Innovation in regulatory approaches for endocrine disrupting chemicals: The journey to risk assessment modernization in Canada.

Globally, regulatory authorities grapple with the challenge of assessing the hazards and risks to human and ecosystem health that may result from exposure to chemicals that disrupt the normal functioning of endocrine systems. Rapidly increasing number of chemicals in commerce, coupled with the reliance on traditional, costly animal experiments for hazard characterization - often with limited sensitivity to many important mechanisms of endocrine disruption -, presents ongoing challenges for chemical regulation. The consequence is a limited number of chemicals for which there is sufficient data to assess if there is endocrine toxicity and hence few chemicals with thorough hazard characterization. To address this challenge, regulatory assessment of endocrine disrupting chemicals (EDCs) is benefiting from a revolution in toxicology that focuses on New Approach Methodologies (NAMs) to more rapidly identify, prioritize, and assess the potential risks from exposure to chemicals using novel, more efficient, and more mechanistically driven methodologies and tools. Incorporated into Integrated Approaches to Testing and Assessment (IATA) and guided by conceptual frameworks such as Adverse Outcome Pathways (AOPs), emerging approaches focus initially on molecular interactions between the test chemical and potentially vulnerable biological systems instead of the need for animal toxicity data. These new toxicity testing methods can be complemented with in silico and computational toxicology approaches, including those that predict chemical kinetics. Coupled with exposure data, these will inform risk-based decision-making approaches. Canada is part of a global network collaborating on building confidence in the use of NAMs for regulatory assessment of EDCs. Herein, we review the current approaches to EDC regulation globally (mainly from the perspective of human health), and provide a perspective on how the advances for regulatory testing and assessment can be applied and discuss the promises and challenges faced in adopting these novel approaches to minimize risks due to EDC exposure in Canada, and our world.

Taste preference, food neophobia and nutritional intake in children consuming a cows' milk exclusion diet: a prospective study.

BACKGROUND: Taste exposure in infancy is known to predict food preferences later in childhood. This is particularly relevant in children with cows' milk allergy who consume a substitute formula and/or a cows' milk exclusion (CME) diet early in life. This prospective study aimed to show whether there is a long-term effect of consuming a substitute formula and CME diet on taste preferences and dietary intake. METHODS: Children were predominantly recruited from two large birth cohort studies in the UK. Two groups were recruited: an experimental group of children who had consumed a CME diet during infancy and a control group who had consumed an unrestricted diet during infancy. Parents completed a food neophobia questionnaire and an estimated prospective food diary. Children completed a taste preference test and their growth was assessed. RESULTS: One hundred and one children with a mean age of 11.5 years were recruited (28 CME and 73 controls). Children in the CME group had a significantly higher preference for bitter taste than those in the control group (P < 0.05). There were significant differences between the groups with respect to the intake of some micronutrients, including riboflavin, iodine, sodium and selenium. Food neophobia did not differ between groups. Some 28% of the CME group were overweight/obese compared to 15% of the control group; however, this difference was not statistically significant. CONCLUSIONS: Consuming a substitute formula and/or a CME diet in infancy has a long-term effect on the preference for bitter taste. Differences exist with respect to the intake of some micronutrients, but not macronutrients. There was a nonsignificant trend towards being overweight and obese in children in the CME group.

Changing prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle of Wight birth cohorts 12 years apart.

