Fostering Governance and Information Partnerships for Chronic Disease Surveillance: The Multi-State EHR-Based Network for Disease Surveillance.

CONTEXT: Electronic health records (EHRs) are an emerging chronic disease surveillance data source and facilitating this data sharing is complex. PROGRAM: Using the experience of the Multi-State EHR-Based Network for Disease Surveillance (MENDS), this article describes implementation of a governance framework that aligns technical, statutory, and organizational requirements to facilitate EHR data sharing for chronic disease surveillance. IMPLEMENTATION: MENDS governance was cocreated with data contributors and health departments representing Texas, New Orleans, Louisiana, Chicago, Washington, and Indiana through engagement from 2020 to 2022. MENDS convened a governance body, executed data-sharing agreements, and developed a master governance document to codify policies and procedures. RESULTS: The MENDS governance committee meets regularly to develop policies and procedures on data use and access, timeliness and quality, validation, representativeness, analytics, security, small cell suppression, software implementation and maintenance, and privacy. Resultant policies are codified in a master governance document. DISCUSSION: The MENDS governance approach resulted in a transparent governance framework that cultivates trust across the network. MENDS's experience highlights the time and resources needed by EHR-based public health surveillance networks to establish effective governance.

Leveraging Electronic Health Record Data for Timely Chronic Disease Surveillance: The Multi-State EHR-Based Network for Disease Surveillance.

CONTEXT: Electronic health record (EHR) data can potentially make chronic disease surveillance more timely, actionable, and sustainable. Although use of EHR data can address numerous limitations of traditional surveillance methods, timely surveillance data with broad population coverage require scalable systems. This report describes implementation, challenges, and lessons learned from the Multi-State EHR-Based Network for Disease Surveillance (MENDS) to help inform how others work with EHR data to develop distributed networks for surveillance. PROGRAM: Funded by the Centers for Disease Control and Prevention (CDC), MENDS is a data modernization demonstration project that aims to develop a timely national chronic disease sentinel surveillance system using EHR data. It facilitates partnerships between data contributors (health information exchanges, other data aggregators) and data users (state and local health departments). MENDS uses query and visualization software to track local emerging trends. The program also uses statistical and geospatial methods to generate prevalence estimates of chronic disease risk measures at the national and local levels. Resulting data products are designed to inform public health practice and improve the health of the population. IMPLEMENTATION: MENDS includes 5 partner sites that leverage EHR data from 91 health system and clinic partners and represents approximately 10 million patients across the United States. Key areas of implementation include governance, partnerships, technical infrastructure and support, chronic disease algorithms and validation, weighting and modeling, and workforce education for public health data users. DISCUSSION: MENDS presents a scalable distributed network model for implementing national chronic disease surveillance that leverages EHR data. Priorities as MENDS matures include producing prevalence estimates at various geographic and subpopulation levels, developing enhanced data sharing and interoperability capacity using international data standards, scaling the network to improve coverage nationally and among underrepresented geographic areas and subpopulations, and expanding surveillance of additional chronic disease measures and social determinants of health.

Equity and Accessibility of Washington State's COVID-19 Digital Exposure Notification Tool (WA Notify): Survey and Listening Sessions Among Community Leaders.

