An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms

Neurons in the developing brain die via apoptosis after DNA damage, while neurons in the adult brain are generally resistant to these insults. The basis for this resistance is a matter of conjecture. We report here that cerebellar granule neurons (CGNs) in culture lose their competence to die in response to DNA damage as a function of time in culture. CGNs at either 1 day in vitro (DIV) or 7 DIV were treated with the DNA damaging agents camptothecin, UV or gamma-irradiation and neuronal survival measured. The younger neurons were effectively killed by these agents, while the older neurons displayed a significant resistance to killing. Neuronal survival did not change with time in culture when cells were treated with C2-ceramide or staurosporine, agents which do not target DNA. The resistance to UV irradiation developed over time in culture and was not due to changes in mitotic rate. Increases in DNA strand breakage, up-regulation of the levels of both p53 and its phosphorylated form and nuclear translocation of p53 were equivalent in both older and younger neurons, indicating a comparable p53 stress response. In addition, we show that treatment of older neurons with pharmacological inhibitors of distinct components of the DNA repair machinery promotes the accumulation of DNA damage and sensitizes these cells to the toxic effects of UV exposure. These data demonstrate that older neurons appear to be more proficient in DNA repair in comparison to their younger counterparts, and that this leads to increased survival after DNA damage.

Do lutein, zeaxanthin, and macular pigment optical density differ with age or age-related maculopathy?

Background and aims Current age-related macular disease (ARMD) treatment includes antioxidant supplementation. Lutein (L) and zeaxanthin (Z) are antioxidants that make up macularpigment within the retina and may reduce the risk of developing ARMD. Ageing and smoking are leading risk factors for developing ARMD. We investigated differences in dietary, supplemental and retinal L and Z, and smoking habits in healthy younger eyes (HY), healthy older eyes (HO) and eyes with an early form of ARMD called age-related maculopathy (ARM). Methods HO, HY and ARM groups were assessed for dietary intakes of L and Z using food diaries. Smoking habits and self-administered quantities of L and Z were obtained via questionnaire. Retinal L and Z levels (macularpigmentopticaldensity, or MPOD) were determined using heterochromatic flicker photometry. Results No significant difference was demonstrated for dietary L and Z intake (?2 = 4.983, p = 0.083) or for MPOD between groups (F = 0.40, p = 0.67). There was a significant difference between the HY (mean ± sd: 1.20 ± 2.99), HO (4.51 ± 7.05) ARM groups (9.15 ± 12.28) for pack years smoked (?2 = 11.61, p = 0.03). Conclusions Our results do not support the theory that ARM develops as a result of L and Z deficiency. Higher pack years smoked may be a factor in disease development. Dietary and supplementary L and Z levels must be obtained when assessing MPOD between groups or over time.

An investigation into children’s inductive reasoning strategies:What drives the development of category induction?