BACKGROUND: While the prevalence of asthma in children is decreasing or remaining the same, time trends in the prevalence of rhinitis in children are not known. Understanding sensitisation trends may help inform about trends in asthma and rhinitis prevalence. OBJECTIVE: To assess time trends of wheeze, rhinitis and aero-allergen sensitisation prevalence at 10 years of age, we compared two birth cohorts established 12 years apart. To gain insight into differences in disease prevalence, we assessed association of family history, early life exposures and sensitisation with wheeze and rhinitis in each cohort. METHODS: The IoW (Isle of Wight) and FAIR (Food Allergy and Intolerance Research) unselected birth cohorts were established in 1989 and 2001 respectively in IoW. Identical ISAAC questionnaire and skin prick test data were collected and compared at 10 years of age. RESULTS: Over the 12-year period from 2001 to 2012, prevalence of lifetime wheeze, current wheeze and those ever treated for asthma decreased by 15.9% (45.5 vs. 29.6, P < 0.001), 3.9% (18.9 vs. 15, P = 0.020) and 8.2% (31.7 vs. 23.5, P = 0.001), respectively. Conversely, current rhinitis and lifetime rhinitis prevalence increased by 5.5% (22.6 vs. 28.1, P = 0.004) and 13% (18.6 vs. 31.7, P < 0.001), respectively. Atopic status remained stable; however, house dust mite (HDM) sensitisation decreased by 5.6% (19.2 vs. 13.6, P = 0.004) and grass sensitisation increased by 3.5% (12.9 vs. 16.4, P = 0.054). Male sex, parental history of asthma and HDM sensitisation were significantly associated with lifetime wheeze in both cohorts, while maternal smoking during pregnancy was a significant risk factor only in the earlier IoW cohort. Parental history of rhinitis and grass sensitisation was significantly associated with lifetime rhinitis in both cohorts, while HDM sensitisation was significant only for the IoW cohort. CONCLUSION: Contrasting changes were noted with falling wheeze and HDM sensitisation but rising rhinitis and grass sensitisation prevalence. Changing prevalence of aero-allergen sensitisations may explain the different time trends observed in these cohorts.

Time trends in the prevalence of peanut allergy: three cohorts of children from the same geographical location in the UK.

BACKGROUND: This article investigated the prevalence of peanut allergy in three cohorts of children born in the same geographical location, Isle of Wight, UK and seeks to determine whether the prevalence of peanut allergy has changed between 1994 and 2004. METHODS: Three cohorts of children (age 3-4 years) born on the Isle of Wight, were assessed for peanut allergy and the outcomes compared: Cohort A: Born in 1989; reviewed at 4 years of age (n = 2181). Cohort B: Born between 1994 and 1996; reviewed between 3 and 4 years of age (n = 1273). Cohort C: Born between 2001 and 2002; reviewed at 3 years of age (n = 891). RESULTS: Peanut sensitization increased significantly from 1.3% in Cohort A to 3.3% (P = 0.003) in Cohort B before falling back to 2.0% in Cohort C (P = 0.145). Similarly, clinical peanut allergy increased significantly from 0.5% in Cohort A to 1.4% (P = 0.023) in Cohort B, with a subsequent fall to 1.2% in Cohort C (P = 0.850). CONCLUSIONS: Our data from three cohorts of 3- to 4-year-old children born in the same geographical area shows that peanut allergy prevalence has changed over time. Peanut sensitization and reported allergy in children born in 1994-1996 increased from 1989 but seems to have stabilized or slightly decreased since the late 1990s, although not significant.

Reaching every district - development and testing of a health micro-planning strategy for reaching difficult to reach populations in Mongolia.

CONTEXT: Since the 1990s, Mongolia has undergone a rapid social and economic transition with migration to the urban areas of the national capital Ulaanbaatar. The main reasons for the migration are social sector decline in rural areas and the potential for employment opportunities in urban areas. There are also new internal patterns of migration in rural and remote areas relating to recent developments in the economic sector. Despite recent innovations in health system management in Mongolia, in some urban and rural and remote locations health services are not sufficiently accessed by the most socially and economically disadvantaged populations. These concerns provided the motivation for the Ministry of Health of Mongolia and development partners to attempt to access the most difficult to reach populations through the development of a micro-planning process referred to as the 'Reaching Every District strategy' (RED). This article describes and analyses RED micro-planning processes and content, and highlights the lessons learned. The main source of data for this planning system development was in the development and testing of the micro-planning process in Byanzurkh District, Ulaanbaatar in June 2008. INTERVENTION: The principal intervention developed and trialed was a health micro-planning strategy for improved access to immunization and maternal and child health services for difficult to reach populations. The planning methodology was a problem-solving approach progressing from health mapping to barrier analysis, to activity planning and costing and finally to monitoring and evaluation. LESSONS LEARNED: Main success factors in the development of the planning methodology were the use of barrier analysis and mapping approaches for data analysis and problem solving at the local level, and re-orientation of management approaches from 'inspection' to supportive supervision. Additionally, although the RED strategy is intended to be an immunization-specific intervention internationally, evidence from the development and trial of the process in Mongolia indicates its potential for wider health systems applications. This is particularly so for detecting and responding to the maternal and child health service needs of the more difficult to reach sub-populations.

Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life.

BACKGROUND: Prevalence and incidence of food hypersensitivity (FHS) and its trends in early childhood are unclear. METHODS: A birth cohort born on the Isle of Wight (UK) between 2001 and 2002 was followed-up prospectively. Children were clinically examined and skin prick tested at set times and invited for food challenges when indicated. RESULTS: Nine hundred and sixty-nine children were recruited and 92.9%, 88.5% and 91.9% of them respectively were assessed at 1, 2 and 3 years of age. Prevalence of sensitization to foods was 2.2%, 3.8% and 4.5% respectively at these ages. Cumulatively, 5.3% [95% confidence interval (CI): 3.9-7.1] children were sensitized to a food. Using open food challenge and a good clinical history, the cumulative incidence of FHS was 6.0% (58/969, 95% CI: 4.6-7.7). Based on double-blinded, placebo-controlled, food challenge (DBPCFC) and a good clinical history, the cumulative incidence was 5.0% (48/969, 95% CI: 3.7-6.5). There is no evidence to suggest that the incidence of FHS has increased, comparing these results with previous studies. Overall, 33.7% of parents reported a food-related problem and of these, 16.1% were diagnosed with FHS by open challenge and history and 12.9% by DBPCFC and history. Main foods implicated were milk, egg and peanut. CONCLUSIONS: By the age of 3 years, 5-6% of children suffer from FHS based on food challenges and a good clinical history. There were large discrepancies between reported and diagnosed FHS. Comparing our data with a study performed in the USA more than 20 years ago, there were no significant differences in the cumulative incidence of FHS.

Comparison of open and double-blind placebo-controlled food challenges in diagnosis of food hypersensitivity amongst children.

BACKGROUND: Correct diagnosis of food hypersensitivity (FHS) is important to ensure appropriate patient care and to accurately establish the population prevalence and incidence. Food challenges play a very important role in the diagnosis of FHS, but it is unclear when open food challenges (OFCs) opposed to double-blind placebo-controlled food challenges (DBPCFCs) should be used. This study investigated the use of OFCs and DBPCFCs when diagnosing FHS. METHODS: Children with a reported history of FHS or with sensitization to a food without known previous consumption were invited to undergo food challenges. Children of consenting parents underwent an OFC and those with a positive OFC were approached to undergo a DBPCFC. Food challenges were either performed as 1-day or 1-week challenges depending on sensitization status and clinical history. RESULTS: Forty-one children underwent both OFCs and DBPCFCs. The positive predictive values for 1-day and 1-week OFCs were 73% (8/11; 95% CI: 39-94%) and 57% (20/35; 95% CI: 39-74%) respectively. There was no evidence to indicate that the younger children were more likely to have a positive OFC confirmed by a DBPCFC compared to older children (Fisher's exact P = 0.53). In the 1-day challenges parents indicated a preference for OFC rather than DBPCFC. By contrast, in the 1-week challenge parents indicated a preference for DBPCFC (P = 0.0192). CONCLUSION: Open food challenge may be suitable for diagnosing immediate objective symptoms, whereas DBPCFC may be needed for the diagnosis of delayed and mainly subjective symptoms, irrespective of the child's age.

Developments in immunization planning in Cambodia--rethinking the culture and organization of national program planning.

