Development and first application of an audit system for screening programs based on the PRECEDE-PROCEED model: an experience with breast cancer screening in the region of Lombardy (Italy).

BACKGROUND: High participation and performance are necessary conditions for the effectiveness of breast cancer screening programs. Here we describe the process to define and test a planning software application and an audit cycle based on the PRECEDE-PROCEED model applied to improving breast cancer screening. We developed a planning software application following the phases of the PRECEDE-PROCEED model. The application was co-designed by local cancer screening program coordinators. An audit model was also developed. The revised application and the audit model were tested by all the coordinators of 15 breast cancer screening programs in the region of Lombardy in a 3-day workshop. The project plans produced using the application were compared with those produced in the previous year for clarity and completeness. RESULTS: The 9 phases of the PRECEDE-PROCEED model were adapted to screening as follows: 1) identification of program goals (i.e., participation, sensitivity, false positive); 2) epidemiological issues; 3) best practices analysis; 4) evidence-based actions to be implemented in the screening center and the relationships with partners and stakeholders; 5) priority setting and identification of solutions for each issue; 6) definition of indicators; 7) monitoring; 8) evaluation; 9) impact assessment. The application automatically generated reports for each phase. During the audit cycle, the regional health authority negotiated the targets to be reached with local authorities and collected the improvement plans generated by the application. The plans produced after the application was adopted were more standardized and had clearer indicators for monitoring and evaluation compared to those produced in the previous year. CONCLUSIONS: The software application helps standardize criteria for planning interventions to improve screening programs and facilitates the implementation of the audit cycle.

[Development of a conceptual model for interpretation of monitoring indicators of childhood obesity prevention from the Italian National Prevention Plan]. / Sviluppo di un modello concettuale di riferimento per l'interpretazione degli indicatori di prevenzione dell'obesità infantile e nell'adolescenza nel Piano nazionale della prevenzione.

BACKGROUND: the Italian National Prevention Plan (PNP) posed the standard to be achieved by Regions for the prevention of obesity in childhood and adolescence. The PNP also set up a monitoring system to assess the impact of implemented policies. OBJECTIVES: to develop a conceptual model to facilitate interpretation of variation in outcome indicators. METHODS: after a systematic review, the DPSEEA («Driving forces¼, «Pressures¼, «State¼, «Exposure¼, «Effect¼, «Actions¼) was identified as the more appropriate framework to assess the results of preventive policies. Factors for each component of the framework were identified and indicators that allow measuring the changing of each of these factors were defined. RESULTS: the included «driving forces¼ were related to the profit-led food industry, to the nutrition environment at school, and to household-level factors. Among the «pressures¼, parenting behaviours, food provided by school canteens, sociocultural factors, social context, physical activity (PA), opportunities at school or after-school were included. In the State, the high consumption of processed food, the large quantities of high-calorie food easy available, the consumption of carbonated and sugar-sweetened beverages, the reduced social function of mealtimes in families, the early cessation of breastfeeding, the reduction of outdoors activity, active transportation, and PA at school for children were identified. The «exposure¼ factors were the reduced opportunities of doing PA and the over-consumption of calories that influence the «effect¼, described as the prevalence of children and adolescents affected by obesity. CONCLUSIONS: through the DPSEEA, a conceptual model was set up; it allows to place in the causal chain the «actions¼ and the mechanisms through which these actions should impact on the «exposure¼ (PA and over-consumption of calories), making the rationale of process and impact indicators explicit.

Core competencies in genetics for healthcare professionals: results from a literature review and a Delphi method.

