Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Genetic susceptibility to environmental toxicants : the interface between human and experimental studies in the development of new toxicological concepts

The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

The hereditary transmission of the glutathione transferase hGSTT1-1 conjugator phenotype in a large family

The polymorphism of human glutathione transferase hGSTT1-1 is expressed in three phenotypes. Experimentally, individuals can be classified as non-conjugators, low conjugators and 'high' conjugators depending on the enzyme activity in blood towards methylene chloride using a gas chromatographic assay. Non-conjugators do not have a functional hGSTT1 gene; however, little is known about the molecular basis of the three conjugator phenotypes. The higher hGSTT1-1 activity in high conjugators may be the result of enzyme induction or be genetically determined. Twenty-nine members of a large family, including three generations were phenotyped and genotyped with respect to hGSTT1-1. The hGSTT1-1 enzyme activity of high conjugators was twice as high as that of low conjugators. The distribution of hGSTT1-1 phenotypes strongly indicates a Mendelian intermediary inheritance, in which a gene-dosage effect results in a doubled enzyme expression in the presence of two functional alleles. The Mendelian intermediary inheritance is further supported by the findings of a semiquantitative polymerase chain reaction method designed to distinguish the three genotypes of hGSTT1 for rapid screening of large study groups.

Misleading conduct arising from public statements : establishing the knowledge base of the target audience

Despite the very substantial body of primary sources and secondary literature on Australia’s much-litigated statutory provisions proscribing misleading or deceptive conduct, the courts have provided little in the way of assistance about how to establish the knowledge base of the target audience at whom the public statement was directed. The purpose of this case note is to compare and contrast two recent decisions of the High Court of Australia that highlight the difficulties faced by applicants in attempting to establish a contravention of the relevant legislation where conduct is directed at a segment of the public or the public as a whole.

Subclinical psychotic experiences in healthy young adults : associations with stress and genetic predisposition

Stress has been identified as a common trigger for psychosis. Dopamine pathways are suggested to be affected by chronic and severe stress and to play an important role in psychosis. This pilot study investigates the potential relationship of stress and psychosis in subclinical psychotic experiences. It was hypothesized that single-nucleotide polymorphisms (SNPs) previously found to be associated with psychiatric disorders would be associated with both stress and subclinical psychotic experiences. University students (N=182) were genotyped for 17 SNPs across 11 genes. Higher stress reporting was associated with rs4680 COMT, rs13211507 HLA region, and rs13107325 SLC39A8. Reports of higher subclinical psychotic experiences were associated with DRD2 SNPs rs17601612 and rs658986 and an AKT1 SNP rs2494732. Replication studies are recommended to further pursue this line of research for identification of markers of psychosis for early diagnosis and intervention.

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Use of genetic decompositions to scaffold the development of a structurally sequenced curriculum for mathematics acceleration

The authors have collaboratively used a graphical language to describe their shared knowledge of a small domain of mathematics, which has in turn scaffolded their re-development of a related curriculum for mathematics acceleration. This collaborative use of the graphical language is reported as a simple descriptive case study. This leads to an evaluation of the graphical language’s usefulness as a tool to support the articulation of the structure of mathematics knowledge. In turn, implications are drawn for how the graphical language may be utilised as the detail of the curriculum is further elaborated and communicated to teachers.

Genetic divergence and echolocation call frequency in cryptic species of Hipposideros larvatus s.l. (Chiroptera : Hipposideridae) from the Indo-Malayan region

The intermediate leaf-nosed bat (Hipposideros larvatus) is a medium-sized bat distributed throughout the Indo-Malay region. In north-east India, bats identified as H. larvatus captured at a single cave emitted echolocation calls with a bimodal distribution of peak frequencies, around either 85 kHz or 98 kHz. Individuals echolocating at 85 kHz had larger ears and longer forearms than those echolocating at 98 kHz, although no differences were detected in either wing morphology or diet, suggesting limited resource partitioning. A comparison of mitochondrial control region haplotypes of the two phonic types with individuals sampled from across the Indo-Malay range supports the hypothesis that, in India, two cryptic species are present. The Indian 98-kHz phonic bats formed a monophyletic clade with bats from all other regional populations sampled, to the exclusion of the Indian 85-kHz bats. In India, the two forms showed 12–13% sequence divergence and we propose that the name Hipposideros khasiana for bats of the 85-kHz phonic type. Bats of the 98-kHz phonic type formed a monophyletic group with bats from Myanmar, and corresponded to Hipposideros grandis, which is suggested to be a species distinct from Hipposideros larvatus. Differences in echolocation call frequency among populations did not reflect phylogenetic relationships, indicating that call frequency is a poor indicator of evolutionary history. Instead, divergence in call frequency probably occurs in allopatry, possibly augmented by character displacement on secondary contact to facilitate intraspecific communication.

