Nox2 regulates endothelial cell cycle arrest and apoptosis via p21 (cip1) and p53

Endothelial cells (EC) express constitutively two major isofonns (Nox2 and Nox4) of the catalytic subunit of NADPH oxidase, which is a major source of endothelial reactive oxygen species. However, the individual roles of these Noxes in endothelial function remain unclear. We have investigated the role of Nox2 in nutrient deprivation-induced cell cycle arrest and apoptosis. In proliferating human dermal microvascular EC, Nox2 mRNA expression was low relative to Nox4 (Nox2:Nox4 similar to 1:13), but was upregulated 24 It after starvation and increased to 8 +/- 3.5-fold at 36 h of starvation. Accompanying the upregulation of Nox2, there was a 2.28 +/- 0.18-fold increase in O-2(-); production, a dramatic induction of p21(cip1) and p53, cell cycle arrest, and the onset of apoptosis (all p < 0.05). All these changes were inhibited significantly by in vitro deletion of Nox2 expression and in coronary microvascular EC isolated from Nox2 knockout mice. In Nox2 knockout cells, although there was a 3.8 +/- 0.5fold increase in Nox4 mRNA expression after 36 h of starvation (p < 0.01), neither production nor the p21(cip1) or p53 expression was increased significantly and only 0.46% of cells were apoptotic. In conclusion, Nox2-derived O-2(-), through the modulation of p21(cip1) and p53 expression, participates in endothelial cell cycle regulation and apoptosis. (c) 2007 Elsevier Inc. All rights reserved.

Investigation of language and motor skills in Serbian speaking children with specific language impairment and in typically developing children

Specific language impairment (SLI) is usually defined as a developmental language disorder which does not result from a hearing loss, autism, neurological and emotional difficulties, severe social deprivation, low non-verbal abilities. Children affected with SLI typically have difficulties with the acquisition of different aspects of language and by definition, their impairment is specific to language and no other skills are affected. However, there has been a growing body of literature to suggest that children with SLI also have non-linguistic deficits, including impaired motor abilities. The aim of the current study is to investigate language and motor abilities of a group of thirty children with SLI (aged between 4 and 7) in comparison to a group of 30 typically developing children matched for chronological age. The results showed that the group of children with SLI had significantly more difficulties on the language and motor assessments compared to the control group. The SLI group also showed delayed onset in the development of all motor skills under investigation in comparison to the typically developing group. More interestingly, the two groups differed with respect to which language abilities were correlated with motor abilities, however Imitation of Complex Movements was the unique skill which reliably predicted expressive vocabulary in both typically developing children and in children with SLI.

Ischaemia differentially regulates GABAB receptor subunits in organotypic hippocampal slice cultures

Reduced synaptic inhibition due to dysfunction of ionotropic GABAA receptors has been proposed as one factor in cerebral ischaemia-induced excitotoxic cell death. However, the participation of the inhibitory metabotropic GABAB receptors in these pathological processes has not been extensively investigated. We used oxygen–glucose deprivation (OGD) and NMDA-induced excitotoxicity as models to investigate whether ischaemia-like challenges alter the protein levels of GABAB1 and GABAB2 receptor subunits in rat organotypic hippocampal slice cultures. Twenty-four hours after the insult both OGD and NMDA produced a marked decrease in the total levels of GABAB2 (75%), while there was no significant change in the levels of GABAB1 after OGD, but an increase after NMDA treatment (100%). The GABAB receptor agonist baclofen (100 μM) was neuroprotective following OGD or NMDA treatment if added before or during the insult. GABAB receptors comprise heterodimers of GABAB1 and GABAB2 subunits and our results suggest that the separate subunits are independently regulated in response to extreme neuronal stress. However, because GABAB2 is required for functional surface expression, down-regulation of this subunit removes an important inhibitory feedback mechanism under pathological conditions.

Ornamental Mediterranean plants in the UK: root adaptations to hypoxia and anoxia

Mediterranean species are popular landscape plants in the UK and well suited to the predicted climate change scenarios of hotter, drier summers. What is less clear is how these species will respond to the more unpredictable rainfall patterns also anticipated, where soil water-logging may become more prevalent, especially in urban environments where soil sealing can restrict drainage. Pot experiments on flooding of four Mediterranean species (Cistus × hybridus, Lavandula angustifolia ‘Munstead’, Salvia officinalis and Stachys byzantina) showed that the effects of waterlogging were only severe when the temperature was high and flooding prolonged. All plants survived the flooding in winter, but during the summer a 17-day flood resulted in the death of 30-40% of the Salvia officinalis and Cistus × hybridus. To examine the response of roots to oxygen deprivation over a range of conditions from total absence of oxygen (anoxia), low oxygen (hypoxia) and full aeration, rooted cuttings of Salvia officinalis were grown in a hydroponic-based system and mixtures of oxygen and nitrogen gases bubbled through the media. Anoxia was found to reduce root development dramatically. When the plants were subjected to a period of hypoxia they responded by increasing the production of lateral roots close to the surface thus enabling them to acclimate to subsequent anoxia. This greatly increased their chances of survival.

