Structural determinants of steroids for cytochrome P450 3A4-mediated metabolism

Cytochrome P450 3A4 (CYP3A4), a major member of cytochrome P450 isoenzymes, metabolizes the majority of steroids in 6beta-position. For the purpose of determining requisite structural features of a series of structurally related steroids for CYP3A4-mediated metabolism, three-dimensional pharmacophore modeling as well as electrotopological state map were conducted for 15 steroids. Though prior studies speculated that the chemical reactivity of the allylic 6beta-position might have a greater influence on CYP3A4 selective 6-hydroxylation than steric constraints in the enzyme, our results reveal that for CYP3A4 steroidal substrates, it is not the chemical reactivity of atoms at 6beta-site, but the pharmacophoric features, i.e. the two hydrophobic rings together with two H-bond donors, that act as the key factors responsible for detemining the CYP3A4 selective 6-hydroxylation of steroids. (C) 2004 Elsevier B.V. All rights reserved.

H5N1 avian influenza re-emergence of Lake Communication Qinghai: phylogenetic and antigenic analyses of the newly isolated viruses and roles of migratory birds in virus circulation

Highly pathogenic avian influenza H5N1 virus has swept west across the globe and caused serious debates on the roles of migratory birds in virus circulation since the first large-scale outbreak in migratory birds of Lake Qinghai, 2005. In May 2006, another outbreak struck Lake Qinghai and six novel strains were isolated. To elucidate these QH06 viruses, the six isolates were subjected to whole-genome sequencing. Phylogenetic analyses show that QH06 viruses are derived from the lineages of Lake Qinghai, 2005. Five of the six novel isolates are adjacent to the strain A/Cygnus olor/Croatia/1/05, and the last one is related to the strain A/duck/Novosibirsk/ 02/05, an isolate of the flyway. Antigenic analyses suggest that QH06 and QH05 viruses are similar to each other. These findings implicate that QH06 viruses of Lake Qinghai may travel back via migratory birds, though not ruling out the possibility of local circulation of viruses of Lake Qinghai.

Early determinants of overweight and obesity at 5 years old in preschoolers from inner of Minas Gerais, Brazil

Introduction: Brazil is experiencing a nutritional transition characterized by a reduction in the prevalence of nutritional deficits and an increase in overweight and obesity, not only in adults but also in children and adolescents.Objectives: This study was designed to evaluate the factors associated with overweight and obesity in Brazilian 5-year-old preschoolers.Methods: A cross-sectional study of a cohort of 232 preschoolers born in Diamantina/Minas Gerais, Brazil, was undertaken. the data, including socioeconomic status, anthropometry, diet, previous history of the preschoolers and family history, were collected between July of 2009 and July of 2010. To identify the factors associated with overweight and obesity, a logistic regression and a hierarchical model were undertaken.Results: Overweight and obesity occurred in 17.2% of the preschoolers. After adjusting for mother's obesity, per capita income, protective food intake, weight gain at age 0-4 months and time spent playing, the factors associated with overweight and obesity that reached statistical significance were mother's obesity [OR = 3.12 (95% CI 1.41-6.91), P = 0.01], weight gain of more than 0.85 kg/month in the first four months of life [OR = 2.16 (95% CI 1.01-4.64), P = 0.041 and lower per capita income [OR = 0.32 (95 %CI 0.13-0.79), P = 0.01].Conclusion: the results show that more weight gain during the first four months of life and being born of mothers with obesity increased the odds of overweight/obesity in the preschoolers, while lower per capita income was a protective factor.

Determinants of port centrality in maritime container transportation.

This paper adapts Freeman’s measures of degree, closeness and betweenness centrality and applies them to assessing: port centrality in relation to direct connectivity; accessibility to all ports in the network (direct and indirect routes) and; as an intermediary between other ports. An additional parameter added to the formulae ensures that the relative importance of available shipping capacity and foreland market coverage are also accounted for. Validation of this adapted measure is provided by the results obtained from an empirical application. These reveal that foreland market coverage exerts a particularly strong influence on a port’s demand and closeness centrality

Examining the post-adoptive infusion of mobile technology in a healthcare domain: determinants and outcomes