In a series of studies, I investigated the developmental changes in children’s inductive reasoning strategy, methodological manipulations affecting the trajectory, and driving mechanisms behind the development of category induction. I systematically controlled the nature of the stimuli used, and employed a triad paradigm in which perceptual cues were directly pitted against category membership, to explore under which circumstances children used perceptual or category induction. My induction tasks were designed for children aged 3-9 years old using biologically plausible novel items. In Study 1, I tested 264 children. Using a wide age range allowed me to systematically investigate the developmental trajectory of induction. I also created two degrees of perceptual distractor – high and low – and explored whether the degree of perceptual similarity between target and test items altered children’s strategy preference. A further 52 children were tested in Study 2, to examine whether children showing a perceptual-bias were in fact basing their choice on maturation categories. A gradual transition was observed from perceptual to category induction. However, this transition could not be due to the inability to inhibit high perceptual distractors as children of all ages were equally distracted. Children were also not basing their strategy choices on maturation categories. In Study 3, I investigated category structure (featural vs. relational category rules) and domain (natural vs. artefact) on inductive preference. I tested 403 children. Each child was assigned to either the featural or relational condition, and completed both a natural kind and an artefact task. A further 98 children were tested in Study 4, on the effect of using stimuli labels during the tasks. I observed the same gradual transition from perceptual to category induction preference in Studies 3 and 4. This pattern was stable across domains, but children developed a category-bias one year later for relational categories, arguably due to the greater demands on executive function (EF) posed by these stimuli. Children who received labels during the task made significantly more category choices than those who did not receive labels, possibly due to priming effects. Having investigated influences affecting the developmental trajectory, I continued by exploring the driving mechanism behind the development of category induction. In Study 5, I tested 60 children on a battery of EF tasks as well as my induction task. None of the EF tasks were able to predict inductive variance, therefore EF development is unlikely to be the driving factor behind the transition. Finally in Study 6, I divided 252 children into either a comparison group or an intervention group. The intervention group took part in an interactive educational session at Twycross Zoo about animal adaptations. Both groups took part in four induction tasks, two before and two a week after the zoo visits. There was a significant increase in the number of category choices made in the intervention condition after the zoo visit, a result not observed in the comparison condition. This highlights the role of knowledge in supporting the transition from perceptual to category induction. I suggest that EF development may support induction development, but the driving mechanism behind the transition is an accumulation of knowledge, and an appreciation for the importance of category membership.

Development of esophageal hypersensitivity following experimental duodenal acidification

OBJECTIVES: As visceral afferents from different regions of the gastrointestinal tract converge at the level of the spinal cord, we hypothesized that sensitization of one gut organ would induce visceral hypersensitivity in another gut organ, remote to the sensitizing stimulus. METHODS: Protocol 1: Eight healthy male volunteers, age 30 +/- 8.2 yr, underwent three studies on different days. Esophageal pain thresholds (PT) were recorded at 10-min intervals prior to and for 2 h following a 30-min duodenal infusion of either 0.15 M hydrochloric acid (HCl), saline, or no infusion. Five subjects repeated the study to demonstrate reproducibility. Protocol 2: Esophageal evoked potentials (EEP) were studied in six subjects on two occasions prior to and 1 h after a 30-min duodenal infusion of 0.15 M HCl or saline. RESULTS: Protocol 1: After acid infusion, there were reproducible reductions in esophageal PT (ICC = 0.88), which were maximal at 110 min (15.05 +/- 2.25 mA) (p < 0.002). Following saline infusion there was an increase in esophageal PT (ICC = 0.71), which was similar to the no-infusion condition (6.21 +/- 1.54 mA vs 8.5 + 7.6 mA; p > 0.05). Protocol 2: Esophageal sensation scores increased (p= 0.02) after acid, but not after saline infusion (p= 0.1). A comparison of the latencies of EEP components prior to and following acid and saline infusion revealed a reduction in the N1 (p= 0.02) and P2 components (p= 0.04). CONCLUSION: This study provides the first objective evidence that duodenal acidification can induce esophageal hypersensitivity associated with changes in sensitivity of the central visceral pain pathway. As the esophagus was remote from the sensitizing stimulus, central sensitization of spinal dorsal horn neurons is likely to have contributed to these changes.

The development of color categories in two languages: a longitudinal study

This study unites investigations into the linguistic relativity of color categories with research on children's category acquisition. Naming, comprehension, and memory for colors were tracked in 2 populations over a 3-year period. Children from a seminomadic equatorial African culture, whose language contains 5 color terms, were compared with a group of English children. Despite differences in visual environment, language, and education, they showed similar patterns of term acquisition. Both groups acquired color vocabulary slowly and with great individual variation. Those knowing no color terms made recognition errors based on perceptual distance, and the influence of naming on memory increased with age. An initial perceptually driven color continuum appears to be progressively organized into sets appropriate to each culture and language. PsycINFO Database Record (c) 2009 APA, all rights reserved

A comparison of the vocational training system of Britain and West Germany as experienced by minimum-age school leavers.

