Triatominae as a model of morphological plasticity under ecological pressure

The use of biochemical and genetic characters to explore species or population relationships has been applied to taxonomic questions since the 60s. In responding to the central question of the evolutionary history of Triatominae, i.e. their monophyletic or polyphyletic origin, two important questions arise (i) to what extent is the morphologically-based classification valid for assessing phylogenetic relationships? and (ii) what are the main mechanisms underlying speciation in Triatominae? Phenetic and genetic studies so far developed suggest that speciation in Triatominae may be a rapid process mainly driven by ecological factors.

South & East Belfast Community Nursing Project - Primary Care Integrated Nursing Model (PDF 524 KB)

South & East Belfast H&SS Trust's final report on Primary Care Integrated Nursing Model. Part of the Department's redesign of community nursing project

Obésité en Suisse: percentiles d'indice de masse corporelle (IMC) d'une population d'enfants et d'adolescents nés en 1980 à Lausanne et écart avec les normes suisses (1955)

OBJECTIVES: The objective of this study is to calculate the percentiles of BMI of a cohort of 1,203 children and adolescents, representing the 95% of the pupils of the school, born in 1980 followed longitudinally between 5 and 16 years. We compare these percentiles with those of the first swiss study, calculated on a cohort born in 1954-1956. METHODS: The percentiles were calculated with the method of Cole, on the basis of weight and height measured during the controls by the school health service, at a non-periodic mean interval of 14 months. RESULTS: The gap between the BMI percentiles of the two cohorts is near zero for the third percentiles, weak but progressively growing with age up to two units of BMI for the 50th percentiles. For the percentiles 97 the difference, straight away present at five years, grows regularly up to 11 years, and remains thereafter for the girls at 4.3 units of BMI, while growing more up to 6.8 units of BMI at 15 years for the boys. The percentages of children and adolescents of the present study with overweight, in accordance with the thresholds of Cole, constant for the girls at 14%, increase for the five to 11.5 years old boys from 13.4% to 17.6% for the 11.5 to 16 years old. The percentage of obesity is 2.7% for the girls, and increase for the same categories for the boys from a percentage of 1.7% to 2.3% for the boys. CONCLUSIONS: The changes during this quarter of century are important, especially for the boys. We can postulate thereafter a very early change in the energy balance. A chronic increase of the food supply, linked or not with a decrease of the physical activity, would be an explanation.

Model-based appraisal of minimum unit pricing for alcohol in Northern Ireland

In 2009, the Sheffield Alcohol Research Group (SARG) at Sheffield University developed the Sheffield Alcohol Policy Model version 2.0 (SAPM) to appraise the potential impact of alcohol policies, including different levels of MUP, for the population of England. In 2013, SARG were commissioned by the DHSSPS and the Department for Social Development to adapt the Sheffield Model to NI in order to appraise the potential impact of a range of alcohol pricing policies. The present report represents the results of this work. Estimates from the Northern Ireland (NI) adaptation of the Sheffield Alcohol Policy Model - version 3 - (SAPM3) suggest: 1. Minimum Unit Pricing (MUP) policies would be effective in reducing alcohol consumption, alcohol related harms (including alcohol-related deaths, hospitalisations, crimes and workplace absences) and the costs associated with those harms. 2. A ban on below-cost selling (implemented as a ban on selling alcohol for below the cost of duty plus the VAT payable on that duty) would have a negligible impact on alcohol consumption or related harms. 3. A ban on price-based promotions in the off-trade, either alone or in tandem with an MUP policy would be effective in reducing alcohol consumption, related harms and associated costs. 4. MUP and promotion ban policies would only have a small impact on moderate drinkers at all levels of income. Somewhat larger impacts would be experienced by increasing risk drinkers, with the most substantial effects being experienced by high risk drinkers. 5. MUP and promotion ban policies would have larger impacts on those in poverty, particularly high risk drinkers, than those not in poverty. However, those in poverty also experience larger relative gains in health and are estimated to marginally reduce their spending due to their reduced drinking under the majority of policies åÊ

Speech by Mr. Micheál Martin TD – Meeting The Challenges Of Cultural Diversity In The Irish Healthcare Sector