BACKGROUND: Advances in genetics and genomics require that healthcare professionals manage and incorporate new technologies into the appropriate clinical practice. The aim of this study was to identify core competencies in genetics for non-geneticists, both physicians and non-physicians. METHODS: We performed a literature review by searching MEDLINE, SCOPUS, and ISI Web of Science databases to identify studies reporting competencies in genetics in terms of knowledge, attitudes and abilities for non-genetic healthcare professionals. Furthermore, we conducted a survey according to a modified Delphi method, involving genetics experts to evaluate the competencies to be included as items of the curricula. RESULTS: Three eligible documents were identified and 3 Delphi rounds were carried out to reach a consensus on the competencies to be incorporated in the curricula. With reference to the curriculum for physicians, 19 items were included in the knowledge domain, 3 in the attitudes and 10 in the abilities domain. We developed two different curricula for non-physicians: one specific for those working in genetic services (20 items in the knowledge domain, 3 in the attitudes and 12 in the abilities) and one for those not working in genetic services (10 items in the knowledge domain, 3 in the attitudes and 2 in the abilities). CONCLUSIONS: We developed 3 curricula in genetics addressed to non-genetic healthcare professionals. They differ in the "knowledge" and "abilities", while the "attitudes" are the same for all the healthcare professionals. Although some concerns about the generalizability of the findings could arise due to the Italian perspective, we envisage the curricula can be used for genetics educational programs in several contexts.

[Development of a conceptual model for interpretation of monitoring indicators of cancer screenings from the Italian National Prevention Plan]. / Sviluppo di un modello concettuale di riferimento per l'interpretazione degli indicatori di monitoraggio degli screening oncologici nel Piano nazionale della prevenzione.

OBJECTIVES: the Italian National Prevention Plan (PNP) posed the standard to be achieved by Italian Regions for the implementation of cervical, breast, and colorectal cancer screening: to invite all of the target populations and to increase the screening uptake up to 50%, 60%, and 50%, respectively, the standard defined by the Essential Levels of Care (LEA). Moreover, for cervical cancer screening, it requires the implementation of HPV-DNA test and, for breast cancer screening, the PNP demands for the definition of diagnostic and follow up pathways for high familial risk women. The PNP also set up a monitoring system to assess the impact of implemented policies. A conceptual model has been defined to facilitate interpretation of variation in outcome indicators. DESIGN: after a systematic review, the DPSEEA (Driving forces, Pressure, State, Exposure, Effect, Actions) was identified as the more appropriate framework to assess the results of preventive policies. Factors for each component of the model were identified and indicators that allow measuring the changing of each of these factors were defined. RESULTS: among the "driving forces", the trust in the health care system and the social capital were included. The presence of opportunistic screening, the competing private clinical activity, the commitment of General Practitioners and "medical" leaders, the attitude to cooperation and to patients' involvement, and the level of agreement between the positions of scientific societies and the recommendations implemented in organized screening programmes were included in the "pressures". In "state", the availability of technological and human resources, the level of management skills and of accessibility were identified. The "exposure" was defined as the coverage of active invitation of the target population and the uptake of screening tests. The "exposure" factors influence the "effect", described as the impact on anticipation of cancer diagnosis, on disease incidence (for cervical and colorectal cancer) and prognosis. The changing in screening programs performance modifies the impact of invitation coverage and test uptake ("exposure"). CONCLUSIONS: through the DPSEEA framework, we set up a logical conceptual model, which includes implementable actions and the mechanisms through which these actions should impact on the "exposure" (invitation coverage and screening uptake) and on the screening performance (quality).

[Omic sciences and capacity building of health professionals: a distance learning training course for Italian physicians, 2017-2018]. / Scienze omiche e capacity building dei professionisti sanitari: corso di formazione a distanza per i medici italiani.

BACKGROUND: Nowadays, a strategy to manage the current "omic revolution" is needed in Italy. Actions aimed to improve genetic/omics "literacy" among health professionals and citizens are necessary, based on recommendations outlined in the Italian 2013 Guidelines on genomics in public health, and the 2018 National Plan for the innovation of the health system based on the omic sciences. MATERIALS AND METHODS: In the context of a project funded by the Italian Ministry of Health, a distance-learning course entitled "Genetic and Genomic practices" was developed, targeted at medical professionals (mainly general practitioners). The main objective of the course was to train physicians in the responsible use of omic technologies. The course was structured according to the main models of adult learning theory (Problem-based-learning and case studies) and delivered on the institutional platform of the Italian National Institute of Health for one year, from February 2017 to February 2018, with the endorsement of the Italian Society of Hygiene and Preventive Medicine and the Italian Society of Human Genetics. RESULTS: In one year, 3,054 participants registered for the course and 53% completed it. About 21% of participants were primary care physicians, 12% were public health physicians and 11% were hospital paediatricians. The most represented age group of participants was 51-65 years and their geographical distribution was 38.5% southern Italy/islands, 36.3% northern Italy and 25.2% central Italy. Pre-test data showed that training needs of primary care physicians was very high. CONCLUSIONS: In the current context, characterized by the "omic revolution", physicians must be able to understand its potential implications for the diagnosis, control and treatment of diseases. It is therefore necessary to work on capacity building of all health professionals involved in various ways in the use of the "omic sciences". Distance-learning training in genetic/genomic practices represents a low-cost, satisfactory and clinically applicable method to improve physicians' knowledge.