The sectoral and occupational structure of Britain and West Germany has increasingly changed over the last fifty years from a manual manufacturing based to a non-manual service sector based one. There has been a trend towards more managerial and less menial type occupations. Britain employs a higher proportion of its population in the service sector than in manufacturing compared to West Germany, except in retailing, where West Germany employs twice as many people as Britain. This is a stable sector of the economy in terms of employment, but the requirements of the workforce have changed in line with changes in the industry in both countries. School leavers in the two countries, faced with the same options (FE, training schemes or employment) have opted for the various options in different proportions: young Germans are staying longer in education before embarking on training and young Britons are now less likely to go straight into employment than ten years ago. Training is becoming more accepted as the normal route into employment with government policy leading the way, but public opinion still slow to respond. This study investigates how vocational training has adapted to the changing requirements of industry, often determined by technological advancements. In some areas e.g. manufacturing industry the changes have been radical, in others such as retailing they have not, but skill requirements, not necessarily influenced by technology have changed. Social-communicative skills, frequently not even considered skills and therefore not included in training are coming to the forefront. Vocational training has adapted differently in the two countries: in West Germany on the basis of an established over-defined system and in Britain on the basis of an out-dated ill-defined and almost non-existent system. In retailing German school leavers opt for two or three year apprenticeships whereas British school leavers are offered employment with or without formalised training. The publicly held view of the occupation of sales assistant is one of low-level skill, low intellectual demands and a job anyone can do. The traditional skills - product knowledge, selling and social-communicative skills have steadily been eroded. In the last five years retailers have recognised that a return to customer service, utilising the traditional skills was going to be needed of their staff to remain competitive. This requires training. The German retail training system responded by adapting its training regulations in a long consultative process, whereas the British experimented with YTS, a formalised training scheme nationwide being a new departure. The thesis evaluates the changes in these regulations. The case studies in four retail outlets demonstrate that it is indeed product knowledge and selling and social-communicative skills which are fundamental to being a successful and content sales assistant in either country. When the skills are recognised and taught well and systematically the foundations for career development in retailing are laid in a labour market which is continually looking for better qualified workers. Training, when planned and conducted professionally is appreciated by staff and customers and of benefit to the company. In retailing not enough systematic training, to recognisable standards is carried out in Britain, whereas in West Germany the training system is nevertheless better prepared to show innovative potential as a structure and is in place on which to build. In Britain the reputation of the individual company has a greater role to play, not ensuring a national provision of good training in retailing.

A survey of some small firms in the rural areas of England: their structure and functions, with special reference to factors that affect their development

This study was concerned with the structure, functions and development, especially the performance, of some rural small firms associated with the Council for Small Industries in Rural Areas (C?SIRA) of England. Forty firms were used as the main basis of analysis. For some aspects of the investigation, however, data from another 54 firms, obtained indirectly through nine CoSIRA Organisers, were also used. For performance-analysis, the 40 firms were firstly ranked according to their growth and profitability rates which were calculated from their financial data. Then each of the variables hypothesised to be related to performance was tested to ascertain its relationship with performance, using the Spearman's Rank Correlation technique. The analysis indicated that each of the four factors .. the principal, the firm itself, its management, and the environment - had a bearing upon the performance of the firm. Within the first factor, the owner-manager's background and attitudes were found to be most important; in the second, the firm's size, age and scope of activities were also found to be correlated with performance; with respect to the third, it was revealed that firms which practised some forms of systems in planning, control and costing performed better than those which did not and, finally with respect to the fourth factor, it was found that some of the services provided by CoSIRA, especially credit finance, were facilitative to the firm's performance. Another significant facet of the firms highlighted by the study was their multifarious roles. These, meeting economic, psychological, sociological and political needs, were considered to be most useful to man and his society. Finally, the study has added light to the structural characteristics of the sampled firms, including various aspects of their development, orientation and organisation, as well as their various structural strengths and weakness. ' .