INTRODUCTION: As part of its health system reconstruction following decades of civil war, Cambodia undertook a program of health sector reform in 1996 to expand coverage of essential health services to the population of 14 million, 80% of whom are resident in over 13 000 rural villages. During this reform period, one of the major national health programs, the National Immunization Program (NIP), adapted its planning system to accommodate changes in social and health sector structure. AIMS: The aims of this article are to review changes made in the approach to national immunization planning and to illustrate how these adaptations can help identify future challenges and opportunities for further improving immunization coverage in Cambodia. Sources of information for the study include immunization plans and data from international and national sources, as well as data from the national health information system. Findings of review: Management and service delivery reforms undertaken by the NIP include (1) strengthening links between immunization, health sector and international health planning; (2) development of immunization program multiyear and financial sustainability plans; (3) strengthening of national program decision making structures and processes; (4) widening of decentralized stakeholder participation in health planning; and (5) implementation of service level micro-planning. OUTCOMES: These management reforms have been associated with significant improvement in public health program performance and outcomes during this period (2003-2006). There has been an increase in vaccination coverage for children under the age of one year, over a five-year period (increase of 29% for fully immunized child at one year of age), with no significant differences in vaccination rates between urban and rural areas, and a sharp decrease in the incidence of vaccine preventable diseases. CONCLUSION: The NIP is now well positioned to take on additional challenges in coming years associated with expanding international partnerships, the continued development of civil society, further health system decentralization, and the requirement to further improve coverage in support of global and regional disease elimination goals. However, as costs continue to rise, planners in the future will need to emphasize the economic and public health benefits of immunization programs in order to sustain increasing levels of national and international investment.

Government advice on peanut avoidance during pregnancy--is it followed correctly and what is the impact on sensitization?

BACKGROUND: In 1998, the UK government issued precautionary advice that pregnant or breast-feeding women with a family history of atopy, may wish to avoid eating peanuts during pregnancy and lactation. This study aimed to assess the compliance with this recommendation and investigate its impact upon peanut sensitization. METHODS: A total of 858 children born immediately after the advice were followed for 2 years and assessed for peanut sensitization. A standardized questionnaire was used to ascertain history of atopy and maternal exposure to peanuts during pregnancy. Following parental consent children were skin prick tested to assess sensitization to peanuts. RESULTS: Sixty-five per cent of mothers had avoided peanuts during pregnancy. Forty-two per cent of the mothers had heard about the government advice, and half modified their diet as a consequence. Neither maternal nor family history of atopy had any significant effect on peanut consumption. Parity did play a role, and mothers having their first child were twice as likely to change their diet (P<0.001). Mothers of 77% of the children sensitized to peanuts had avoided peanuts during pregnancy. In this cohort study maternal consumption of peanut during pregnancy was not associated with peanut sensitization in the infant. CONCLUSIONS: The majority of mothers in this cohort avoided peanut consumption during pregnancy. It is likely that either the government advice is misunderstood by mothers, or that those who communicate the advice have not fully explained who it is targeted at.

Reliability and validity of a maternal food frequency questionnaire designed to estimate consumption of common food allergens.

BACKGROUND: Maternal food intake during pregnancy may influence the development of food hypersensitivity (FHS) in the child. A food frequency questionnaire estimating the frequency with which some of the mains food allergens are consumed was designed and validated. MATERIALS AND METHODS: Pregnant women were recruited at the ante-natal clinic of St. Mary's Hospital, Isle of Wight, UK. A food frequency questionnaire was developed and validated by comparing responses to information recorded in 7 days food diaries. The reliability of the food frequency questionnaire was evaluated by asking women to complete the questionnaire on two separate occasions at 30 and 36 weeks gestation. RESULTS: Fifty-seven women completed the validity study and 91 women completed the reliability study. For both validity and reliability, questions with dichotomous response categories showed the highest level of agreement. Frequency of intake of foods commonly "hidden" in foods produced the lowest validity and reliability scores. In the validity study responses to the food frequency questionnaire identically matched information recorded in the food diaries 80% of the time, on average. In the reliability study, responses were identical on both questionnaires 85% of the time on average. CONCLUSION: In this study a food frequency questionnaire estimating the frequency with which some of the main food allergens are consumed during pregnancy was designed and validated. This food frequency questionnaire could be used in future studies to assess the role of maternal food intake in the development of FHS in the infant.