Disinvestment in cancer care: a survey investigating European countries' opinions and views.

Background: The current economic context calls for rationalizing health resources that can be pursued through disinvestment from low value health technologies to invest in the best performing ones, ensuring high healthcare quality. Oncology is a field where, because of high costs of health technologies and rapid innovation, disinvestment is crucial. Methods: On this basis, the research team investigated through a survey, based on a questionnaire, opinions and views of representatives of European countries about disinvestment, in terms of fields of application, potential advocates and barriers, specifically focusing on cancer care. Results: A total of 17 questionnaires were filled in (response rate: 32.1%). The survey showed disinvestment is applied in several countries as a tool for containing health care expenditures and identifying obsolete technologies/ineffective interventions. Clinicians' resistance to change and industries' opposition are recognized as the most important barriers to the implementation of disinvestment policies. Potential targets of disinvestment in cancer are seen in diagnostic and therapeutic areas. Conclusion: Despite the agreement on fields of waste and of disinvestment policies, operational methods to put disinvestment in place are lacking. Since they should rely on an inclusive assessment of the technology, Health Technology Assessment may represent a good approach.

Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference.

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by "one size fits all" protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept.

[Experimenting an instrument for cancer screening programming in Italy]. / Sperimentazione di uno strumento per la programmazione dei programmi di screening oncologici in Italia.

Increased participation in cancer screening programs is undoubtedly a primary objective in Public Health. The Green and Kreuter model, structured in an Access program, was presented to the Regional Coordinators for cancer screening during specific training events. This survey was carried out to verify their appreciation of the model and whether those who participated in the project intended to use the program.

The diffusion of screening programmes in Italy, years 2011-2012.

In this report, we present the results of cancer screening programmes in Italy for the years 2011-2012. This report is produced by the National centre for screening monitoring (ONS), together with the Italian professional multidisciplinary screening groups: GISMa (Italian group for mammographic screening), GISCor (Italian group for colorectal screening), and GISCi (Italian group for cervical screening). Since 2004, ONS has been monitoring and supporting Italian screening programmes, in accordance with a decree issued by the Ministry of Health. Multidisciplinary groups work with ONS and provide the know-how required to promote the quality of public health programmes. The following is a brief outline of the Italian screening programme setting: screening programmes (cervical, mammographic, colorectal) have been a Basic Healthcare Parameter (livello essenziale di assistenza, LEA) since 2001; guidelines are provided by the Ministry of Health's Department of Prevention in agreement with regional governments; regional governments are responsible for the organization, management, and quality assurance of screening programmes; since 2004, ONS has been responsible for monitoring and promoting screening programmes nationwide; the results of the screening programmes of each region are evaluated annually by the Ministry of Health in terms of coverage and impact.

Personality profiles and coping styles in migraine patients with fibromyalgia comorbidity.

