Six theories of neoliberalism

This article takes as its starting point the observation that neoliberalism is a concept that is ‘oft-invoked but ill-defined’. It provides a taxonomy of uses of the term neoliberalism to include: (1) an all-purpose denunciatory category; (2) ‘the way things are’; (3) an institutional framework characterizing particular forms of national capitalism, most notably the Anglo-American ones; (4) a dominant ideology of global capitalism; (5) a form of governmentality and hegemony; and (6) a variant within the broad framework of liberalism as both theory and policy discourse. It is argued that this sprawling set of definitions are not mutually compatible, and that uses of the term need to be dramatically narrowed from its current association with anything and everything that a particular author may find objectionable. In particular, it is argued that the uses of the term by Michel Foucault in his 1978–9 lectures, found in The Birth of Biopolitics, are not particularly compatible with its more recent status as a variant of dominant ideology or hegemony theories. It instead proposes understanding neoliberalism in terms of historical institutionalism, with Foucault’s account of historical change complementing MaxWeber’s work identifying the distinctive economic sociology of national capitalisms.

Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: Potential markers for aggressive phenotypes

BACKGROUND AND OBJECTIVES Polymorphisms of the VEGF gene are known to affect the biological behaviour of cancers but have seldom been studied in thyroid cancer. The aim of the current study is to evaluate the prevalence and relevance of VEGF-A polymorphisms and mRNA expression in papillary thyroid carcinoma (PTC). MATERIALS AND METHODS Genomic DNA and total RNA were isolated from paraffin-embedded tissue from 91 PTC (51 conventional PTC and 40 follicular variant) and 78 control thyroid tissues. Three DNA polymorphisms (+936C > T, +405C > G and -141A > C) in the 3' and 5' untranslated region (3'-UTR, 5'-UTR) of VEGF-A were studied using PCR and RFLP. Also, the mRNA expression of VEGF-A in these tissues was studied by real-time PCR. RESULTS Distribution of polymorphisms in the 5'-UTR (VEGF-VEGF -141A > C and +405C > G) and 3'-UTR (VEGF +936C > T) were all significantly different in PTC and benign thyroid tissue (p = 0.0001, 0.001 and 0.028 respectively). The VEGF -141 C allele was more common in PTC with lymph node metastases (p = 0.026). VEGF + 405 Galleles andVEGF +936 CC genotype were more common in PTC of advanced pathological staging (p = 0.018 and 0.017 respectively). Also, increased expression of VEGF-A mRNA was noted in PTC compared to control (p = 0.009). Within the group of patients with conventional PTC, those with lymph nodal metastases had a higher level of VEGF-A mRNA expression than other patients (p = 0.0003). CONCLUSION These findings suggest that VEGF polymorphisms and mRNA expression may predict the aggressiveness behaviour of thyroid cancer.

Signet-ring cell carcinoma of colorectum : current perspectives and molecular biology

PURPOSE Colorectal signet-ring cell carcinoma (SRCC) is rare, and very little detailed information on the molecular biology of the disease is available. METHODS The literature on the clinical, pathological and, in particular, the molecular biology of this rare entity was critically reviewed. The reviewed articles take into account a total of 1,817 cases of SRCC, but only 143 cases have molecular data available. The characteristics of two patients with colorectal SRCC were also discussed. RESULTS Colorectal SRCC mostly occurs in younger patients, is larger and has different site predilection compared with conventional colorectal adenocarcinoma. It can occur as one of the synchronous cancers in the colorectum. The cancer is usually diagnosed at advanced stages because of the late manifestation of symptoms, and aggressive treatment strategy is required. Limited reports in the literature have shown that the variant of colorectal cancer demonstrated a different pattern of genetic alterations of common growth kinase-related oncogenes (K-ras, BRAF), tumour suppressor genes (p53, p16), gene methylation and cell adhesion-related genes related to the Wingless signalling pathway (E-cadherin and beta-catenin) from conventional colorectal adenocarcinoma. Colorectal SRCC also showed high expression of mucin-related genes and genes related to the gastrointestinal system. There was also a higher prevalence of microsatellite instability-high tumours and low Cox-2 expression in colorectal SRCC as opposed to conventional adenocarcinoma. CONCLUSIONS Colorectal SRCC has unique molecular pathological features. The unique molecular profiles in SRCC may provide molecular-based improvements to patient management in colorectal SRCC.

Crafting and retelling everyday lives : disabled people's contribution to bioethical concerns

This commentary draws out themes from the narrative symposium on “living with the label “disability”” from the perspective of auto/biography and critical disability studies in the humanities. It notes the disconnect between the experiences discussed in the stories and the preoccupations of bioethicists. Referencing Rosemarie Garland-Thompson’s recent work, it suggests that life stories by people usually described as “disabled” offer narrative, epistemic and ethical resources for bioethics. The commentary suggests that the symposium offers valuable conceptual tools and critiques of taken-for-granted terms like “dependency”. It notes that these narrators do not un–problematically embrace the term “disability”, but emphasize the need to redefine, strategically deploy or reject this term. Some accounts are explicitly critical of medical practitioners while others redefine health and wellbeing, emphasizing the need for reciprocity and respect for the knowledge of people with disability, including knowledge from their experience of “the variant body” (Leach Scully, 2008).

Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.

Contrast transfer function correction applied to cryo-electron tomography and sub-tomogram averaging

Cryo-electron tomography together with averaging of sub-tomograms containing identical particles can reveal the structure of proteins or protein complexes in their native environment. The resolution of this technique is limited by the contrast transfer function (CTF) of the microscope. The CTF is not routinely corrected in cryo-electron tomography because of difficulties including CTF detection, due to the low signal to noise ratio, and CTF correction, since images are characterised by a spatially variant CTF. Here we simulate the effects of the CTF on the resolution of the final reconstruction, before and after CTF correction, and consider the effect of errors and approximations in defocus determination. We show that errors in defocus determination are well tolerated when correcting a series of tomograms collected at a range of defocus values. We apply methods for determining the CTF parameters in low signal to noise images of tilted specimens, for monitoring defocus changes using observed magnification changes, and for correcting the CTF prior to reconstruction. Using bacteriophage PRDI as a test sample, we demonstrate that this approach gives an improvement in the structure obtained by sub-tomogram averaging from cryo-electron tomograms.

Adenovirus species C is associated with chronic suppurative lung diseases in children

Background The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). Methods Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV+). Presence of bacterial infection (defined as ≥104 colony-forming units/mL) was compared between BAL HAdV+ and HAdV negative (HAdV−) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. Results Species C HAdVs were identified in 23 of 24 (96%) HAdV+ children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV+ BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38–7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV+. Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). Conclusions HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV+ of the lower airways and influences the likelihood of bacterial coinfection

Cloning and tissue distribution of novel splice variants of the ovine ghrelin gene

Background The ghrelin axis is involved in the regulation of metabolism, energy balance, and the immune, cardiovascular and reproductive systems. The manipulation of this axis has potential for improving economically valuable traits in production animals, and polymorphisms in the ghrelin (GHRL) and ghrelin receptor (GHSR) genes have been associated with growth and carcass traits. Here we investigate the structure and expression of the ghrelin gene (GHRL) in sheep, Ovis aries. Results We identify two ghrelin mRNA isoforms, which we have designated Δex2 preproghrelin and Δex2,3 preproghrelin. Expression of Δex2,3 preproghrelin is likely to be restricted to ruminants, and would encode truncated ghrelin and a novel C-terminal peptide. Both Δex2 preproghrelin and canonical preproghrelin mRNA isoforms were expressed in a range of tissues. Expression of the Δex2,3 preproghrelin isoform, however, was restricted to white blood cells (WBC; where the wild-type preproghrelin isoform is not co-expressed), and gastrointestinal tissues. Expression of Δex2 preproghrelin and Δex2,3 preproghrelin mRNA was elevated in white blood cells in response to parasitic worm (helminth) infection in genetically susceptible sheep, but not in resistant sheep. Conclusions The restricted expression of the novel preproghrelin variants and their distinct WBC expression pattern during parasite infection may indicate a novel link between the ghrelin axis and metabolic and immune function in ruminants.

Stop-signal task difficulty and the right inferior frontal gyrus

The stop-signal paradigm is increasingly being used as a probe of response inhibition in basic and clinical neuroimaging research. The critical feature of this task is that a cued response is countermanded by a secondary ‘stop-signal’ stimulus offset from the first by a ‘stop-signal delay’. Here we explored the role of task difficulty in the stop-signal task with the hypothesis that what is critical for successful inhibition is the time available for stopping, that we define as the difference between stop-signal onset and the expected response time (approximated by reaction time from previous trial). We also used functional magnetic resonance imaging (fMRI) to examine how the time available for stopping affects activity in the putative right inferior frontal gyrus and presupplementary motor area (right IFG-preSMA) network that is known to support stopping. While undergoing fMRI scanning, participants performed a stop-signal variant where the time available for stopping was kept approximately constant across participants, which enabled us to compare how the time available for stopping affected stop-signal task difficulty both within and between subjects. Importantly, all behavioural and neuroimaging data were consistent with previous findings. We found that the time available for stopping distinguished successful from unsuccessful inhibition trials, was independent of stop-signal delay, and affected successful inhibition depending upon individual SSRT. We also found that right IFG and adjacent anterior insula were more strongly activated during more difficult stopping. These findings may have critical implications for stop-signal studies that compare different patient or other groups using fixed stop-signal delays.

Influence of polymorphisms of GSTM1 and GSTT1 for risk of renal cell cancer in workers with long-term high occupational exposure to trichloroethene

Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 (GSTM1 +) and 18 at least one functional GSTT1 (GSTT1 +). Among the 48 reference workers, 17 were GSTM1 + and 31 were GSTT1 +. Odds ratios for renal cell cancer were 2.7 for GSTM1 + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.