It gives me great pleasure to accept the invitation to address this conference on “Meeting the Challenges of Cultural Diversity in the Irish Healthcare Sector” which is being organised by the Irish Health Services Management Institute in partnership with the National Consultative Committee on Racism and Interculturalism. The conference provides an important opportunity to develop our knowledge and understanding of the issues surrounding cultural diversity in the health sector from the twin perspectives of patients and staff. Cultural diversity has over recent years become an increasingly visible aspect of Irish society bringing with it both opportunities and challenges. It holds out great possibilities for the enrichment of all who live in Ireland but it also challenges us to adapt creatively to the changes required to realise this potential and to ensure that the experience is a positive one for all concerned but particularly for those in the minority ethnic groups. In the last number of years in particular, the focus has tended to be on people coming to this country either as refugees, asylum seekers or economic migrants. Government figures estimate that as many as 340,000 immigrants are expected in the next six years. However ethnic and cultural diversity are not new phenomena in Ireland. Travellers have a long history as an indigenous minority group in Ireland with a strong culture and identity of their own. The changing experience and dynamics of their relationship with the wider society and its institutions over time can, I think, provide some valuable lessons for us as we seek to address the more numerous and complex issues of cultural diversity which have arisen for us in the last decade. Turning more specifically to the health sector which is the focus of this conference, culture and identity have particular relevance to health service policy and provision in that The first requirement is that we in the health service acknowledge cultural diversity and the differences in behaviours and in the less obvious areas of values and beliefs that this often implies. Only by acknowledging these differences in a respectful way and informing ourselves of them can we address them. Our equality legislation – The Employment Equality Act, 1998 and the Equal Status Act, 2000 – prohibits discrimination on nine grounds including race and membership of the Traveller community. The Equal Status Act prohibits discrimination on an individual basis in relation to the nine grounds while for groups it provides for the promotion of equality of opportunity. The Act applies to the provision of services including health services. I will speak first about cultural diversity in relation to the patient. In this respect it is worth mentioning that the recognition of cultural diversity and appropriate responses to it were issues which were strongly emphasised in the public consultation process which we held earlier this year in the context of developing National Anti-Poverty targets for the health sector and also our new national health strategy. Awareness and sensitivity training for staff is a key requirement for adapting to a culturally diverse patient population. The focus of this training should be the development of the knowledge and skills to provide services sensitive to cultural diversity. Such training can often be most effectively delivered in partnership with members of the minority groups themselves. I am aware that the Traveller community, for example, is involved in in-service training for health care workers. I am also aware that the National Consultative Committee on Racism and Interculturalism has been involved in training with the Eastern Regional Health Authority. We need to have more such initiatives. A step beyond the sensitivity training for existing staff is the training of members of the minority communities themselves as workers in our health services. Again the Traveller community has set an example in this area with its Primary Health Care Project for Travellers. The Primary Health Care for Travellers Project was established in 1994 as a joint partnership initiative with the Eastern Health Board and Pavee Point, with ongoing technical assistance being provided from the Department of Community Health and General Practice, Trinity College, Dublin. This project was the first of its kind in the country and has facilitated The project included a training course which concentrated on skills development, capacity building and the empowerment of Travellers. This confidence and skill allowed the Community Health Workers to go out and conduct a baseline survey to identify and articulate Travellers’ health needs. This was the first time that Travellers were involved in this process; in the past their needs were assumed. The results of the survey were fed back to the community and they prioritised their needs and suggested changes to the health services which would facilitate their access and utilisation. Ongoing monitoring and data collection demonstrates a big improvement in levels of satisfaction and uptake and ulitisation of health services by Travellers in the pilot area. This Primary Health Care for Travellers initiative is being replicated in three other areas around the country and funding has been approved for a further 9 new projects. This pilot project was the recipient of a WHO 50th anniversary commemorative award in 1998. The project is developing as a model of good practice which could inspire further initiatives of this type for other minority groups. Access to information has been identified in numerous consultative processes as a key factor in enabling people to take a proactive approach to managing their own health and that of their families and in facilitating their access to health services. Honouring our commitment to equity in these areas requires that information is provided in culturally appropriate formats. The National Health Promotion Strategy 2000-2005, for example, recognises that there exists within our society many groups with different