The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

DNA methylation at the novel CpG sites in the promoter of MED15/PCQAP gene as a biomarker for head and neck cancers

Head and neck cancers (HNCs) represent a significant and ever-growing burden to the modern society, mainly due to the lack of early diagnostic methods. A significant number of HNCs is often associated with drinking, smoking, chewing beetle nut, and human papilloma virus (HPV) infections. We have analyzed DNA methylation patterns in tumor and normal tissue samples collected from head and neck squamous cell carcinoma (HNSCC) patients who were smokers. We have identified novel methylation sites in the promoter of the mediator complex subunit 15 (MED15/PCQAP) gene (encoing a co-factor important for regulation of transcription initiation for promoters of many genes), hypermethylated specifically in tumor cells. Two clusters of CpG dinucleotides methylated in tumors, but not in normal tissue from the same patients, were identified. These CpG methylation events in saliva samples were further validated in a separate cohort of HNSCC patients (who developed cancer due to smoking or HPV infections) and healthy controls using methylation-specific PCR (MSP). We used saliva as a biological medium because of its non-invasive nature, close proximity to the tumors, easiness and it is an economically viable option for large-scale screening studies. The methylation levels for the two identified CpG clusters were significantly different between the saliva samples collected from healthy controls and HNSCC individuals (Welch's t-test returning P, 0.05 and Mann-Whitney test P, 0.01 for both). The developed MSP assays also provided a good discriminative ability with AUC values of 0.70 (P, 0.01) and 0.63 (P, 0.05). The identified novel CpG methylation sites may serve as potential non-invasive biomarkers for detecting HNSCC. © the authors.

Canagliflozin : something new for type 2 diabetes, but is it safe and efficacious?

Evaluation of Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab 2013. [Epub ahead of print] and Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomized, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50 INTRODUCTION Inhibition of the sodium-glucose cotransporter 2 (SGLT2), to promote the excretion of glucose, is a new paradigm in the treatment of type 2 diabetes. AREAS COVERED Canagliflozin is an SGLT2 inhibitor, which has been the subject of two recent clinical trials, which are evaluated. EXPERT OPINION Studies with canagliflozin, in subjects with type 2 diabetes, have shown that its use is associated with reductions in HbA1c and body weight and small reductions in blood pressure and triglycerides, while increasing high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. As monotherapy in Japanese subjects, or in comparison with glimepiride in CANTATA-SU (CANagliflozin Treatment and Trial Analysis versus SUlphonylurea), canagliflozin causes a low incidence of hypoglycemia, and this is an advantage over glimepiride. However, one of the disadvantages with canagliflozin, which was also highlighted in CANTATA-SU, is that canagliflozin can cause urogenital infections, which are not observed with other antidiabetic drugs. The Federal Drug Administration has recently approved canagliflozin for use in type 2 diabetes, while directing that a clinical outcome safety trial be undertaken. We are concerned that canagliflozin has been approved for use in type 2 diabetes prior to a clinical outcome study of efficacy being undertaken and without the outcome of further safety testing.

Donald Ezekiel AM : passionate and innovative contact lens practitioner and manufacturer

Donald Ezekiel (known to all as ‘Don’) was born in Singapore on September 12, 1936, to a German mother and Iraqi father. His parents were Jewish refugees, who met in Batavia,1 married and alternately lived in Batavia and Singapore. The family established their primary residence in Singapore after Don’s older brother Eric (later to become a haematologist) was born in 1934. The Ezekiel family was forced to flee in 1941 when the Japanese bombed Singapore and were fortunate to obtain passage on a hospital ship to Perth. They returned to Singapore after the war but left again on their own accord in 1951 due to race riots. The Ezekiels sold up everything in Singapore and decided to settle in Perth...

Experimental Study of crack propagation in carbon steel using acoustic emission

Acoustic emission technique has become a significant and powerful structural health monitoring tool for structures. Researches to date have been done on crack location, fatigue crack propagation in materials and severity assessment of failure using acoustic emission technique. Determining severity of failure in steel structures using acoustic emission technique is still a challenge to accurately determine the relationship between the severity of crack propagation and acoustic emission activities. In this study three point bending test on low carbon steel samples along with acoustic emission technique have been used to determine crack propagation and severity. A notch is introduced at the tension face of the loading point to the samples to initiate the crack. The results show that the percentage of load drop of the steel specimen has a reciprocal relationship with the crack opening i.e. crack opening zones are influenced by the loading rate. In post yielding region, common acoustic emission signal parameters such as, signal strength, energy and amplitudes are found to be higher than those at pre-yielding and at yielding.