Occupational and non-occupational risk factors in bladder cancer patients in an industrialized area located in former East-Germany [Berufliche und außerberufliche Risikofaktoren für das Harnblasenkarzinom in einem ehemaligen Industriegebiet der neuen Bundesländer]

Purpose: Several occupational carcinogens are metabolized by polymorphic enzymes. The distribution of the polymorphic enzymes N-acetyltransferase 2 (NAT2; substrates: aromatic amines), glutathione S-transferase M1 (GSTM1; substrates: e.g., reactive metabolites of polycyclic aromatic hydrocarbons), and glutathione S-transferase T1 (GSTT1; substrates: small molecules with 1-2 carbon atoms) were investigated. Material and Methods: At the urological department in Lutherstadt Wittenberg, 136 patients with a histologically proven transitional cell cancer of the urinary bladder were investigated for all occupations performed for more than 6 months. Several occupational and non-occupational risk factors were asked. The genotypes of NAT2, GSTM1, and GSTT1 were determined from leucocyte DNA by PCR. Results: Compared to the general population in Middle Europe, the percentage of GSTT1 negative persons (22.1 %) was ordinary; the percentage of slow acetylators (59.6%) was in the upper normal range, while the percentage of GSTM1 negative persons (58.8%) was elevated in the entire group. Shifts in the distribution of the genotypes were observed in subgroups who had been exposed to asbestos (6/6 GSTM1 negative, 5/6 slow acetylators), rubber manufacturing (8/10 GSTM1 negative), and chlorinated solvents (9/15 GSTM1 negative). Conclusions: The overrepresentation of GSTM1 negative bladder cancer patients also in this industrialized area and more pronounced in several occupationally exposed subgroups points to an impact of the GSTM1 negative genotype in bladder carcinogenesis. [Article in German]

Cytochrome p450 1b1, a new keystone in gene-environment interactions related to human head and neck cancer?

Alcohol consumption and tobacco smoking are major causes of head and neck cancers, and regional differences point to the importance of research into gene-environment interactions. Much interest has been focused on polymorphisms of CYP1A1 and of GSTM1 and GSTT1, but a number of studies have not demonstrated significant effects. This has mostly been ascribed to small sample sizes. In general, the impact of polymorphisms of metabolic enzymes appears inconsistent, with some reports of weak-to-moderate associations, and with others of no elevation of risks. The classical cytochrome P450 isoenzyme considered for metabolic activation of polycyclic aromatic hydrocarbons (PAH) is CYP1A1. A new member of the CYP1 family, CYP1B1, was cloned in 1994, currently representing the only member of the CYP1B subfamily. A number of single nucleotide polymorphisms of the CYP1B1 gene have been reported. The amino acid substitutions Val432Leu (CYP1B1*3) and Asn453Ser (CYP1B1*4), located in the heme binding domain of CYP1B1, appear as likely candidates to be linked with biological effects. CYP1B1 activates a wide range of PAH, aromatic and heterocyclic amines. Very recently, the CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squamous 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 pointed to interactive effects. This provides new molecular evidence that tobacco smoke-specific compounds relevant to head and neck carcinogenesis are metabolically activated through CYP1B1 and is consistent with a major pathogenetic relevance of PAH as ingredients of tobacco smoke.

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.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Effects of dietary folate intake on migraine disability and frequency

Objective Migraine is a highly disabling disease affecting a significant proportion of the Australian population. The Methylenetetrahydrofolate Reductase (MTHFR) C677T variant has been associated with increased levels of homocysteine and risk of migraine with aura (MA). Folic acid, Vitamin B6 and B12 supplementation has been previously shown to reduce increased levels of homocysteine and decrease migraine symptoms. However the influence of dietary folate intake on migraine has been unclear. The aim of the current study was to analyse the association of dietary folate intake in the form of dietary folate equivalent (DFE), folic acid (FA) and total food folate (TFF) on migraine frequency, severity and disability. Methods A cohort of 141 adult females of Caucasian descent with MA was genotyped for the MTHFRC677T variant using restriction enzyme digestion. Dietary folate information was collected from all participants and analysed using the “FoodWorks” 2009 package. Folate consumption was compared to migraine frequency, severity and disability using linear regression. Results A significant inverse relation was observed between DFE [R2= 0.201, P= 0.045, CI (-0.004, -0.001)] and FA [R2= 0.255, P= 0.036, 95% CI (-0.009, -0.002)] consumption and migraine frequency. It was also observed that in individuals with the CC genotype for the MTHFR C677T variant, migraine frequency was significantly linked to FA consumption [R2= 0.077, P= 0.029, CI (-0.009, -0.005)]. Conclusions The results from this study indicate that folate intake in the form of folic acid may influence migraine frequency in female MA sufferers.