requirements which need to be identified and accommodated when planning and implementing health promotion interventions. These groups include Travellers, refugees and asylum seekers, people with intellectual, physical or sensory disability and the gay and lesbian community. The Strategy acknowledges the challenge involved in being sensitive to the potential differences in patterns of poor health among these different groups. The Strategic aim is to promote the physical, mental and social well-being of individuals from these groups. The objective of the Strategy on these issues are: While our long term aim may be to mainstream responses so that our health services is truly multicultural, we must recognise the need at this point in time for very specific focused responses particularly for groups with poor health status such as Travellers and also for refugees and asylum seekers. In the case of refugees and asylum seekers examples of targeted services are screening for communicable diseases – offered on a voluntary basis – and psychological support services for those who have suffered trauma before coming here. The two approaches of targeting and mainstreaming are not mutually exclusive. A combination of both is required at this point in time but the balance between them must be kept under constant review in the light of changing needs. A major requirement if we are to meet the challenge of cultural diversity is an appropriate data and research base. I think it is important that we build up our information and research data base in partnership with the minority groups themselves. We must establish what the health needs of diverse groups are; we must monitor uptake of services and how well we are responding to needs and we must monitor outcomes and health status. We must also examine the impact of the policies in other sectors on the health of minority groups. The National Health Information Strategy, currently being developed, and the recently published National Strategy for Health Research – Making Knowledge Work for Health provide important frameworks within which we can improve our data and research base. A culturally diverse health sector workforce – challenges and opportunities The Irish health service can benefit greatly from successful international recruitment. There has been a strong non-national representation amongst the medical profession for more than 30 years. More recently there have been significant increases in other categories of health service workers from overseas. The Department recognises the enormous value that overseas recruitment brings over a wide range of services and supports the development of effective and appropriate recruitment strategies in partnership with health service employers. These changes have made cultural diversity an important issue for all health service organisations. Diversity in the workplace is primarily about creating a culture that seeks, respects, values and harnesses difference. This includes all the differences that when added together make each person unique. So instead of the focus being on particular groups, diversity is about all of us. Change is not about helping “them” to join “us” but about critically looking at “us” and rooting out all aspects of our culture that inappropriately exclude people and prevent us from being inclusive in the way we relate to employees, potential employees and clients of the health service. International recruitment benefits consumers, Irish employees and the overseas personnel alike. Regardless of whether they are employed by the health service, members of minority groups will be clients of our service and consequently we need to be flexible in order to accommodate different cultural needs. For staff, we recognise that coming from other cultures can be a difficult transition. Consequently health service employers have made strong efforts to assist them during this period. Many organisations provide induction courses, religious facilities (such as prayer rooms) and help in finding suitable accommodation. The Health Service Employers Agency (HSEA) is developing an equal opportunities/diversity strategy and action plans as well as training programmes to support their implementation, to ensure that all health service employment policies and practices promote the equality/diversity agenda to continue the development of a culturally diverse health service. The management of this new environment is extremely important for the health service as it offers an opportunity to go beyond set legal requirements and to strive for an acceptance and nurturing of cultural differences. Workforce cultural diversity affords us the opportunity to learn from the working practices and perspectives of others by allowing personnel to present their ideas and experience through teamwork, partnership structures and other appropriate fora, leading to further improvement in the services we provide. It is important to ensure that both personnel units and line managers communicate directly with their staff and demonstrate by their actions that they intend to create an inclusive work place which doesn´t demand that minority staff fit. Contented, valued employees who feel that there is a place for them in the organisation will deliver a high quality health service. Your conference here today has two laudable aims – to heighten awareness and assist health care staff to work effectively with their colleagues from different cultural backgrounds and to gain a greater understanding of the diverse needs of patients from minority ethnic backgrounds. There is a synergy in these aims and in the tasks to which they give rise in the management of our health service. The creative adaptations required for one have the potential to feed into the other. I would like to commend both organisations which are hosting this conference for their initiative in making this event happen, particularly at this time – Racism in the Workplace Week. I look forward very much to hearing the outcome of your deliberations. Thank you.