Acoustic emission activity from the two main types of small multi-cylinder diesel engine fuel injection systems

Effective fuel injector operation and efficient combustion are two of the most critical aspects when Diesel engine performance, efficiency and reliability are considered. Indeed, it is widely acknowledged that fuel injection equipment faults lead to increased fuel consumption, reduced power, greater levels of exhaust emissions and even unexpected engine failure. Previous investigations have identified fuel injector related acoustic emission activity as being caused by mechanisms such as fuel line pressure build-up; fuel flow through injector nozzles, injector needle opening and closing impacts and premixed combustion related pulses. Few of these investigations however, have attempted to categorise the close association and interrelation that exists between fuel injection equipment function and the acoustic emission generating mechanisms. Consequently, a significant amount of ambiguity remains in the interpretation and categorisation of injector related AE activity with respect to the functional characteristics of specific fuel injection equipment. The investigation presented addresses this ambiguity by detailing a study in which AE signals were recorded and analysed from two different Diesel engines employing the two commonly encountered yet fundamentally different types of fuel injection equipment. Results from tests in which faults were induced into fuel injector nozzles from both indirect-injection and direct-injection engines show that functional differences between the main types of fuel injection equipment results in acoustic emission activity which can be specifically related to the type of fuel injection equipment used.

Cultural beliefs about societal change: A three-mode principal component analysis in China, Australia, and Japan

People’s beliefs about where society has come from and where it is going have personal and political consequences. Here, we conduct a detailed investigation of these beliefs through re-analyzing Kashima et al.’s (Study 2, n = 320) data from China, Australia, and Japan. Kashima et al. identified a “folk theory of social change” (FTSC) belief that people in society become more competent over time, but less warm and moral. Using three-mode principal components analysis, an under-utilized analytical method in psychology, we identified two additional narratives: Utopianism/Dystopianism (people becoming generally better or worse over time) and Expansion/Contraction (an increase/decrease in both positive and negative aspects of character over time). Countries differed in endorsement of these three narratives of societal change. Chinese endorsed the FTSC and Utopian narratives more than other countries, Japanese held Dystopian and Contraction beliefs more than other countries, and Australians’ narratives of societal change fell between Chinese and Japanese. Those who believed in greater economic/technological development held stronger FTSC and Expansion/Contraction narratives, but not Utopianism/Dystopianism. By identifying multiple cultural narratives about societal change, this research provides insights into how people across cultures perceive their social world and their visions of the future.

Reggae borderzones, reggae graveyards: Bob Marley fandom in Bali

The road from Bali’s international airport to the island’s most renowned tourist area, Kuta Beach, leads past a number of establishments claiming affiliation to reggae music and Rastafarianism in large, appropriately coloured billboards. A sign outside a tee shirt shop bears the words RASTA MANIA within a green, yellow and red border, and a stick figure caricaturing negritude, the logo of this clothing label. In the window display hangs a tee shirt, and upon it Bob Marley’s wizened face. His lips pinch a cone-shaped spliff, and he squints behind a veil of airbrushed smoke. A leanto sign on the sidewalk outside Apache Bar announce REGGAE BANDS NIGHTLY. This barn of coconut wood and thatch nestles behind Wendy’s Ice Cream Parlour and Chi Chi’s Mexican Bar. Its timber walls emulate a rustic, spaghetti Western aesthetic and are adorned with portraits of native Americans. In addition to the reggae bands, nightly, Apache bar unites young Japanese women with local ‘guides’.2

Book review: "Hip Hop Japan: Rap and the Paths of Cultural Globalization’ by Ian Condry, Durham: Duke University Press

Had it been published a decade earlier, Hip-hop Japan might have been cited as a good example of the kind of multi-sited ethnography George Marcus (1998) proposes. Hip-hop Japan is a critical study of cultural globalisation. It presents as much theoretical interpretation, discussions of Japanese popular culture in general, and reviews of formulations of the Japanese self by Japanese scholars, as it does of Japanese hip-hop per se. In fact, the latter is relatively thinly described, as Condry’s project is to demonstrate how Japanese hip-hop’s particularities are made up from a mix of US hip-hop, Japanese modes of fandom, contestatory uses of the Japanese language and the specific logics of the Japanese popular music recording industry. The book journeys into these worlds as much as it does into the world of Japanese hip-hop.