Making DNA without iron: induction of a manganese-dependent ribonucleotide reductase in response to iron starvation

Ribonucleotide reductases supply cells with their deoxyribonucleotides. Three enzyme types are known, classes I, II and III. Class II enzymes are anaerobic whereas class I enzymes are aerobic, and so class I and II enzymes are often produced by the same organism under opposing oxygen regimes. Escherichia coli contains two types of class I enzyme (Ia and Ib) with the Fe-dependent Ia enzyme (NrdAB) performing the major role aerobically, leaving the purpose of the Ib enzyme (NrdEF) unclear. Several papers have recently focused on the class Ib enzymes showing that they are Mn (rather than Fe) dependent and suggesting that the E. coli NrdEF may function under redox-stress conditions. A paper published in this issue of Molecular Microbiology from James Imlay's group confirms that this unexplained NrdEF Ib enzyme is Mn-dependent, but shows that it does not substitute for NrdAB during redox stress. Instead, a role during iron restriction is demonstrated. Thus, the purpose of NrdEF (and possibly other class Ib enzymes) is to enhance growth under aerobic, low-iron conditions, and to functionally replace the Fe-dependent NrdAB when iron is unavailable. This finding reveals a new mechanism by which bacteria adjust to life under iron deprivation.

A new role for heme, facilitating release of iron from the bacterioferritin iron biomineral

Bacterioferritin (BFR) from Escherichia coli is a member of the ferritin family of iron storage proteins and has the capacity to store very large amounts of iron as an Fe(3+) mineral inside its central cavity. The ability of organisms to tap into their cellular stores in times of iron deprivation requires that iron must be released from ferritin mineral stores. Currently, relatively little is known about the mechanisms by which this occurs, particularly in prokaryotic ferritins. Here we show that the bis-Met-coordinated heme groups of E. coli BFR, which are not found in other members of the ferritin family, play an important role in iron release from the BFR iron biomineral: kinetic iron release experiments revealed that the transfer of electrons into the internal cavity is the rate-limiting step of the release reaction and that the rate and extent of iron release were significantly increased in the presence of heme. Despite previous reports that a high affinity Fe(2+) chelator is required for iron release, we show that a large proportion of BFR core iron is released in the absence of such a chelator and further that chelators are not passive participants in iron release reactions. Finally, we show that the catalytic ferroxidase center, which is central to the mechanism of mineralization, is not involved in iron release; thus, core mineralization and release processes utilize distinct pathways.

Curriculum theory, curriculum policy and the problem of ill-disciplined thinking

This paper examines the implications of policy fracture and arms length governance within the decision making processes currently shaping curriculum design within the English education system. In particular it argues that an unresolved ‘ideological fracture’ at government level has been passed down to school leaders whose response to the dilemma is distorted by the target-driven agenda of arms length agencies. Drawing upon the findings of a large scale on-line survey of history teaching in English secondary schools, this paper illustrates the problems that occur when policy making is divorced from curriculum theory, and in particular from any consideration of the nature of knowledge. Drawing on the social realist theory of knowledge elaborated by Young (2008), we argue that the rapid spread of alternative curricular arrangements, implemented in the absence of an understanding of curriculum theory, undermines the value of disciplined thinking to the detriment of many young people, particularly those in areas of social and economic deprivation.

The shape of change: memetic analysis of poverty definitions from the 1970s to the 2000s

The authors illustrate how notions of poverty are constructed around specific ‘memes’, or replicating units of cultural information, around which concepts and ideas develop and change. Three ‘memes’ characterising definitions of poverty over the previous years were identified: ‘basic needs’, ‘multidimensional’ and ‘deprivation’. The analysis illustrated the semantic space in which each term was utilised and to the extent it changed and modified over time by different actors. The results revealed how ‘memes’ compete with one another across the discourse. Within this competition, older concepts are almost never fully abandoned, but rather repackaged and reutilised. Thus, new definitions of poverty are less innovative than portrayed in the wider literature.

School effectiveness and the displacement of equity discourses in education

An essential aspect of school effectiveness theory is the shift from the social to the organisational context, from the macro- to the micro-culture. The school is represented largely as a bounded institution, set apart, but also in a precarious relationship with the broader social context. It is ironic that at a time when social disadvantage appears to be increasing in Britain and elsewhere, school effectiveness theory places less emphasis on poverty, deprivation and social exclusion. Instead, it places more emphasis on organisational factors such as professional leadership, home/school partnerships, the monitoring of academic progress, shared vision and goals. In this article, the authors evaluate the extent to which notions of effectiveness have displaced concerns about equity in theories of educational change. They explore the extent to which the social structures of gender, ethnicity, sexualities, special needs, social class, poverty and other historical forms of inequality have been incorporated into or distorted and excluded from effectiveness thinking.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.

What next for children's services? Can policy at a local or national level have any significant impact on the outcomes for children and their families?