Fibromyalgia syndrome (FM) is frequently associated with migraine. In this study we aimed to compare personality profiles and coping styles across 23 migraine without aura patients sharing FM comorbidity (MWA-FM), 28 migraine without aura patients without FM symptoms (MWA) and 51 age- and sex-matched controls, by means of Big Five Questionnaire (BFQ) and Coping Orientation to Problem Experienced (COPE), and to correlate main results with clinical features. The "Energy" personality factor was significantly reduced in patients presenting with FM symptoms, compared to both migraine without aura patients and controls. A low score in "Dynamism" sub-item with a high score in denial coping style was able to distinguish MWA from MW-FM groups with an accuracy of 82.35% (Wilks lambda=0.98; chi-square=8.99, DF=1, p=0.005). In particular, lower "Dynamism" scores corresponded to a major expression of allodynia, fatigue, anxiety, depression, headache frequency and poor quality of sleep and life. Avoidance from active coping with stressful events may facilitate worsening of migraine and fibromyalgia comorbidity.

[Implementation of Italian guidelines on public health genomics in Italy: a challenging policy of the NHS]. / Le policy di genomica in sanità pubblica in Italia: le sfide nella implementazione delle linee guida nel sistema sanitario nazionale.

BACKGROUND: Genomics and related fields are becoming increasingly relevant in health care practice. Italy is the first European country that has a structured policy of Public Health Genomics. Nevertheless, what should be the role of genomics in a public health perspective and how public health professionals should engage with advances in genomics' knowledge and technology, is still not entirely clear. METHODS: A description of the regulatory framework made-up by the Italian government in the last years is provided. In order to implement the national guidelines on Public Health Genomics published in 2013, key issues including the ethical, legal and social aspects within an evidence-based framework should be warranted and are herewith discussed. CONCLUSIONS: Genomics and predictive medicine are considered one of the main intervention areas by the National Prevention Plan 2010-2012, and dedicated guidelines were published in 2013. In order to implement such guidelines, we envisage a coordinated effort between stakeholders to guide development in genomic medicine, towards an impact on population health. There is also room to implement knowledge on how genomics can be integrated into health systems in an appropriate and sustainable way. Learning programs are needed to spread knowledge and awareness of genomics technology, in particular on genomic testing for complex diseases.

[Methods to increase participation in cancer screening programmes]. / Metodi per aumentare la partecipazione ai programmi di screening oncologici.

OBJECTIVE: to synthesize scientific evidences about methods to increase cervical, breast and colorectal cancer screening participation. METHODS: a multidisciplinary working group has been set up to define the scope of the report and to conduct the evaluation. The scope and the final evaluation have been submitted to a stakeholder committee, including the Ministry of Health, the National Screening Observatory, regional screening program coordinators, scientific societies, and Lega Italiana Lotta ai Tumori, for comments and integrations. A systematic review of the principal biomedical and social literature databases was conducted to identify experimental and observational studies, updating the existing review by Jepson and coll. (Health Technol Assess. 2000;4(14):i-vii, 1-133). RESULTS: 5900 have been identified, 900 relevant for the topic.Among those, 148 reported quantitative information on intervention efficacy, other 90 came from the previous review. Organised screening programmes, based on invitation letter or on GP involvement,were consistently effective in increasing participation compared to spontaneous screening. Interventions are classified according to their target: individual, community, test simplification, health operators, health service organization. The report presents meta-analyses on efficacy, analyses of cost-effectiveness, impact on organisation and social inequality, and ethical and legal issues, of all the intervention reported in the literature. CONCLUSIONS: there are several interventions consistently effective in any context, some of them have minimal impact on costs and health service resources.

[The diffusion of screening programmes in Italy, year 2010]. / La diffusione dei programmi di screening in Italia, anno 2010.

The national meeting of the National Centre for Screening Monitoring (ONS) was given the title "The screening during the crisis" as we realize that the severe economical crisis of our country influences all the health policies and, as a consequence, screening programs. Within this global scenario, the results of 2010 concerning screening programs can be considered as still positive even if the gap between the North and the Central Regions as compared to the South remains. In short, in 2010 almost 9.5 millions people were invited to undergo a screening examination (3,450,000; 2,496,000 and 3,464,000 for cervical, mammographic and colorectal cancer respectively). As compared to the previous year, a large increase was observed for colorectal screening.Whereas a slight decrease was observed both for cervical and for mammographic screening. The latter trend was partially due to the overload consequent to the extension of the programme to women younger than fifty in a couple of regions (Emilia-Romagna and Piemonte). More than 4.3 millions of subjects actually complied to the invitation (1,375,000; 1,382,000 and 1,582,000 for cervical, mammographic and colorectal cancer, respectively). As a consequence of these activities were identified 6,015 breast cancers (31% of annual occurring breast cancers in Italy in the age group 50-69 years according to the most update estimates of breast cancer occurrence), 4,597 CIN2 or more severe cervical lesions, 2,916 colorectal cancers (15% of annual occurring CRC cancer in Italy in the age group 50-69 years) and 15,049 advanced adenomas.