An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis.

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

The effects of a double blind, placebo controlled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children.

AIMS: To determine whether artificial food colourings and a preservative in the diet of 3 year old children in the general population influence hyperactive behaviour. METHODS: A sample of 1873 children were screened in their fourth year for the presence of hyperactivity at baseline (HA), of whom 1246 had skin prick tests to identify atopy (AT). Children were selected to form the following groups: HA/AT, not-HA/AT, HA/not-AT, and not-HA/not-AT (n = 277). After baseline assessment, children were subjected to a diet eliminating artificial colourings and benzoate preservatives for one week; in the subsequent three week within subject double blind crossover study they received, in random order, periods of dietary challenge with a drink containing artificial colourings (20 mg daily) and sodium benzoate (45 mg daily) (active period), or a placebo mixture, supplementary to their diet. Behaviour was assessed by a tester blind to dietary status and by parents' ratings. RESULTS: There were significant reductions in hyperactive behaviour during the withdrawal phase. Furthermore, there were significantly greater increases in hyperactive behaviour during the active than the placebo period based on parental reports. These effects were not influenced by the presence or absence of hyperactivity, nor by the presence or absence of atopy. There were no significant differences detected based on objective testing in the clinic. CONCLUSIONS: There is a general adverse effect of artificial food colouring and benzoate preservatives on the behaviour of 3 year old children which is detectable by parents but not by a simple clinic assessment. Subgroups are not made more vulnerable to this effect by their prior levels of hyperactivity or by atopy.

Management systems response to improving immunization coverage in developing countries: a case study from Cambodia.

INTRODUCTION: In contrast to the initial success following the establishment of the National Immunization Program (NIP) in Cambodia in 1986, infant vaccination coverage rates against the six expanded program immunization diseases have not improved since 1995. In response, the NIP of the Ministry of Health has undertaken a series of institutional initiatives to address the problem of static or declining rates of coverage. The aim of this paper is to describe and assess management strategies undertaken by the NIP in Cambodia in support of improved immunization coverage. METHODS: Sources of information used in preparing this report include international literature, national coverage and surveillance data, government policy documentation, information generated by national strategic planning and health centre microplanning processes, a functional analysis of human resources, and data quality audits. RESULTS: The NIP has implemented planning, organizational development and human resource development responses to the problem of low coverage. These have included: integration of the nip strategic and operational plans into the health sector plan; strengthening of needs-based microplanning; establishment of a national monitoring and management support strategy; and the introduction of performance-based agreements between levels of government for improved immunization coverage. CONCLUSIONS: Our analysis of these findings, in particular of the international literature, suggests that NIP's responses have been appropriate, and that the development of NIP management systems and capacity will increase the likelihood for sustained immunization coverage gains within a reform environment of health system decentralization. In 2003, there are early signs that the reform processes undertaken by the NIP have resulted in improved immunization coverage in targeted areas, and this should place the national program in a stronger position to lift immunization coverage in 2004.

Overview of devolution of health services in the Philippines.

INTRODUCTION: In 1991 the Philippines Government introduced a major devolution of national government services, which included the first wave of health sector reform, through the introduction of the Local Government Code of 1991. The Code devolved basic services for agriculture extension, forest management, health services, barangay (township) roads and social welfare to Local Government Units. In 1992, the Philippines Government devolved the management and delivery of health services from the National Department of Health to locally elected provincial, city and municipal governments. AIM: The aim of this review is to (i) Provide a background to the introduction of devolution to the health system in the Philippines and to (ii) describe the impact of devolution on the structure and functioning of the health system in defined locations. METHOD: International literature was reviewed on the subjects of decentralization. Rapid appraisals of health management systems were conducted in both provinces. Additional data were accessed from the rural health information system and previous consultant reports. RESULTS: Subsequent to the introduction of devolution, quality and coverage of health services declined in some locations, particularly in rural and remote areas. It was found that in 1992-1997, system effects included a breakdown in management systems between levels of government, declining utilization particularly in the hospital sector, poor staff morale, a decline in maintenance of infrastructure and under financing of operational costs of services. CONCLUSION: The aim of decentralization is to widen decision-making space of middle level managers, enhance resource allocations from central to peripheral areas and to improve the efficiency and effectiveness of health services management. The findings of the historical review of devolution in the Philippines reveals some consistencies with the international literature, which describe some negative effects of decentralization, and provide a rationale for the Philippines in undertaking a second wave of reform in order to 'make devolution work'.