Diabetes: Prevention and Model for Patient Care

The National Diabetes Working Group has made a number of policy guidance recommendations. These relate to the model of care for people with diabetes as well as recommendations for how services prevent and manage diabetes in the population. Read the Report (PDF, 240kb)

Combining probabilistic land-use change and tree population dynamics modelling to simulate responses in mountain forests

Altitudinal tree lines are mainly constrained by temperature, but can also be influenced by factors such as human activity, particularly in the European Alps, where centuries of agricultural use have affected the tree-line. Over the last decades this trend has been reversed due to changing agricultural practices and land-abandonment. We aimed to combine a statistical land-abandonment model with a forest dynamics model, to take into account the combined effects of climate and human land-use on the Alpine tree-line in Switzerland. Land-abandonment probability was expressed by a logistic regression function of degree-day sum, distance from forest edge, soil stoniness, slope, proportion of employees in the secondary and tertiary sectors, proportion of commuters and proportion of full-time farms. This was implemented in the TreeMig spatio-temporal forest model. Distance from forest edge and degree-day sum vary through feed-back from the dynamics part of TreeMig and climate change scenarios, while the other variables remain constant for each grid cell over time. The new model, TreeMig-LAb, was tested on theoretical landscapes, where the variables in the land-abandonment model were varied one by one. This confirmed the strong influence of distance from forest and slope on the abandonment probability. Degree-day sum has a more complex role, with opposite influences on land-abandonment and forest growth. TreeMig-LAb was also applied to a case study area in the Upper Engadine (Swiss Alps), along with a model where abandonment probability was a constant. Two scenarios were used: natural succession only (100% probability) and a probability of abandonment based on past transition proportions in that area (2.1% per decade). The former showed new forest growing in all but the highest-altitude locations. The latter was more realistic as to numbers of newly forested cells, but their location was random and the resulting landscape heterogeneous. Using the logistic regression model gave results consistent with observed patterns of land-abandonment: existing forests expanded and gaps closed, leading to an increasingly homogeneous landscape.

Comparative population genomics in animals uncovers the determinants of genetic diversity.

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies.

A Grounded Theory Model of the Counselling Referral Process in Primary Care Methadone Treatment in Ireland.

In terms of the treatment of illicit drug abuse, methadone maintenance is a well researched and widely applied systematic response. The approach to primary care methadone treatment in Ireland is based on the methadone protocol. Primary care plays a central role in the delivery of methadone treatment. Beginning with a view that a system evolves within the constraints and influencing factors of its context, the aim of this thesis is to model the process that has developed by which patients on primary care methadone treatment are referred to counselling. It investigates the role primary care practitioners perceive they have in relation to managing the psychosocial aspects of the methadone patient's treatment regime. It analyzes individual medical practitioner counselling referral mechanisms to determine what common processes operate across different practitioners. It identifies the factors that influence the use of counselling on primary care methadone programmes and structures these in a cause/effect model. This research used interviews and documentary analysis to acquire grounded data. The sample consisted primarily of medical practitioners involved in the delivery of methadone programmes. Others closely involved in the implementation of drug treatment in the primary care context made up the balance of interviewees. The study used a grounded theory methodology to induce the process that was latent in the grounded data. Concepts emerging were grouped under the headings of referral factors, decision making factors and factors related to the unique positioning of primary care at the interface between medicine and society. The core finding was that, in primary care in Ireland, there is no psychological model to complement the pharmacological intervention of methadone substitution. The findings from this study offer insight into the factors at work and their impacts, in the context of the use of counselling in primary care methadone treatment. The study suggests a possible direction for further evolution of opiate abuse treatment in Ireland which would transform it from a harm reduction to a holistic patient centric paradigm.This resource was contributed by The National Documentation Centre on Drug Use.

Reverse transcription quantitative real-time polymerase chain reaction reference genes in the spared nerve injury model of neuropathic pain : validation and literature search