The development of collaborative skills in young children

This thesis examines young children's early collaborative development when engaged in joint tasks with both a peer and a parent. It begins by examining how the term "collaborative" has been applied and researched in previous literature. As collaboration is found to usually require dialogue, and intersubjectivity is seen as an important component in the construction of both collaboration and dialogue, the ability to construct intersubjectivity is the subject of the rest of the chapter. The chapter concludes by introducing the research questions that underpin the experiments that follow. A number of experiments are then described. Experiments 1 and 2 investigate age differences in interaction styles and the communication strategies used by similar aged dyads. Experiments 3 and 4 investigate differences due to the age of the child and/or the status of the information giver (either parent or child) in the styles of interaction and the communication strategies used by parent and child dyads. Experiment 5 investigates the benefits of collaborating with a parent, and finally, Experiment 6 examines the collaborative ability of pre-schools. The thesis identifies a series of skills required for successful collaboration. These include recognition of a joint goal and the need to suppress individual desires, the ability to structure joint interaction, moving from role-based to a negotiating style, and communicative skills, for example, asking for clarification. Other reasons for children's failure in collaborative tasks involve task-related skills, such as the development of spatial terms, and failure to recognise the need for accuracy. The findings support Vygotsky's theory that when working with an adult, children perform at a higher level than when working with a peer. Evidence was also found of parents scaffolding the interaction for their children. However, further research is necessary to establish that such scaffolding skills affect the child's development of collaborative interactive skills.

The chromatic visual evoked response as an indication of visual development

In an endeavour to provide further insight into the maturation of the cortical visual system in human infants, chromatic transient pattern reversal visual evoked potentials to red/green stimuli, were studied in a group of normal full term infants between the ages of 1 and 14 weeks post term in both cross sectional and longitudinal studies. In order to produce stimuli in which luminance cues had been eliminated with an aim to eliciting a chromatic response, preliminary studies of isoluminance determination in adults and infants were undertaken using behavioural and electrophysiological techniques. The results showed close similarity between the isoluminant ratio for adults and infants and all values were close to photometric isoluminance. Pattern reversal VEPs were recorded to stimuli of a range of red/green luminance ratios and an achromatic checkerboard. No transient VEP could be elicited with an isoluminant chromatic pattern reversal stimulus from any infant less than 7 weeks post term and similarly, all infants more than 7 weeks post term showed clear chromatic VEPs. The chromatic response first appeared at that age as a major positive component (P1) of long latency. This was delayed and reduced in comparison to the achromatic response. As the infant grew older, the latency of the P1 component decreased with the appearance of N1 and N by the 10th week post term. This finding was consistent throughout all infants assessed. In a behavioural study, no infant less than 7 weeks post term demonstrated clear discrimination of the chromatic stimulus, while those infants older than 7 weeks could do so. These findings are reviewed with respect to current neural models of visual development.

The development of the visual system in pre-term infants as assessed by electrophysiological techniques

In an endeavour to provide further insight into the maturation of the human visual system, the contiguous development of the pattern reversal VEP, flash VEP and flash ERG was studied in a group of neurologically normal pre-term infants, born between 28 and 35 weeks gestation. Maturational changes were observed in all the evoked electrophysiological responses recorded, these were mainly characterised by an increase in the complexity of the waveform and a shortening in the latency of the response. Initially the ERG was seen to consist of a broad b-wave only, with the a-wave emerging at an average age of 40 weeks PMA. The a-wave showed only a slight reduction in latency and a modest increase in amplitude as the infant grows older, whereas the changes seen in the ERG b-wave were much more dramatic. Pattern reversal VEPs were successfully recorded for the first time during the pre-term period. Flash VEPs were also recorded for comparison. The neonatal pattern reversal VEP consistently showed a major positive component (P1) of long latency. As the infant grew older, the latency of the P1 component decreased and was found to be negatively correlated with PMA at recording. The appearance of the N1 and N2 components became more frequent as the infant matured. The majority of infants were found to be myopic at birth and refractive error was correlated with PMA, with emmetropisation occurring at about 45 weeks PMA. The pattern reversal VEP in response to 2o checks was apparently unaffected by refractive error.