BACKGROUND: In November 2020, WA Notify, Washington State's COVID-19 digital exposure notification tool, was launched statewide to mitigate ongoing COVID-19 transmission. WA Notify uses the Bluetooth proximity-triggered, Google/Apple Exposure Notification Express framework to distribute notifications to users who have added or activated this tool on their smartphones. This smartphone-based tool relies on sufficient population-level activation to be effective; however, little is known about its adoption among communities disproportionately impacted by the COVID-19 pandemic or what barriers might limit its adoption and use among diverse populations. OBJECTIVE: We sought to (1) conduct a formative exploration of equity-related issues that may influence the access, adoption, and use of WA Notify, as perceived by community leaders of populations disproportionately impacted by the COVID-19 pandemic; and (2) generate recommendations for promoting the equitable access to and impact of this novel intervention for these communities. METHODS: We used a 2-step data collection process to gather the perspectives of community leaders across Washington regarding the launch and implementation of WA Notify in their communities. A web-based, brief, and informational survey measured the perceptions of the community-level familiarity and effectiveness of WA Notify at slowing the spread of COVID-19 and identified potential barriers and concerns to accessing and adopting WA Notify (n=17). Semistructured listening sessions were conducted to expand upon survey findings and explore the community-level awareness, barriers, facilitators, and concerns related to activating WA Notify in greater depth (n=13). RESULTS: Our findings overlap considerably with those from previous mobile health equity studies. Digital literacy, trust, information accessibility, and misinformation were highlighted as key determinants of the adoption and use of WA Notify. Although WA Notify does not track users or share data, community leaders expressed concerns about security, data sharing, and personal privacy, which were cited as outweighing the potential benefits to adoption. Both the survey and informational sessions indicated low community-level awareness of WA Notify. Community leaders recommended the following approaches to improve engagement: tailoring informational materials for low-literacy levels, providing technology navigation, describing more clearly that WA Notify can help the community, and using trusted messengers who are already engaged with the communities to communicate about WA Notify. CONCLUSIONS: As digital public health tools, such as WA Notify, emerge to address public health problems, understanding the key determinants of adoption and incorporating equity-focused recommendations into the development, implementation, and communication efforts around these tools will be instrumental to their adoption, use, and retention.

Healthcare providers' knowledge, readiness, prescribing behaviors, and perceived barriers regarding routine HIV testing and pre-exposure prophylaxis in DeLand, Florida.

OBJECTIVES: Florida ranks highest in the United States among newly diagnosed HIV infections. This ranking reflects the need for investigation of healthcare providers' knowledge, readiness, prescribing behaviors, and perceived barriers to routine HIV testing and pre-exposure prophylaxis. METHODS: We adapted national questionnaires with questions co-developed with Florida Department of Health to form a 25-item instrument. Questionnaires were distributed to the population of eligible healthcare providers in DeLand, Florida. RESULTS: Results from an approximate 20% response rate that encompasses 12 providers demonstrate baseline findings to inform future studies. For example, 75% of respondents were aware of FL Administrative Code 64D-3.042 that pregnant women should receive HIV testing during first and third trimesters. However, 50% of respondents rarely or never offer tests to pregnant women according to practice guidelines. About 75% of respondents strongly agree or agree with willingness to prescribe pre-exposure prophylaxis to high-risk patients, yet 8.3% always or very often prescribe pre-exposure prophylaxis. CONCLUSIONS: Results convey the importance of and need for greater collaboration between providers and the Florida Department of Health to enhance providers' knowledge, readiness, and, ultimately, behaviors regarding routine HIV testing and pre-exposure prophylaxis prescription.

Institutionalizing the academic health department within the context of the 3-fold academic mission.

A mature model of an academic health department (AHD) that has been institutionalized over 2 decades is described within the context of the 3-fold traditional mission of academics (teaching, research, and service/practice). This adaptive model for AHDs, based on mutual benefits that can be viewed through the lenses of both the academic health center mission and the public health functions and services, has important implications for AHD sustainability. Continued collaboration in any academic-public health partnership will depend in part on the commitments of the changing leadership. However, institutionalizing support for the academic mission enables this collaboration to transcend changing leadership styles and priorities. The collaboration of Duval County Health Department and University of Florida College of Medicine-Jacksonville is an example of a model of AHD that has endured major changes in leadership within both the academic center and the Duval County Health Department.

Sexological deliberation and social engineering: Albert Moll and the sterilisation debate in late imperial and Weimar Germany.

The physician and sexologist Albert Moll, from Berlin, was one of the main protagonists within the German discourse on the opportunities and dangers of social engineering, by eugenic interventions into human life in general, as well as into reproductive hygiene and healthcare policy in particular. One of the main sexological topics that were discussed intensively during the late-Wilhelminian German Reich and the Weimar Republic was the question of the legalisation of voluntary and compulsory sterilisations on the basis of medical, social, eugenic, economic or criminological indications. As is clear from Moll's conservative principles of medical ethics, and his conviction that the genetic knowledge required for eugenically indicated sterilisations was not yet sufficiently elaborated, he had doubts and worries about colleagues who were exceedingly zealous about these surgical sterilisations--especially Gustav Boeters from Saxony.

The relationship between perceived discrimination and patient experiences with health care.