In England at both strategic and operational levels, policy-makers in the public sector have undertaken considerable work on implementing the findings of the Every Child Matters report and subsequently through the Children's Act 2004. Legislation has resulted in many local authorities seeking to implement more holistic approaches to the delivery of children's services. At a strategic level this is demonstrated by the creation of integrated directorate structures providing for a range of services, from education to children's social care. Such services were generally under the management of the Director of Children's Services, holding statutory responsibilities for the delivery of services formally divided into the three sectors of education, health and social services. At a national level, more fundamental policy developments have sought to establish a framework through which policy-makers can address the underlying causes of deprivation, vulnerability and inequality. The Child Poverty Act, 2010, which gained Royal Assent in 2010, provides for a clear intention to reduce the number of children in poverty, acknowledging that ‘the best way to eradicate child poverty is to address the causes of poverty, rather than only treat the symptoms’. However, whilst the policy objectives of both pieces of legislation hold positive aspirations for children and young people, a change of policy direction through a change of government in May 2010 seems to be in direct contrast to the intended focus of these aims. This paper explores the impact of new government policy on the future direction of children's services both at the national and local levels. At the national level, we question the ability of the government to deliver the aspirations of the Child Poverty Act, 2010, given the broad range of influences and factors that can determine the circumstances in which a child may experience poverty. We argue that poverty is not simply an issue of the pressure of financial deprivation, but that economic recession and cuts in government spending will further increase the number of children living in poverty.

Variation in the use of chemotherapy in lung cancer

Factors influencing the use of chemotherapy for the initial (6 months) treatment of lung cancer in South East England were investigated. The variables explored as possibly influencing the use of chemotherapy were sex, age, the year of diagnosis, the type of lung cancer, the stage, the index of multiple deprivation and the cancer network of residence. Chi2 analysis and multivariate logistic regression models were used to examine the effect of each of the variables on the use of chemotherapy. The results showed a highly significant trend in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 13.6% in 1994 to 29.3% in 2003. However, age, cancer network and type of lung cancer had the strongest influence on the use of chemotherapy. This finding is important when we consider that the NHS Cancer Plan aims at improving inequalities in cancer care in the UK.

Factors influencing the use of antitumoral chemotherapy in the South East of England

Influences on the use of chemotherapy for the treatment of cancer within the South East region of England for patients diagnosed with colorectal, lung, breast and prostate cancer were investigated. The variables investigated as possibly influencing the selection of chemotherapy were the sex of the patients, their age, the year of diagnosis, the cancer site, the cancer stage, the index of multiple deprivation (IMD) and the cancer network of residence. Logistic regression used to adjust the proportion receiving chemotherapy in relation to other variables considered showed significant differences in the proportion of patients receiving chemotherapy between different cancer sites and different networks. There was also a highly significant trend seen in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 10.6% in 1993 to 24.3% in 2002. Age, stage and cancer site seemed to have the most influence on the use of chemotherapy.

Managing artisanal and small-scale mining in forest areas: perspectives from a poststructural political ecology

Artisanal and small-scale mining (ASM) is an activity intimately associated with social deprivation and environmental degradation, including deforestation. This paper examines ASM and deforestation using a broadly poststructural political ecology framework. Hegemonic discourses are shown to consistently influence policy direction, particularly in emerging approaches such as Corporate Social Responsibility and the Forest Stewardship Council. A review of alternative discourses reveals that the poststructural method is useful for critiquing the international policy arena but does not inform new approaches. Synthesis of the analysis leads to conclusions that echo a growing body of literature advocating for policies to become increasingly sensitive to local contexts, synergistic between actors at difference scales, and to be integrated across sectors.

Highly efficient neural differentiation of human somatic stem cells, isolated by minimally invasive periodontal surgery

Neural stem cells (NSCs) are potential sources for cell therapy of neurodegenerative diseases and for drug screening. Despite their potential benefits, ethical and practical considerations limit the application of NSCs derived from human embryonic stem cells (ES) or adult brain tissue. Thus, alternative sources are required to satisfy the criteria of ready accessibility, rapid expansion in chemically defined media and reliable induction to a neuronal fate. We isolated somatic stem cells from the human periodontium that were collected during minimally invasive periodontal access flap surgery as part of guided tissue regeneration therapy. These cells could be propagated as neurospheres in serum-free medium, which underscores their cranial neural crest cell origin. Culture in the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) under serum-free conditions resulted in large numbers of nestin-positive/Sox-2-positive NSCs. These periodontium-derived (pd) NSCs are highly proliferative and migrate in response to chemokines that have been described as inducing NSC migration. We used immunocytochemical techniques and RT-PCR analysis to assess neural differentiation after treatment of the expanded cells with a novel induction medium. Adherence to substrate, growth factor deprivation, and retinoic acid treatment led to the acquisition of neuronal morphology and stable expression of markers of neuronal differentiation by more than 90% of the cells. Thus, our novel method might provide nearly limitless numbers of neuronal precursors from a readily accessible autologous adult human source, which could be used as a platform for further experimental studies and has potential therapeutic implications.