Objective and psychophysical studies of infant visual development

Distortion or deprivation of vision during an early `critical' period of visual development can result in permanent visual impairment which indicates the need to identify and treat visually at-risk individuals early. A significant difficulty in this respect is that conventional, subjective methods of visual acuity determination are ineffective before approximately three years of age. In laboratory studies, infant visual function has been quantified precisely, using objective methods based on visual evoked potentials (VEP), preferential looking (PL) and optokinetic nystagmus (OKN) but clinical assessment of infant vision has presented a particular difficulty. An initial aim of this study was to evaluate the relative clinical merits of the three techniques. Clinical derivatives were devised, the OKN method proved unsuitable but the PL and VEP methods were evaluated in a pilot study. Most infants participating in the study had known ocular and/or neurological abnormalities but a few normals were included for comparison. The study suggested that the PL method was more clinically appropriate for the objective assessment of infant acuity. A study of normal visual development from birth to one year was subsequently conducted. Observations included cycloplegic refraction, ophthalmoscopy and preferential looking visual acuity assessment using horizontally and vertically oriented square wave gratings. The aims of the work were to investigate the efficiency and sensitivity of the technique and to study possible correlates of visual development. The success rate of the PL method varied with age; 87% of newborns and 98% of infants attending follow-up successfully completed at least one acuity test. Below two months monocular acuities were difficult to secure; infants were most testable around six months. The results produced were similar to published data using the acuity card procedure and slightly lower than, but comparable with acuity data derived using extended PL methods. Acuity development was not impaired in infants found to have retinal haemorrhages as newborns. A significant relationship was found between newborn binocular acuity and anisometropia but not with other refractive findings. No strong or consistent correlations between grating acuity and refraction were found for three, six or twelve months olds. Improvements in acuity and decreases in levels of hyperopia over the first week of life were suggestive of recovery from minor birth trauma. The refractive data was analysed separately to investigate the natural history of refraction in normal infants. Most newborns (80%) were hyperopic, significant astigmatism was found in 86% and significant anisometropia in 22%. No significant alteration in spherical equivalent refraction was noted between birth and three months, a significant reduction in hyperopia was evident by six months and this trend continued until one year. Observations on the astigmatic component of the refractive error revealed a rather erratic series of changes which would be worthy of further investigation since a repeat refraction study suggested difficulties in obtaining stable measurements in newborns. Astigmatism tended to decrease between birth and three months, increased significantly from three to six months and decreased significantly from six to twelve months. A constant decrease in the degree of anisometropia was evident throughout the first year. These findings have implications for the correction of infantile refractive error.

Development of visual evoked responses to tritan,red-green and luminance stimuli in human infants

The principal aim of this work was to investigate the development of the S-cone colour-opponent pathway in human infants aged 4 weeks to 6 months. This was achieved by recording transient visual evoked responses to pattern-onset stimuli along a tritanopic confusion axis (tritan stimuli) at and around the adult isoluminant match. For comparison, visual evoked responses to red-green and luminance-modulated stimuli were recorded from the same infants at the same ages. Evoked responses were also recorded from colour-normal adults for comparison with those of the infants. The transient VEP allowed observation of response morphology as luminance differences were introduced to the chromatic stimuli. In this way, an estimate of isoluminance was possible in infants. Estimated isoluminant points for a group of six infants aged 6 to 10 weeks closely approximated the adult isoluminant match. This finding has implications for the use of photometric isoluminance in infant work, and suggests that photopic spectral sensitivity is similar in infants and adults. Abnormalities of the visual evoked responses to tritan, red-green and luminance-modulated stimuli in an infant with cystic fibrosis are reported. The results suggest abnormal function of the retino-striate visual pathway in this infant, and it is argued that these may be secondary to his illness, although data from more infants with cystic fibrosis are needed to clarify this further. A group of nine healthy infants demonstrated evoked responses to tritan stimuli by 4 to 10 weeks and to red-green stimuli by 6 to 11 weeks post-term age. Responses to luminance-modulated stimuli were present in all nine infants at the earliest age tested, namely 4 weeks post-term. The slightly earlier age of onset of evoked responses to tritan stimuli than for red-green may be explained by the relatively lower cone contrast afforded by red-green stimuli. Latency of the evoked response to both types of chromatic stimuli and to luminance-modulated stimuli decreased with age at a similar rate, suggesting that the visual pathways transmitting luminance and chromatic information mature at similar rates in young infants.

