Conditional volatility and firm size:an empirical analysis of UK equity portfolios

The techniques and insights from two distinct areas of financial economic modelling are combined to provide evidence of the influence of firm size on the volatility of stock portfolio returns. Portfolio returns are characterized by positive serial correlation induced by the varying levels of non-synchronous trading among the component stocks. This serial correlation is greatest for portfolios of small firms. The conditional volatility of stock returns has been shown to be well represented by the GARCH family of statistical processes. Using a GARCH model of the variance of capitalization-based portfolio returns, conditioned on the autocorrelation structure in the conditional mean, striking differences related to firm size are uncovered.

Data transmission by frequency-hopped multilevel frequency shift keying

Spread spectrum systems make use of radio frequency bandwidths which far exceed the minimum bandwidth necessary to transmit the basic message information.These systems are designed to provide satisfactory communication of the message information under difficult transmission conditions. Frequency-hopped multilevel frequency shift keying (FH-MFSK) is one of the many techniques used in spread spectrum systems. It is a combination of frequency hopping and time hopping. In this system many users share a common frequency band using code division multiplexing. Each user is assigned an address and the message is modulated into the address. The receiver, knowing the address, decodes the received signal and extracts the message. This technique is suggested for digital mobile telephony. This thesis is concerned with an investigation of the possibility of utilising FH-MFSK for data transmission corrupted by additive white gaussian noise (A.W.G.N.). Work related to FH-MFSK has so far been mostly confined to its validity, and its performance in the presence of A.W.G.N. has not been reported before. An experimental system was therefore constructed which utilised combined hardware and software and operated under the supervision of a microprocessor system. The experimental system was used to develop an error-rate model for the system under investigation. The performance of FH-MFSK for data transmission was established in the presence of A.W.G.N. and with deleted and delayed sample effects. Its capability for multiuser applications was determined theoretically. The results show that FH-MFSK is a suitable technique for data transmission in the presence of A.W.G.N.

Is the clustering of neurofibrillary tangles in Alzheimer's patients related to the cells of origin of specific cortico-cortical projections?

The spatial pattern of cellular neurofibrillary tangles (NFT) was studied in the supra- and infragranular layers of various cortical regions in cases of Alzheimer's disease (AD). The objective was to test the hypothesis that NFT formation was associated with the cells of origin of specific cortico-cortical projections. The novel feature of the study was that pattern analysis enabled the dimension and spacing of NFT clusters along the cortical ribbon to be estimated. In the majority of brain regions studied, NFT occurred in clusters of neurons which were regularly spaced along the cortical strip. This pattern is consistent with the predicted distribution of the cells of origin of specific cortico-cortico projections. Mean NFT cluster size varied from 250 to > 12800 microns in different cortical tissues suggesting either variation in the size of the cell clusters or a dynamic process in the development of NFT in relation to these cell clusters. The formation of NFT in cell clusters which may give rise to the feed-forward and feed-back cortico-cortical projections suggests a possible route of spread of NFT pathology in AD between cortical regions and from the cortex to subcortical areas.

Alzheimer's disease: size class frequency distribution of senile plaques: do they indicate when a brain tissue was affected?

The size class frequency distribution of a sample of senile plaques (SP) was determined in a total of 20 brain regions from 5 elderly cases of Alzheimer's disease (AD). The purpose of the study was to determine whether a comparison of the frequency distributions could be used to determine the chronology of SP development in the AD brain. SP from 10 microns to a maximum diameter of 160 microns were present in the tissue and the size class frequency distributions were positively skewed. The frequency distributions varied between brain regions in: (1) the size class containing the mode, (2) the degree of positive skew, and (3) the ratio of large to small SP. In most patients the ratio of large to small SP was higher in the hippocampus or adjacent gyrus compared with temporal, parietal and frontal neocortex. If the diameter of a SP reflects its age in the tissue than the data suggest that SP formed earlier either in the hippocampus or adjacent gyrus compared with the other neocortical tissues. However, this conclusion rests on a number of assumptions including: (1) that SP diameter is directly related to age, (2) that SP development occurs at similar rates in different brain regions and (3) that, once formed, SP are not removed from the tissue by astrocytes.