Clinical features of headache patients with fibromyalgia comorbidity.

Our previous study assessed the prevalence of fibromyalgia (FM) syndrome in migraine and tension-type headache. We aimed to update our previous results, considering a larger cohort of primary headache patients who came for the first time at our tertiary headache ambulatory. A consecutive sample of 1,123 patients was screened. Frequency of FM in the main groups and types of primary headaches; discriminating factor for FM comorbidity derived from headache frequency and duration, age, anxiety, depression, headache disability, allodynia, pericranial tenderness, fatigue, quality of life and sleep, and probability of FM membership in groups; and types of primary headaches were assessed. FM was present in 174 among a total of 889 included patients. It prevailed in the tension-type headache main group (35%, p < 0.0001) and chronic tension-type headache subtype (44.3%, p < 0.0001). Headache frequency, anxiety, pericranial tenderness, poor sleep quality, and physical disability were the best discriminating variables for FM comorbidity, with 81.2% sensitivity. Patients presenting with chronic migraine and chronic tension-type headache had a higher probability of sharing the FM profile (Bonferroni test, p < 0.01). A phenotypic profile where headache frequency concurs with anxiety, sleep disturbance, and pericranial tenderness should be individuated to detect the development of diffuse pain in headache patients.

The diffusion of screening programmes in Italy, year 2009.

In 2009, screening programmes in Italy continued to have positive results, as well as retaining some of the issues encountered in previous years. Overall, in 2009 over 9,000,000 people were invited to undergo a screening examination (3,547,000, 2,522,000 and 2,994,000, for cervical, breast, and colorectal cancer, respectively). More than 4 million people actually took up the invitation (1,393,000, 1,363,000, and 1,423,000 for cervical, breast, and colorectal cancer, respectively). The screening activities led to the finding of 5,973 breast cancers (36% of annual occurring breast cancers in Italy in the 50-69 year age group), 4 454 CIN2 or more severe cervical lesions, 2,556 colorectal cancers (16% of annual occurring CRC cancer in Italy in the 50-69 year age group), and 13,554 advanced adenomas.

Capacity Building of Health Professionals on Genetics and Genomics Practice: Evaluation of the Effectiveness of a Distance Learning Training Course for Italian Physicians.

BACKGROUND: The rapid spread of personalized medicine requires professionals to manage the "omics revolution." Therefore, the genetics/genomics literacy of healthcare professionals should be in line with the continuous advances in this field, in order to implement its potential implications for diagnosis, control and treatment of diseases. The present study investigates the effectiveness of a distance learning course on genetics and genomics targeted at medical doctors. METHODS: In the context of a project funded by the Italian Ministry of Health, we developed a distance learning course, entitled Genetics and Genomics practice. The course focused on genetic/genomics testing, pharmacogenetics and oncogenomics and was developed according to andragogical training methods (Problem-based Learning and Case-based Learning). We used a pre-test vs. post-test study design to assess knowledge improvement on a set of 10 Multiple Choice Questions (MCQs). We analyzed the proportion of correct answers for each question pre and post-test and the mean score difference stratified by gender, age, professional status and medical discipline. Moreover, the test was submitted to the participants 8 months after the conclusion of the course (follow-up), in order to assess the retained knowledge. RESULTS: The course was completed by 1,637 Italian physicians, most of which were primary care physicians (20.8%), public health professionals (11.5%) and specialist pediatricians (10.6%). The proportion of correct answers increased in the post-test for all the MCQs. The overall mean score significantly increased, from 59.46 in the pre-test to 71.42 in the post-test (p < 0.0001). The comparison in test performance between follow-up and pre-test demonstrated an overall knowledge improvement. CONCLUSION: Genomics literacy among healthcare professionals is essential to ensure optimal translation to healthcare delivery of research. The results of this course suggest that distance-learning training in genetic/genomics practice represents an effective method to improve physicians' knowledge in the immediate and mid-term time scale. A preprint version of this paper is available at: https://www.researchsquare.com/article/rs-10083/v1.