The healthcare industry is beginning to appreciate the benefits which can be obtained from using Mobile Health Systems (MHS) at the point-of-care. As a result, healthcare organisations are investing heavily in mobile health initiatives with the expectation that users will employ the system to enhance performance. Despite widespread endorsement and support for the implementation of MHS, empirical evidence surrounding the benefits of MHS remains to be fully established. For MHS to be truly valuable, it is argued that the technological tool be infused within healthcare practitioners work practices and used to its full potential in post-adoptive scenarios. Yet, there is a paucity of research focusing on the infusion of MHS by healthcare practitioners. In order to address this gap in the literature, the objective of this study is to explore the determinants and outcomes of MHS infusion by healthcare practitioners. This research study adopts a post-positivist theory building approach to MHS infusion. Existing literature is utilised to develop a conceptual model by which the research objective is explored. Employing a mixed-method approach, this conceptual model is first advanced through a case study in the UK whereby propositions established from the literature are refined into testable hypotheses. The final phase of this research study involves the collection of empirical data from a Canadian hospital which supports the refined model and its associated hypotheses. The results from both phases of data collection are employed to develop a model of MHS infusion. The study contributes to IS theory and practice by: (1) developing a model with six determinants (Availability, MHS Self-Efficacy, Time-Criticality, Habit, Technology Trust, and Task Behaviour) and individual performance-related outcomes of MHS infusion (Effectiveness, Efficiency, and Learning), (2) examining undocumented determinants and relationships, (3) identifying prerequisite conditions that both healthcare practitioners and organisations can employ to assist with MHS infusion, (4) developing a taxonomy that provides conceptual refinement of IT infusion, and (5) informing healthcare organisations and vendors as to the performance of MHS in post-adoptive scenarios.

Lower extremity amputation in people with diabetes: Trends and determinants

Introduction: The prevalence of diabetes is rising rapidly. Assessing quality of diabetes care is difficult. Lower Extremity Amputation (LEA) is recognised as a marker of the quality of diabetes care. The focus of this thesis was first to describe the trends in LEA rates in people with and without diabetes in the Republic of Ireland (RoI) in recent years and then, to explore the determinants of LEA in people with diabetes. While clinical and socio-demographic determinants have been well-established, the role of service-related factors has been less well-explored. Methods: Using hospital discharge data, trends in LEA rates in people with and without diabetes were described and compared to other countries. Background work included concordance studies exploring the reliability of hospital discharge data for recording LEA and diabetes and estimation of diabetes prevalence rates in the RoI from a nationally representative study (SLAN 2007). To explore determinants, a systematic review and meta-analysis assessed the effect of contact with a podiatrist on the outcome of LEA in people with diabetes. Finally, a case-control study using hospital discharge data explored determinants of LEA in people with diabetes with a particular focus on the timing of access to secondary healthcare services as a risk factor. Results: There are high levels of agreement between hospital discharge data and medical records for LEA and diabetes. Thus, hospital discharge data was deemed sufficiently reliable for use in this PhD thesis. A decrease in major diabetes-related LEA rates in people with diabetes was observed in the RoI from 2005-2012. In 2012, the relative risk of a person with diabetes undergoing a major LEA was 6.2 times (95% CI 4.8-8.1) that of a person without diabetes. Based on the systematic review and meta-analysis, contact with a podiatrist did not significantly affect the relative risk (RR) of LEA in people with diabetes. Results from the case-control study identified being single, documented CKD and documented hypertension as significant risk factors for LEA in people with diabetes whilst documented retinopathy was protective. Within the seven year time window included in the study, no association was detected between LEA in patients with diabetes and timing of patient access to secondary healthcare for diabetes management. Discussion: Many countries have reported reduced major LEA rates in people with diabetes coinciding with improved organisation of healthcare systems. Reassuringly, these first national estimates in people with diabetes in the RoI from 2005 to 2012 demonstrated reducing trends in major LEA rates. This may be attributable to changes in diabetes care and also, secular trends in smoking, dyslipidaemia and hypertension. Consistent with international practice, LEA trends data in Ireland can be used to monitor quality of care. Quantifying this improvement precisely, though, is problematic without robust denominator data on the prevalence of diabetes. However, a reduction in major diabetes-related LEA rates suggests improved quality of diabetes care. Much controversy exists around the reliability of hospital discharge data in the RoI. This thesis includes the first multi-site study to explore this issue and found hospital discharge data reliable for the reporting of the procedure of LEA and diagnosis of diabetes. This project did not detect protective effects of access to services including podiatry and secondary healthcare for LEA in people with diabetes. A major limitation of the systematic review and meta-analysis was the design and quality of the included studies. The data available in the area of effect of contact with a podiatrist on LEA risk are too sparse to say anything definitive about the efficacy of podiatry on LEA. Limitations of the case-control study include lack of a diabetes register in Ireland, restricted information from secondary healthcare and lack of data available from primary healthcare. Due to these issues, duration of disease could not be accounted for in the study which limits the conclusions that can be drawn from the results. The model of diabetes care in the RoI is currently undergoing a re-configuration with plans to introduce integrated care. In the future, trends in LEA rates should be continuously monitored to evaluate the effectiveness of changes to the healthcare system. Efforts are already underway to improve the availability of routine data from primary healthcare with the recent development of the iPCRN (Irish Primary Care Research Network). Linkage of primary and secondary healthcare records with a unique patient identifier should be the goal for the future.