The spatial pattern of beta-amyloid (Abeta) deposits in Alzheimer’s disease patients is related to apolipoprotein genotype

The spatial patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits was studied in the frontal and temporal cortex in cases of Alzheimer’s disease (AD) expressing different apolipoprotein (Apo E) genotypes. No significant differences in the density of the three Abeta deposit subtypes were observed in individuals expressing genotypes e2/3 and e3/3 compared with those expressing e3/4 and e4/4. In all patients, Abeta deposit subtypes occurred in the tissue in clusters. Chi-square contingency analyses of the data suggested that the cluster size of the diffuse and classic Abeta deposits was unrelated to Apo E genotype. However, the primitive (‘neuritic’) type Abeta deposits occurred more frequently in smaller, denser clusters in individuals expressing genotypes e3/4 and e4/4 compared with those expressing e2/3 and e3/3. Hence, the presence of the e4 allele may be associated with a more specific pattern of neuronal degeneration in the frontal and temporal cortex in AD.

Are neuritic plaques in Alzheimer’s disease related to neurofibrillary tangles?

The density and spatial patterns of neuritic plaques (NP) and cellular neurofibrillary tangles (cNFT) were studied in various brain regions in cases of Alzheimer’s disease. The objective was to test the hypothesis that NP develop from cNFT. cNFT were most abundant in the cornu Ammonis (CA) region of the hippocampus while NP were most abundant in gyri adjacent to the hippocampus. The density of NP in a brain region was positively correlated with the density of cNFT. In 83% of brain regions examined, NP occurred in clusters and in 51% the clusters exhibited a regular periodicity parallel to the tissue boundary. cNFT were clustered in 97% of brain regions, 61% exhibiting a regular periodicity. Mean cluster size of NP in a brain region was not significantly correlated with the cluster size of the cNFT. In most cortical regions, clusters of NP and cNFT were spatially unrelated to each other. However, coincident clusters of NP and cNFT were observed in the CA region of the hippocampus in 4/5 patients. It was concluded that the spatial patterns of the NP and cNFT clusters were not consistent with the hypothesis that the majority of NP evolved from cNFT.

Investigation of the role of protein kinase C (PKC) in cytostasis induced by tumour promoting phorbol esters and related compounds

Protein kinase C (PKC) is considered to be the major receptor for tumour promoting phorbol esters such as 12-0- tetradecanoylphorbol-13-acetate (TPA). These agents evoke a plethora of biological effects on cells in culture. The growth of A549 human lung carcinoma cells maintained in medium fortified with 10% foetal calf serum (FCS) is arrested for 6 days by TPA and other biologically active phorbol esters. In the work described in this thesis, the hypothesis was tested that modulation of PKC activity is closely related to events pivotal for cytostasis to occur. The effect of several phorbol esters, of newly synthesized analogues of diacylglycerols (DAG) and of bryostatins (bryos) on cell growth and ability to modulate activity of PKC has been investigated.Determination of the subcellular distribution of PKC following treatment of cells with TPA and partial enzyme purification by non-denaturing poly-acrylamide gel electrophoresis revealed translocation of enzyme activity from cytosoUc to paniculate fraction. Chronic exposure of cells to TPA resulted in a time and concentration dependent degradation of enzyme activity. Synthetic DAG and DAG analogues, unable to arrest the growth of cells at non-toxic concentrations, were neither able to affect subcellular PKC distribution nor compete effectively for phorbol ester binding sites at physiologically relevant concentrations. Bryos 1,2,4 and 5, natural products, possessing antineoplastic activity in mice, elicited transient arrest of A549 cell growth in vitro. They successfully competed for phorbol ester receptors in A549 cells with exquisite affinity and induced a shift in sub-cellular PKC distribution, though not to the same extent as PTA. Enzyme down-regulation resulted from prolonged exposure of cells to nanomolar concentrations of bryos. In vivo studies demonstrated that neither PDBu nor bryo 1 was able to inhibit A549 xenograft growth in athymic mice. The growth of A549 cell populations cultured under conditions of serum-deprivation was inhibited only transiently by biologically active phorbol esters. Fortification of serum-free medium with EGF or fetuin was able to partially restore sensitivity to maintained growth arrest by PTA. PKC translocation to the paniculate cellular fraction and subsequent enzyme down-regulation, induced by TPA, occurred in a manner similar to that observed in serum-supplemented cells. However, total PKC activity and cytosolic phorbol ester binding potential were greatly reduced in the serum-deprived cell population. Western blot analysis using monospecific monoclonal antibodies revealed the presence of PKC-a in both A549 cell populations, with significantly reduced protein levels in serum- deprived cells. PKC-/9 was not detected in either cell population.

