitivity, a measure of an individual's intrinsic DNA repair capacity against free radical damage, as a risk factor for the disease. As part of the case-control analysis, 167 previously untreated patients and 177 age- and sex-matched healthy controls were assessed for various lifestyle factors including tobacco and alcohol habits, occupational exposures, and diet. Mutagen sensitivity expressed by each individual was determined by quantifying bleomycin-induced chromosomal breaks within peripheral blood lymphocytes in vitro. Consistent with our initial observations and those of others, mutagen hypersensitivity was strongly associated with increased risk of head and neck cancer (odds ratio, 4.95; 95% confidence interval, 2.67 to 9.17) after adjusting for age, sex, and race. Low intake of vitamins C and E was also associated with an increased risk of disease and was interactive with mutagen sensitivity in risk estimates. Individuals with both a low intake of various antioxidants and increased chromosomal sensitivity to oxidant-induced DNA damage were at greatest risk. This study supports the concept that the risk of head and neck cancer is determined by a balance of factors that either enhance or protect against free radical oxygen damage, including innate capacities for DNA repair.     

The vinylchloride liver, an occupational environmental disease]

Two cases of hyaline membrane disease are presented complicated by severe, interstitial emphysema and resulting in death from air embolus. This is consistent with the experimental evidence of other investigators that shows that such an air embolus may be more common complication of hyaline membrane disease than previously expected.