Nursing Management : Fluid, Electrolyte, and Acid-Base Imbalances

Lewis’s Medical-Surgical Nursing: Assessment and Management of Clinical Problems, 4th Edition is the most comprehensive go-to reference for essential information about all aspects of professional nursing care of patients. Using the nursing process as a framework for practice, the fourth edition has been extensively revised to reflect the rapid changing nature of nursing practice and the increasing focus on key nursing care priorities. Building on the strengths of the third Australian and New Zealand edition and incorporating relevant global nursing research and practice from the prominent US title Medical-Surgical Nursing, 9Th Edition, Lewis’s Medical-Surgical Nursing, 4th Edition is an essential resource for students seeking to understand the role of the professional nurse in the contemporary health environment.

Method of symptom assessment influences cognitive, affective and somatic post-concussion-like symptom base rates

Primary objective: To investigate whether assessment method influences the type of post-concussion-like symptoms. Methods and procedures: Participants were 73 Australian undergraduate students (Mage = 24.14, SD = 8.84; 75.3% female) with no history of mild traumatic brain injury (mTBI). Participants reported symptoms experienced over the previous 2 weeks in response to an open-ended question (free report), mock interview and standardized checklist (British Columbia Post-concussion Symptom Inventory; BC-PSI). Main outcomes and results: In the free report and checklist conditions, cognitive symptoms were reported significantly less frequently than affective (free report: p < 0.001; checklist: p < 0.001) or somatic symptoms (free report: p < 0.001; checklist: p = 0.004). However, in the mock structured interview condition, cognitive and somatic symptoms were reported significantly less frequently than affective symptoms (both p < 0.001). No participants reported at least one symptom from all three domains when assessed by free report, whereas most participants did so when symptoms were assessed by a mock structured interview (75%) or checklist (90%). Conclusions: Previous studies have shown that the method used to assess symptoms affects the number reported. This study shows that the assessment method also affects the type of reported symptoms.

All about that base : differing player experiences in video game genres and the unique case of MOBA games

Video games provide unique interactive player experiences (PX) often categorised into different genres. Prior research has looked at different game genres, but rarely through a PX lens. Especially, PX in the emerging area of massive online battle arena (MOBA) games is not well understood by researchers in the field. We address this knowledge gap by presenting a PX study of different game genres, which we followed up with a second semi-structured interview study about PX in MOBA games. Among the results of our analyses are that games that are likely played with other players, such as MOBA games, stimulate less immersion and presence for players. Additionally, while challenge and frustration are significantly higher in this genre, players get a sense of satisfaction from teamwork, competition and mastery of complex gameplay interactions. Our study is the first to contribute a comprehensive insight into key motivators of MOBA players and how PX in this genre is different from other genres.

Optimising ketocarotenoid production in potato tubers : effect of genetic background, transgene combinations and environment

Astaxanthin is a high value carotenoid produced by some bacteria, a few green algae, several fungi but only a limited number of plants from the genus Adonis. Astaxanthin has been industrially exploited as a feed supplement in poultry farming and aquaculture. Consumption of ketocarotenoids, most notably astaxanthin, is also increasingly associated with a wide range of health benefits,as demonstrated in numerous clinical studies. Currently astaxanthin is produced commercially by chemical synthesis or from algal production systems. Several studies have used a metabolic engineering approach to produce astaxanthin in transgenic plants. Previous attempts to produce transgenic potato tubers biofortified with astaxanthin have met with limited success. In this study we have investigated approaches to optimising tuber astaxanthin content. It is demonstrated that the selection of appropriate parental genotype for transgenic approaches and stacking carotenoid biosynthetic pathway genes with the cauliflower Or gene result in enhanced astaxanthin content, to give six-fold higher tuber astaxanthin content than has been achieved previously. Additionally we demonstrate the effects of growth environment on tuber carotenoid content in both wild type and astaxanthin-producing transgenic lines and describe the associated transcriptome and metabolome restructuring.