Investigation of the antiproliferative properties of tumour promoting phorbol esters and related compounds

Tumour promoting phorbol esters such as 12-0-tetradecanoylphorbol-13-acetate (TPA) exert a multitude of biological effects on many cellular systems, many of which are believed to be mediated via the activation of the enzyme protein kinase C (PKC). TPA and other biologically active phorbol esters inhibited the proliferation of the A549 human lung carcinoma cell line. However, after 5-6 days culture in the continued presence of the phorbol ester cells began to proliferate at a rate similar to that of untreated cells. Resistance to TPA was lost following subculturing, although subculture in the presence of 10 nM TPA for more than 9 weeks resulted in a more resistant phenotype. The selection of a TPA-resistant subpopulation was not responsible for the observed resistance. The antiproliferative properties of other PKC activators were investigated. Mezerein induced the same antiproliferative effects as TPA but synthetic diacylglycerols (DAGs), the presumed physiological ligands of PKC, exerted only a non-specific cytotoxic influence on growth. Bryostatins 1 and 2 were able to induce transient growth arrest of A549 cells in a manner similar to phorbol esters at nanomolar concentrations, but at higher concentrations blocked both their own antiproliferative action and also that of phorbol esters and mezerein. Fourteen compounds synthesized to mimic features of the phorbol ester pharmacophore and/or DAGs did not mimic the antiproliferative properties of TPA in A549 cells and exerted only a DAG-like non-specific cytotoxicity at high concentrations. The subcellular distribution and activity of PKC was determined following partial purification by non-denaturing polyacrylamide gel electrophoresis. Treatment with TPA, mezerein or bryostatins resulted in a concentration-dependent shift of PKC activity from the cytosol to cellular membranes within 30 min. Significant translocation was not observed on treatment with DAGs. Chronic exposure of cells to TPA caused a time- and concentration dependent down-regulation of functional PKC activity. A complete loss of PKC activity was also observed on treatment with growth-inhibitory concentrations of bryostatins. No PKC activity was detected in cells resistant to the growth-inhibitory influence of TPA. Measurement of intracellular Ca2+ concentrations using A549 cells cultured on Cytodex 1 microcarrier beads revealed that TPA, mezerein and the bryostatins induced a similar rapid rise in intracellular Ca2+ levels.

Efficacy of memantine on behavioral and psychological symptoms related to dementia:a systematic meta-analysis

BACKGROUND: The behavioral and psychological symptoms related to dementia (BPSD) are difficult to manage and are associated with adverse patient outcomes. OBJECTIVE: To systematically analyze the data on memantine in the treatment of BPSD. METHODS: We searched MEDLINE, EMBASE, Pharm-line, the Cochrane Centre Collaboration, www.clinicaltrials.gov, www.controlled-trials.com, and PsycINFO (1966-July 2007). We contacted manufacturers and scrutinized the reference sections of articles identified in our search for further references, including conference proceedings. Two researchers (IM and CF) independently reviewed all studies identified by the search strategy. We included 6 randomized, parallel-group, double-blind studies that rated BPSD with the Neuropsychiatric Inventory (NPI) in our meta-analysis. Patients had probable Alzheimer's disease and received treatment with memantine for at least one month. Overall efficacy of memantine on the NPI was established with a t-test for the average difference between means across studies, using a random effects model. RESULTS: Five of the 6 studies identified had NPI outcome data. In these 5 studies, 868 patients were treated with memantine and 882 patients were treated with placebo. Patients on memantine improved by 1.99 on the NPI scale (95% Cl -0.08 to -3.91; p = 0.041) compared with the placebo group. CONCLUSIONS: Initial data appear to indicate that memantine decreases NPI scores and may have a role in managing BPSD. However, there are a number of limitations with the current data; the effect size was relatively small, and whether memantine produces significant clinical benefit is not clear.