Can parents accurately perceive hyperactivity in their child?

In all, 1872 children were recruited as part of a larger study concerning food additives and behaviours in preschool children. This figure represented 70% of the whole population of 3 1/4 -year-old children resident on the Isle of Wight, UK. Parents completed an assessment concerning their perceptions of their child's behaviour. The results of this assessment were compared with scores on two validated parental questionnaires, the Weiss Werry Peters (WWP) hyperactivity scale and the Emotionality, Activity and Sociability Temperament Questionnaire (EAS), which were used to assess hyperactivity. The accuracy of parents in perceiving hyperactivity in their children was found to be around 50% if the child was hyperactive, and 89% if the child was not hyperactive. The implications of these findings for services are discussed. Frequencies of potential risk groups for future Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder were also suggested.

Binding of plasminogen and tissue plasminogen activator to plasmin-modulated factor X and factor Xa.

Previous work in our laboratory has suggested that the fibrinolytic enzyme plasmin (Pn) inactivates coagulation factors X (FX) and Xa (FXa) in the presence of Ca(2+) and anionic phospholipid (aPL), producing fragments which bind plasminogen (Pg) and accelerate tissue plasminogen activator (t-PA). Our goals here were to determine if the Pn-mediated fragments of FX or FXa remain associated, whether they directly bind t-PA, and to quantify their interaction with Pg. Binding to aPL, benzamidine-Sepharose, or the active-site inhibitor dansyl-Glu-Gly-Arg-chloromethyl ketone demonstrated that Pn cleavage yielded noncovalent heterodimers of a fragment containing the aPL-binding domain (FXgamma(47) or FXagamma(33)) and a 13-kDa fragment (FXgamma(13) or FXagamma(13)). Both ligand blotting and surface plasmon resonance (SPR) showed that Pn-cleaved FX and FXa bound t-PA directly when Pn-treatment was effected in the presence of aPL and Ca(2+). Using SPR, apparent K(d) values of 1-3 microM and 0.3-0.4 microM were measured directly and by competition for the FXgamma(47/13)-Pg and FXagamma(33/13)-Pg interactions, respectively. For the first time, Pg-binding to a receptor was shown to be Ca(2+) enhanced, although primarily mediated by C-terminal lysine residues. Mathematical modeling of kinetic data suggesting two Pg per FXgamma(47/13) or FXagamma(33/13) was consistent with our conclusion that each subunit of FXgamma(47/13) or FXagamma(33/13) contains a C-terminal lysine. Earlier X-ray structures show that these Lys residues are distal from each other and the membrane, supporting the model where each interacts with a separate Pg. t-PA acceleration by FXgamma(47/13) or FXagamma(33/13) may therefore involve simultaneous presentation of two substrate molecules.

The impact of health system reform on remote health in Cambodia and the Philippines.

UNLABELLED: Remoteness is commonly conceived of in the Western health context in terms of geographical or social isolation. These features of remoteness also apply to the developing nation context. However, the international context has additional dimensions of remoteness that impact significantly on health outcomes. These are the economic, social and political realities of poverty and insecurity in remote populations. Based on the experiences of implementation of health development projects in Cambodia and The Philippines in the 1990's, this paper describes the character of poverty and insecurity and it's impact on health outcomes. It also describes recent health sector reforms of decentralisation and devolution, and discusses the degree to which these reforms have responded to the health needs of remote populations. CONCLUSION: Poverty and insecurity are dominant factors in reducing access to essential health services and hence impact negatively on health outcomes, particularly for women and children. Recent health sector reforms have not as yet demonstrated tangible benefits for the health of remote populations.