Development of a multicellular co-culture model of normal and cystic fibrosis human airways in vitro

Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians and arises due to mutations in a chloride channel, called cystic fibrosis transmembrane conductance regulator. A hallmark of this disease is the chronic bacterial infection of the airways, which is usually, associated with pathogens such as Pseudomonas aeruginosa, S. aureus and recently becoming more prominent, B. cepacia. The excessive inflammatory response, which leads to irreversible lung damage, will in the long term lead to mortality of the patient at around the age of 40 years. Understanding the pathogenesis of CF currently relies on animal models, such as those employing genetically-modified mice, and on single cell culture models, which are grown either as polarised or non-polarised epithelium in vitro. Whilst these approaches partially enable the study of disease progression in CF, both types of models have inherent limitations. The overall aim of this thesis was to establish a multicellular co-culture model of normal and CF human airways in vitro, which helps to partially overcome these limitations and permits analysis of cell-to-cell communication in the airways. These models could then be used to examine the co-ordinated response of the airways to infection with relevant pathogens in order to validate this approach over animals/single cell models. Therefore epithelial cell lines of non-CF and CF background were employed in a co-culture model together with human pulmonary fibroblasts. Co-cultures were grown on collagen-coated permeable supports at air-liquid interface to promote epithelial cell differentiation. The models were characterised and essential features for investigating CF infections and inflammatory responses were investigated and analysed. A pseudostratified like epithelial cell layer was established at air liquid interface (ALI) of mono-and co-cultures and cell layer integrity was verified by tight junction (TJ) staining and transepithelial resistance measurements (TER). Mono- and co-cultures were also found to secrete the airway mucin MUC5AC. Influence of bacterial infections was found to be most challenging when intact S. aureus, B. cepacia and P. aeruginosa were used. CF mono- and co-cultures were found to mimic the hyperinflammatory state found in CF, which was confirmed by analysing IL-8 secretions of these models. These co-culture models will help to elucidate the role fibroblasts play in the inflammatory response to bacteria and will provide a useful testing platform to further investigate the dysregulated airway responses seen in CF.

Preterm infants with video-EEG confirmed seizures:outcome at 30 months of age

Our aim was to identify early predictors of poor neurodevelopmental outcome and of subsequent epilepsy in very early preterm and late preterm newborns with neonatal seizures.

Institutions, finance and the level of development:the impact on entrepreneurship in transition

We investigate the impact of institutions on entrepreneurial entry, based on a large cross-country sample, combining working age population data generated by the GEM project with macro level indicators. Our four key findings indicate that: (a) institutional obstacles to entrepreneurship have different impact in rich countries compared to poor countries; (b) institutional obstacles have a stronger impact on 'opportunity entrepreneurship' than on 'necessity entrepreneurship'; (c) two institutional indicators - property right protection and access to finance - appear to have a dominant impact on entrepreneurship; (d) institutions have a long term impact. More than ten years after the Soviet system imploded in Central and Eastern Europe, these countries still experience significantly lower levels of entrepreneurship than economies coming from different legal traditions.