Disorganising principles: Corporeal fragmentation and the possibilities for repair

Dancers investigate ever-expanding relationships to embodiment through the variety of unique choreographic signatures that are continually erupting in professional practice. They live fragmented lineages that are interrupted and redirected as they traverse between various projects led by different choreographers or the same choreographer pursuing different creative goals. As contemporary dance continues to reconceive ways of moving, the dominant lineages of dance training are less useful as reference points through which dancers can recalibrate bodily activity and thus rebalance. In this chapter, I examine the impulse towards fragmentation in contemporary dance and explore how moments of agency for dancers might arise and be seized within the complexities of this environment. These issues are discussed in relation to my encounter with a bodywork therapy of Japanese origin, Amatsu, which I studied throughout 2012, and through the teaching principles of Gill Clarke as illuminated through the Minding Motion project, which explored Clarke’s pedagogy for Tanzplan, Germany 2010 (Diehl and Lampert, 2011). Moments from performance and bodywork practice are offered as examples throughout the chapter.

Estimates of lost material stock of buildings and roads due to the great east Japan earthquake and tsunami

This article describes research conducted for the Japanese government in the wake of the magnitude 9.0 earthquake and tsunami that struck eastern Japan on March 11, 2011. In this study, material stock analysis (MSA) is used to examine the losses of building and infrastructure materials after this disaster. Estimates of the magnitude of material stock that has lost its social function as a result of a disaster can indicate the quantities required for reconstruction, help garner a better understanding of the volumes of waste flows generated by that disaster, and also help in the course of policy deliberations in the recovery of disaster-stricken areas. Calculations of the lost building and road materials in the five prefectures most affected were undertaken. Analysis in this study is based on the use of geographical information systems (GIS) databases and statistics; it aims to (1) describe in spatial terms what construction materials were lost, (2) estimate the amount of infrastructure material needed to rehabilitate disaster areas, and (3) indicate the amount of lost material stock that should be taken into consideration during government policy deliberations. Our analysis concludes that the material stock losses of buildings and road infrastructure are 31.8 and 2.1 million tonnes, respectively. This research approach and the use of spatial MSA can be useful for urban planners and may also convey more appropriate information about disposal based on the work of municipalities in disaster-afflicted areas.

Public and private mitigation for natural disasters in Japan

An increasing number of studies analyze the relationship between natural disaster damage and income levels, but they do not consider the distinction between public and private disaster mitigation. This paper empirically distinguishes these two types of mitigation using Japanese prefectural panel data from 1975 to 2007. Our results show that public mitigation rather than private mitigation has contributed to mitigating the total damage resulting from natural disasters. Our estimation of cost-benefit ratios for each prefecture confirms that the mitigation efforts of urban prefectures are less effective than those of rural prefectures in focusing on both large and frequent/small disasters. Hence, urban prefectures need to reassess their public mitigation measures. Furthermore, to lessen the damage resulting from extreme catastrophes, policy makers are required to invest in improved mitigation infrastructures when faced with a high probability of disasters.

Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets

BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition. METHODS Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations. RESULTS Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis. CONCLUSIONS Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Transportation disadvantage impedance indexing: A methodological approach to reduce policy shortcomings

Access to transport systems and the connection to such systems provided to essential economic and social activities are critical to determine households' transportation disadvantage levels. In spite of the developments in better identifying transportation disadvantaged groups, the lack of effective policies resulted in the continuum of the issue as a significant problem. This paper undertakes a pilot case investigation as test bed for a new approach developed to reduce transportation policy shortcomings. The approach, ‘disadvantage-impedance index’, aims to ease transportation disadvantages by employing representative parameters to measure the differences between policy alternatives run in a simulation environment. Implemented in the Japanese town of Arao, the index uses trip-making behaviour and resident stated preference data. The results of the index reveal that even a slight improvement in accessibility and travel quality indicators makes a significant difference in easing disadvantages. The index, integrated into a four-step model, proves to be highly robust and useful in terms of quick diagnosis in capturing effective actions, and developing potentially efficient policies.