Diabetes screening. Does it make a difference in the Aboriginal and Torres Strait Islander population?

BACKGROUND: The prevalence of diabetes in the Aboriginal and Torres Strait Islander population is relatively high. A high proportion of cases are undiagnosed. Diabetes is one of a number of increasingly prevalent chronic diseases which have been described collectively as a noncommunicable disease epidemic. OBJECTIVE: To review the existing literature relating to the actual or potential benefit of screening for diabetes in the Aboriginal and Torres Strait Islander population. DISCUSSION: There is a strong case for screening for diabetes as part of an opportunistic or planned periodic health examination (PHE). As well as fasting venous plasma glucose, this integrated approach should include assessment of weight, blood pressure, presence of microalbuminuria and hyperlipidaemia. General practitioners need to be sensitive to cultural issues and power relationships, as well as considering 'structural' impediments to good health, such as affordability and availability of nutritious food, rather than focus solely on individual 'lifestyle' issues.

Identification of three HLA-A*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus.

The Ag specificity of the CTL response against CMV is directed almost entirely to a single CMV tegument protein, the phosphoprotein pp65. We report the identification of three peptides derived from the protein pp65 that displayed a high or intermediate binding to HLA-A*0201 molecules, which were also able to induce an in vitro CTL response in peripheral blood lymphocytes from CMV seropositive individuals. The peptide-specific CTLs generated were capable of recognizing the naturally processed pp65 either presented by CMV-infected cells or by cells infected with an adenovirus construct expressing pp65 in an HLA-A*0201-restricted manner. Thus, we were able to demonstrate responses to subdominant CTL epitopes in CMV-pp65 that were not detected in polyclonal cultures obtained by conventional stimulations. We also found that the amino acid sequences of the three peptides identified as HLA-A*0201-restricted CTL epitopes were conserved among different wild-type strains of CMV obtained from renal transplant patients, an AIDS patient, and a congenitally infected infant, as well as three laboratory strains of the virus (AD169, Towne and Davis). These observations suggest that these pp65 CTL peptide epitopes could potentially be used as synthetic peptide vaccines or for other therapeutic strategies aimed at HLA-A*0201-positive individuals, who represent approximately 40% of the European Caucasoid population. However, strain variation must be taken in consideration when the search for CTL epitopes is extended to other HLA class I alleles, because these mutations may span potential CTL epitopes for other HLA molecules, as it is described in this study.

Two clinical isolates and the Toledo strain of cytomegalovirus contain endothelial cell tropic variants that are not present in the AD169, Towne, or Davis strains.

The highly fibroblast-passaged AD169, Towne, and Davis strains of cytomegalovirus (CMV) were found to have a restricted capacity to infect endothelial cells in vitro. Although such replication could be increased by a combination of low speed centrifugation and sodium butyrate treatment, the extracellular virus produced was infectious for fibroblasts but not for endothelial cells. In contrast, the low passage Toledo strain, and a low passage fibroblast-grown clinical isolate of CMV, C1F, could be continually passaged in endothelial cells, giving the strains C1FE and Toledo.E. Whilst, using the conditions described above, initial infection of endothelial cells with AD169 or C1F resulted in similar titres of extracellular virus as assayed on fibroblasts, only the virus from the C1F strain was infectious for endothelial cells. Passage of C1F in fibroblasts decreased its ability to infect endothelial cells, whilst retaining equal ability to infect fibroblasts. Although endothelial-cell-passaged cell-free C1FE virus was endothelial cell-tropic, it was still much more infectious for fibroblasts than for endothelial cells. It is concluded that the C1F and Toledo strains, but not the AD169, Towne, or Davis strains, contained endothelial cell tropic variants, which could be lost on passage through fibroblasts, but retained on passage through endothelial cells. Furthermore, virus in an ex vivo source of CMV, a blood specimen, was found to be more tropic for fibroblasts than for endothelial cells, suggesting that in vivo CMV exists as quasi strains with different cell tropism, some of which might be lost in vitro by passage in an inappropriate cell type.