La douleur neuropathique est définie comme une douleur causée par une lésion du système nerveux somato-sensoriel. Elle se caractérise par des douleurs exagérées, spontanées, ou déclenchées par des stimuli normalement non douloureux (allodynie) ou douloureux (hyperalgésie). Bien qu'elle concerne 7% de la population, ses mécanismes biologiques ne sont pas encore élucidés. L'étude des variations d'expressions géniques dans les tissus-clés des voies sensorielles (notamment le ganglion spinal et la corne dorsale de la moelle épinière) à différents moments après une lésion nerveuse périphérique permettrait de mettre en évidence de nouvelles cibles thérapeutiques. Elles se détectent de manière sensible par reverse transcription quantitative real-time polymerase chain reaction (RT- qPCR). Pour garantir des résultats fiables, des guidelines ont récemment recommandé la validation des gènes de référence utilisés pour la normalisation des données ("Minimum information for publication of quantitative real-time PCR experiments", Bustin et al 2009). Après recherche dans la littérature des gènes de référence fréquemment utilisés dans notre modèle de douleur neuropathique périphérique SNI (spared nerve injury) et dans le tissu nerveux en général, nous avons établi une liste de potentiels bons candidats: Actin beta (Actb), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ribosomal proteins 18S (18S), L13a (RPL13a) et L29 (RPL29), hypoxanthine phosphoribosyltransferase 1 (HPRT1) et hydroxymethyl-bilane synthase (HMBS). Nous avons évalué la stabilité d'expression de ces gènes dans le ganglion spinal et dans la corne dorsale à différents moments après la lésion nerveuse (SNI) en calculant des coefficients de variation et utilisant l'algorithme geNorm qui compare les niveaux d'expression entre les différents candidats et détermine la paire de gènes restante la plus stable. Il a aussi été possible de classer les gènes selon leur stabilité et d'identifier le nombre de gènes nécessaires pour une normalisation la plus précise. Les gènes les plus cités comme référence dans le modèle SNI ont été GAPDH, HMBS, Actb, HPRT1 et 18S. Seuls HPRT1 and 18S ont été précédemment validés dans des arrays de RT-qPCR. Dans notre étude, tous les gènes testés dans le ganglion spinal et dans la corne dorsale satisfont au critère de stabilité exprimé par une M-value inférieure à 1. Par contre avec un coefficient de variation (CV) supérieur à 50% dans le ganglion spinal, 18S ne peut être retenu. La paire de gènes la plus stable dans le ganglion spinal est HPRT1 et Actb et dans la corne dorsale il s'agit de RPL29 et RPL13a. L'utilisation de 2 gènes de référence stables suffit pour une normalisation fiable. Nous avons donc classé et validé Actb, RPL29, RPL13a, HMBS, GAPDH, HPRT1 et 18S comme gènes de référence utilisables dans la corne dorsale pour le modèle SNI chez le rat. Dans le ganglion spinal 18S n'a pas rempli nos critères. Nous avons aussi déterminé que la combinaison de deux gènes de référence stables suffit pour une normalisation précise. Les variations d'expression génique de potentiels gènes d'intérêts dans des conditions expérimentales identiques (SNI, tissu et timepoints post SNI) vont pouvoir se mesurer sur la base d'une normalisation fiable. Non seulement il sera possible d'identifier des régulations potentiellement importantes dans la genèse de la douleur neuropathique mais aussi d'observer les différents phénotypes évoluant au cours du temps après lésion nerveuse.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale: some case studies

Every year, debris flows cause huge damage in mountainous areas. Due to population pressure in hazardous zones, the socio-economic impact is much higher than in the past. Therefore, the development of indicative susceptibility hazard maps is of primary importance, particularly in developing countries. However, the complexity of the phenomenon and the variability of local controlling factors limit the use of processbased models for a first assessment. A debris flow model has been developed for regional susceptibility assessments using digital elevation model (DEM) with a GIS-based approach.. The automatic identification of source areas and the estimation of debris flow spreading, based on GIS tools, provide a substantial basis for a preliminary susceptibility assessment at a regional scale. One of the main advantages of this model is its workability. In fact, everything is open to the user, from the data choice to the selection of the algorithms and their parameters. The Flow-R model was tested in three different contexts: two in Switzerland and one in Pakistan, for indicative susceptibility hazard mapping. It was shown that the quality of the DEM is the most important parameter to obtain reliable results for propagation, but also to identify the potential debris flows sources.

Coevolution of adaptive technology, maladaptive culture and population size in a producer-scrounger game.

Technology (i.e. tools, methods of cultivation and domestication, systems of construction and appropriation, machines) has increased the vital rates of humans, and is one of the defining features of the transition from Malthusian ecological stagnation to a potentially perpetual rising population growth. Maladaptations, on the other hand, encompass behaviours, customs and practices that decrease the vital rates of individuals. Technology and maladaptations are part of the total stock of culture carried by the individuals in a population. Here, we develop a quantitative model for the coevolution of cumulative adaptive technology and maladaptive culture in a 'producer-scrounger' game, which can also usefully be interpreted as an 'individual-social' learner interaction. Producers (individual learners) are assumed to invent new adaptations and maladaptations by trial-and-error learning, insight or deduction, and they pay the cost of innovation. Scroungers (social learners) are assumed to copy or imitate (cultural transmission) both the adaptations and maladaptations generated by producers. We show that the coevolutionary dynamics of producers and scroungers in the presence of cultural transmission can have a variety of effects on population carrying capacity. From stable polymorphism, where scroungers bring an advantage to the population (increase in carrying capacity), to periodic cycling, where scroungers decrease carrying capacity, we find that selection-driven cultural innovation and transmission may send a population on the path of indefinite growth or to extinction.