Understanding the IT-related attitudes and needs of persons with age-related macular degeneration : a case study

In the UK, 20 per cent of people aged 75 years and over are living with sight loss; this percentage is expected to increase as the population ages (RNIB, 2011). Age-Related Macular Degeneration (AMD) is the UK’s leading cause of severe visual impairment amongst the elderly. It accounts for 16,000 blind/partial sight registrations per year and is the leading cause of blindness among people aged 55 years and older in western countries (Bressler, 2004). Our ultimate goal is to develop an assistive mobile application to support accurate and convenient diet data collection on which basis to then provide customised dietary advice and recommendations in order to help support individuals with AMD to mitigate their ongoing risk and retard the progression of the disease. In this paper, we focus on our knowledge elicitation activities conducted to help us achieve a deep and relevant understanding of our target user group. We report on qualitative findings from focus groups and observational studies with persons with AMD and interviews with domain experts which enable us to fully appreciate the impact that technology may have on our intended users as well as to inform the design and structure of our proposed mobile assistive application.

Small Ubiquitin-related Modifier (SUMO)-1 promotes glycolysis in hypoxia

Under conditions of hypoxia, most eukaryotic cells undergo a shift in metabolic strategy, which involves increased flux through the glycolytic pathway. Although this is critical for bioenergetic homeostasis, the underlying mechanisms have remained incompletely understood. Here, we report that the induction of hypoxia-induced glycolysis is retained in cells when gene transcription or protein synthesis are inhibited suggesting the involvement of additional post-translational mechanisms. Post-translational protein modification by the small ubiquitin related modifier-1 (SUMO-1) is induced in hypoxia and mass spectrometric analysis using yeast cells expressing tap-tagged Smt3 (the yeast homolog of mammalian SUMO) revealed hypoxia-dependent modification of a number of key glycolytic enzymes. Overexpression of SUMO-1 in mammalian cancer cells resulted in increased hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion. Supporting this, non-transformed cells also demonstrated increased glucose uptake upon SUMO-1 overexpression. Conversely, cells overexpressing the de-SUMOylating enzyme SENP-2 failed to demonstrate hypoxia-induced glycolysis. SUMO-1 overexpressing cells demonstrated focal clustering of glycolytic enzymes in response to hypoxia leading us to hypothesize a role for SUMOylation in promoting spatial re-organization of the glycolytic pathway. In summary, we hypothesize that SUMO modification of key metabolic enzymes plays an important role in shifting cellular metabolic strategies toward increased flux through the glycolytic pathway during periods of hypoxic stress. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Designing a mobile diet diary application with and for older adults with AMD:a case ctudy

Age-Related Macular Degeneration (AMD) is the UK’s leading cause of severe visual impairment amongst the elderly. It accounts for 16,000 blind/partial sight registrations per year and is the leading cause of blindness among people aged 55 years and older in western countries (Bressler, 2004). Our research aims to design and develop a self-monitoring, ability-reactive technology (SMART) for users with AMD to support their dietary-based AMD risk mitigation and progression retardation over time. In this paper, we reflect on our experience of adapting and applying a participatory design (PD) approach to support the effective design of our application with and for older adults with AMD. We introduce the outcome of a series of PD sessions with older adults with AMD - that is, a paper prototype of our proposed application which focuses on accessibility for our target users - and discuss implications for the eventual prototype development

Dietary analysis and patterns of nutritional supplement use in normal and age-related macular disease affected subjects:a prospective cross-sectional study