Childhood obesity in Ireland: recent trends and modifiable determinants

Background: Childhood obesity is a global epidemic posing a significant threat to the health and wellbeing of children. To reverse this epidemic, it is essential that we gain a deeper understanding of the complex array of driving factors at an individual, family and wider ecological level. Using a social-ecological framework, this thesis investigates the direction, magnitude and contribution of risk factors for childhood overweight and obesity at multiple levels of influence, with a particular focus on diet and physical activity. Methods: A systematic review was conducted to describe recent trends (from 2002-2012) in childhood overweight and obesity prevalence in Irish school children from the Republic of Ireland. Two datasets (Cork Children’s Lifestyle [CCLaS] Study and the Growing Up in Ireland [GUI] Study) were used to explore determinants of childhood overweight and obesity. Individual lifestyle factors examined were diet, physical activity and sedentary behaviour. The determinants of physical activity were also explored. Family factors examined were parental weight status and household socio-economic status. The impact of food access in the local area on diet quality and body mass index (BMI) was investigated as an environmental level risk factor. Results: Between 2002 and 2012, the prevalence of childhood overweight and obesity in Ireland remained stable. There was some evidence to suggest that childhood obesity rates may have decreased slightly though one in four Irish children remained either overweight or obese. In the CCLaS study, overweight and obese children consumed more unhealthy foods than normal weight children. A diet quality score was constructed based on a previously validated adult diet score. Each one unit increase in diet quality was significantly associated with a decreased risk of childhood overweight and obesity. Individual level factors (including gender, being a member of a sports team, weight status) were more strongly associated with physical activity levels than family or environmental factors. Overweight and obese children were more sedentary and less active than normal weight children. There was a dose response relationship between time spent at moderate to vigorous physical activity (MVPA) and the risk of childhood obesity independent of sedentary time. In contrast, total sedentary time was not associated with the risk of childhood obesity independent of MVPA though screen time was associated with childhood overweight and obesity. In the GUI Study, only one in five children had 2 normal weight parents (or one normal weight parent in the case of single parent families). Having overweight and obese parents was a significant risk factor for overweight and obesity regardless of socio-economic characteristics of the household. Family income was not associated with the odds of childhood obesity but social class and parental education were important risk factors for childhood obesity. Access to food stores in the local environment did not impact dietary quality or the BMI of Irish children. However, there was some evidence to suggest that the economic resources of the family influenced diet and BMI. Discussion: Though childhood overweight and obesity rates appear to have stabilised over the previous decade, prevalence rates are unacceptably high. As expected, overweight and obesity were associated with a high energy intake and poor dietary quality. The findings also highlight strong associations between physical inactivity and the risk of overweight and obesity, with effect sizes greater than what have been typically found in adults. Important family level determinants of childhood overweight and obesity were also identified. The findings highlight the need for a multifaceted approach, targeting a range of modifiable determinants to tackle the problem. In particular, policies and interventions at the shared family environment or community level may be an effective mean of tackling this current epidemic.

Human oesophagus: A convenient antigenic substrate for the determination of anti-endomysium antibodies in the serological diagnosis of coeliac disease

SCOPUS: ar.j

Host determinants of HIV-1 control in African Americans.

We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10(-10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701.

Determinants of protection among HIV‐exposed seronegative persons: an overview.

Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.

Environmental and genetic determinants of colony morphology in yeast.

Nutrient stresses trigger a variety of developmental switches in the budding yeast Saccharomyces cerevisiae. One of the least understood of such responses is the development of complex colony morphology, characterized by intricate, organized, and strain-specific patterns of colony growth and architecture. The genetic bases of this phenotype and the key environmental signals involved in its induction have heretofore remained poorly understood. By surveying multiple strain backgrounds and a large number of growth conditions, we show that limitation for fermentable carbon sources coupled with a rich nitrogen source is the primary trigger for the colony morphology response in budding yeast. Using knockout mutants and transposon-mediated mutagenesis, we demonstrate that two key signaling networks regulating this response are the filamentous growth MAP kinase cascade and the Ras-cAMP-PKA pathway. We further show synergistic epistasis between Rim15, a kinase involved in integration of nutrient signals, and other genes in these pathways. Ploidy, mating-type, and genotype-by-environment interactions also appear to play a role in the controlling colony morphology. Our study highlights the high degree of network reuse in this model eukaryote; yeast use the same core signaling pathways in multiple contexts to integrate information about environmental and physiological states and generate diverse developmental outputs.

The impact of host immune status on the within-host and population dynamics of antigenic immune escape.

Antigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity--through vaccination--has on the production of new antigenic variants.