The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model.

OBJECTIVES: To determine whether nalmefene combined with psychosocial support is cost-effective compared with psychosocial support alone for reducing alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels (DRLs) as defined by the WHO, and to evaluate the public health benefit of reducing harmful alcohol-attributable diseases, injuries and deaths. DESIGN: Decision modelling using Markov chains compared costs and effects over 5 years. SETTING: The analysis was from the perspective of the National Health Service (NHS) in England and Wales. PARTICIPANTS: The model considered the licensed population for nalmefene, specifically adults with both alcohol dependence and high/very high DRLs, who do not require immediate detoxification and who continue to have high/very high DRLs after initial assessment. DATA SOURCES: We modelled treatment effect using data from three clinical trials for nalmefene (ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941)). Baseline characteristics of the model population, treatment resource utilisation and utilities were from these trials. We estimated the number of alcohol-attributable events occurring at different levels of alcohol consumption based on published epidemiological risk-relation studies. Health-related costs were from UK sources. MAIN OUTCOME MEASURES: We measured incremental cost per quality-adjusted life year (QALY) gained and number of alcohol-attributable harmful events avoided. RESULTS: Nalmefene in combination with psychosocial support had an incremental cost-effectiveness ratio (ICER) of £5204 per QALY gained, and was therefore cost-effective at the £20,000 per QALY gained decision threshold. Sensitivity analyses showed that the conclusion was robust. Nalmefene plus psychosocial support led to the avoidance of 7179 alcohol-attributable diseases/injuries and 309 deaths per 100,000 patients compared to psychosocial support alone over the course of 5 years. CONCLUSIONS: Nalmefene can be seen as a cost-effective treatment for alcohol dependence, with substantial public health benefits. TRIAL REGISTRATION NUMBERS: This cost-effectiveness analysis was developed based on data from three randomised clinical trials: ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941).

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). However, the treatment must be taken indefinitely and is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene), and is also bound to the alpha1-acid glycoprotein (AAG) in plasma. Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations were measured in 59 patients receiving Glivec® at diverse dosage regimens, using a validated chromatographic method developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one-compartment model with first-order absorption described the data appropriately, with an average apparent clearance of 12.4 l/h, a volume of distribution of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T and the AAG phenotype appears to modulate the disposition of imatinib. Large inter-individual variability (CV %) remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help in individualising the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Population genetic structure of the major malaria vector Anopheles darlingi (Diptera: Culicidae) from the Brazilian Amazon, using microsatellite markers

The population genetic structure of Anopheles darlingi, the major human malaria vector in the Neotropics, was examined using seven microsatellite loci from nine localities in central and western Amazonian Brazil. High levels of genetic variability were detected (5-25 alleles per locus; H E = 0.519-0.949). There was deviation from Hardy-Weinberg Equilibrium for 59.79% of the tests due to heterozygote deficits, while the analysis of linkage disequilibrium was significant for only two of 189 (1.05%) tests, most likely caused by null alleles. Genetic differentiation (F ST = 0.001-0.095; Nm = 4.7-363.8) indicates that gene flow is extensive among locations < 152 km apart (with two exceptions) and reduced, but not absent, at a larger geographic scale. Genetic and geographic distances were significantly correlated (R² = 0.893, P < 0.0002), supporting the isolation by distance (IBD) model. The overall estimate of Ne was 202.4 individuals under the linkage disequilibrium model, and 8 under the heterozygote excess model. Analysis of molecular variance showed that nearly all variation (~ 94%) was within sample locations. The UPGMA phenogram clustered the samples geographically, with one branch including 5/6 of the state of Amazonas localities and the other branch the Acre, Rondônia, and remaining Amazonas localities. Taken together, these data suggest little genetic structure for An. darlingi from central and western Amazonian Brazil. These findings also imply that the IBD model explains nearly all of the differentiation detected. In practical terms, populations of An. darlingi at distances < 152 km should respond similarly to vector control measures, because of high gene flow.