Background: Poor diet is thought to be a risk factor for many diseases, including age-related macular disease (ARMD), which is the leading cause of blind registration in those aged over 60 years in the developed world. The aims of this study were 1) to evaluate the dietary food intake of three subject groups: participants under the age of 50 years without ARMD (U50), participants over the age of 50 years without ARMD (O50), and participants with ARMD (AMD), and 2) to obtain information on nutritional supplement usage. Methods: A prospective cross-sectional study designed in a clinical practice setting. Seventy-four participants were divided into three groups: U50; 20 participants aged < 50 years, from 21 to 40 (mean ± SD, 37.7 ± 10.1 years), O50; 27 participants aged > 50 years, from 52 to 77 (62.7 ± 6.8 years), and ARMD; 27 participants aged > 50 years with ARMD, from 55 to 79 (66.0 ± 5.8 years). Participants were issued with a three-day food diary, and were also asked to provide details of any daily nutritional supplements. The diaries were analysed using FoodBase 2000 software. Data were input by one investigator and statistically analysed using Microsoft Excel for Microsoft Windows XP software, employing unpaired t-tests. Results: Group O50 consumed significantly more vitamin C (t = 3.049, p = 0.005) and significantly more fibre (t = 2.107, p = 0.041) than group U50. Group ARMD consumed significantly more protein (t = 3.487, p = 0.001) and zinc (t = 2.252, p = 0.029) than group O50. The ARMD group consumed the highest percentage of specific ocular health supplements and the U50 group consumed the most multivitamins. Conclusions: We did not detect a deficiency of any specific nutrient in the diets of those with ARMD compared with age- and gender-matched controls. ARMD patients may be aware of research into use of nutritional supplementation to prevent progression of their condition.

Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice

Although the association between maternal periconceptional diet and adult offspring health is well characterised, our understanding of the impact of paternal nutrition at the time of conception on offspring phenotype remains poorly defined. Therefore, we determined the effect of a paternal preconception low protein diet (LPD on adult offspring cardiovascular and metabolic health in mice. Male C57BL/6 mice were fed either normal protein diet (NPD; 18% casein or LPD (9% casein for 7 wk before mating. At birth, a reduced male-to-female ratio (P = 0.03 and increased male offspring weight (P = 0.009 were observed in litters from LPD compared with NPD stud males with no differences in mean litter size. LPD offspring were heavier than NPD offspring at 2 and 3 wk of age (P <0.02. However, no subsequent differences in body weight were observed. Adult male offspring derived from LPD studs developed relative hypotension (decreased by 9.2 mmHg and elevated heart rate (P <0.05, whereas both male and female offspring displayed vascular dysfunction and impaired glucose tolerance relative to NPD offspring. At cull (24 wk, LPD males had elevated adiposity (P = 0.04, reduced heart-to-body weight ratio (P = 0.04, and elevated circulating TNF-α levels (P = 0.015 compared with NPD males. Transcript expression in offspring heart and liver tissue was reduced for genes involved in calcium signaling (Adcy, Plcb, Prkcb and metabolism (Fto in LPD offspring (P <0.03. These novel data reveal the impact of suboptimal paternal nutrition on adult offspring cardiovascular and metabolic homeostasis, and provide some insight into the underlying regulatory mechanisms.

Parental diet, pregnancy outcomes and offspring health:metabolic determinants in developing oocytes and embryos

The periconceptional period, embracing the terminal stages of oocyte growth and post-fertilisation development up to implantation, is sensitive to parental nutrition. Deficiencies or excesses in a range of macro- and micronutrients during this period can lead to impairments in fertility, fetal development and long-term offspring health. Obesity and genotype-related differences in regional adiposity are associated with impaired liver function and insulin resistance, and contribute to fatty acid-mediated impairments in sperm viability and oocyte and embryo quality, all of which are associated with endoplasmic reticulum stress and compromised fertility. Disturbances to maternal protein metabolism can elevate ammonium concentrations in reproductive tissues and disturb embryo and fetal development. Associated with this are disturbances to one-carbon metabolism, which can lead to epigenetic modifications to DNA and associated proteins in offspring that are both insulin resistant and hypertensive. Many enzymes involved in epigenetic gene regulation use metabolic cosubstrates (e.g. acetyl CoA and S-adenosyl methionine) to modify DNA and associated proteins, and so act as 'metabolic sensors' providing a link between parental nutritional status and gene regulation. Separate to their genomic contribution, spermatozoa can also influence embryo development via direct interactions with the egg and by seminal plasma components that act on oviductal and uterine tissues. © IETS 2014.