Are There Effective Interventions to Increase Physical Activity in Children and Young People? An Umbrella Review.

BACKGROUND: Obesity and physical inactivity among children and young people are public health concerns. While numerous interventions to promote physical activity are available, little is known about the most effective ones. This study aimed to summarize the existing evidence on interventions that aim to increase physical activity. METHODS: A systematic review of reviews was conducted. Systematic reviews and meta-analyses published from January 2010 until November 2017 were identified through PubMed, Scopus and the Cochrane Library. Two reviewers independently assessed titles and abstracts, performed data extraction and quality assessment. Outcomes as level of physical activity and body mass index were collected in order to assess the efficacy of interventions. RESULTS: A total 30 studies examining physical activity interventions met the inclusion criteria, 15 systematic reviews and 15 meta-analyses. Most studies (N = 20) were implemented in the school setting, three were developed in preschool and childcare settings, two in the family context, five in the community setting and one miscellaneous context. Results showed that eight meta-analyses obtained a small increase in physical activity level, out of which five were conducted in the school, two in the family and one in the community setting. Most promising programs had the following characteristics: included physical activity in the school curriculum, were long-term interventions, involved teachers and had the support of families. CONCLUSION: The majority of interventions to promote physical activity in children and young people were implemented in the school setting and were multicomponent. Further research is needed to investigate nonschool programs.

Cost-effectiveness analysis of genetic diagnostic strategies for Lynch syndrome in Italy.

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients ≥ than 70 years old (Strategy 3) were analyzed and compared to the "no testing" strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between €1,753,059.93-€10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from €941.24 /QALY to €1,681.93 /QALY, thus supporting that "universal testing" versus "no testing" is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS screening in Italy.

Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature.

Oxidative stress contributes to cardiovascular complications of diabetes, in part, by reducing the bioavailability of nitric oxide (NO). We investigated the mechanisms whereby the insulin sensitizer rosiglitazone may ameliorate oxidative stress in the vasculature of spontaneously hypertensive rats (SHR). Nine-week-old SHR were treated by gavage for 7 wk with rosiglitazone (5 mg x kg(-1) x day(-1)) or vehicle control. Treatment of SHR with rosiglitazone lowered systolic blood pressure, reduced fasting plasma insulin and asymmetrical dimethylarginine, and increased insulin sensitivity (when compared with vehicle treatment). In vessel homogenates and serum from rosiglitazone-treated SHR, SOD activity was enhanced, while 8-iso-PGF(2alpha) (lipid peroxidation product) was reduced (when compared with samples from vehicle-treated SHR). Moreover, expression of p22phox (catalytic subunit of NADPH oxidase) as well as nitrotyrosine and superoxide content were all reduced in the aortas of rosiglitazone-treated SHR. In mesenteric vascular beds (MVB) isolated ex vivo from rosiglitazone-treated SHR, NO-dependent vasodilator actions of insulin were improved when compared with MVB from vehicle-treated SHR. Acute pretreatment of MVB from vehicle-treated SHR with apocynin (NADPH oxidase inhibitor) enhanced vasodilator actions of insulin (results comparable to those in MVB from rosiglitazone-treated SHR). In Langendorff heart preparations from rosiglitazone-treated SHR, ischemia/reperfusion injury caused infarcts 40% smaller than in hearts from vehicle-treated SHR. Acute pretreatment of hearts from vehicle-treated SHR with apocynin produced similar results. Finally, rosiglitazone treatment of endothelial cells in primary culture reduced superoxide induced by insulin-resistant conditions. We conclude that rosiglitazone therapy in SHR increases SOD activity and decreases p22phox expression in the vasculature to reduce oxidant stress leading to an improved cardiovascular phenotype.