BACKGROUND: Prior studies have shown that racial/ethnic minorities have lower Consumer Assessments of Healthcare Providers and Systems (CAHPS) scores. Perceived discrimination may mediate the relationship between race/ethnicity and patient experiences with care. OBJECTIVE: To examine the relationship between perceived discrimination based on race/ethnicity and Medicaid insurance and CAHPS reports and ratings of care. METHODS: The study analyzed 2007 survey data from 1509 Florida Medicaid beneficiaries. CAHPS reports (getting needed care, timeliness of care, communication with doctor, and health plan customer service) and ratings (personal doctor, specialist care, overall health care, and health plan) of care were the primary outcome variables. Patient perceptions of discrimination based on their race/ethnicity and having Medicaid insurance were the primary independent variables. Regression analysis modeled the effect of perceptions of discrimination on CAHPS reports and ratings controlling for age, sex, education, self-rated health status, race/ethnicity, survey language, and fee-for-service enrollment. SEs were corrected for correlation within plans. RESULTS: Medicaid beneficiaries reporting discrimination based on race/ethnicity had lower CAHPS scores, ranging from 15 points lower (on a 0-100 scale) for getting needed care to 6 points lower for specialist rating, compared with those who never experienced discrimination. Similar results were obtained for perceived discrimination based on Medicaid insurance. CONCLUSIONS: Perceptions of discrimination based on race/ethnicity and Medicaid insurance are prevalent and are associated with substantially lower CAHPS reports and ratings of care. Practices must develop and implement strategies to reduce perceived discrimination among patients.

Policy implications for local application of the 2009 Youth Risk Behavior Survey, Duval County, Florida.

INTRODUCTION: Youth Risk Behavior Survey (YRBS) data have rarely been analyzed at the subcounty level. The purpose of this study was to explore the feasibility of such analysis and its potential to inform local policy and resource allocation. METHODS: We administered the 2009 YRBS to 5,860 students from 46 public middle and high schools in Duval County, Florida. In addition to asking core questions, we asked a set of questions customized for local needs, including questions about zip codes. These data were used to simulate subcounty areas consistent with areas identified by behavioral, morbidity, mortality, and health disparity surveillance. We oversampled Duval County and used weighting procedures that adjusted for subcounty areas. RESULTS: Many Duval County health risk behavior rates were higher than those for Florida overall but did not vary significantly within the county. Physical activity and violence-related behaviors were exceptions that reflect major health disparities in parts of the county with a high proportion of racial/ethnic minorities. CONCLUSION: This study demonstrated that collecting subcounty data in large metropolitan areas is feasible and that analysis of these data at the local level has implications for policy. Some health risk behaviors were common across the county, indicating the need for health promotion and disease prevention programs at the school district level. Other health risk behaviors were more prevalent in specific areas of the county and may have been exacerbated by state or local policies such as restrictions on physical education. Health disparities remain a challenge throughout the country; reducing them will require more extensive data-driven problem solving at state and local levels.

Perinatal periods of risk: phase 2 analytic methods for further investigating feto-infant mortality.

The perinatal periods of risk (PPOR) methods provide a framework and tools to guide large urban communities in investigating their feto-infant mortality problem. The PPOR methods have 11 defined steps divided into three analytic parts: (1) Analytic Preparation; (2) Phase 1 Analysis-identifying the opportunity gaps or populations and risk periods with largest excess mortality; and (3) Phase 2 Analyses-investigating these opportunity gaps. This article focuses on the Phase 2 analytic methods, which systematically investigate the opportunity gaps to discover which risk and preventive factors are likely to have the largest effect on improving a community's feto-infant mortality rate and to provide additional information to better direct community prevention planning. This article describes the last three PPOR epidemiologic steps for investigating identified opportunity gaps: identifying the mechanism for excess mortality; estimating the prevalence of risk and preventive factors; and estimating the impact of these factors. While the three steps provide a common strategy, the specific analytic details are tailored for each of the four perinatal risk periods. This article describes the importance, prerequisites, alternative approaches, and challenges of the Phase 2 methods. Community examples of the methods also are provided.

Perinatal periods of risk: analytic preparation and phase 1 analytic methods for investigating feto-infant mortality.

The Perinatal Periods of Risk (PPOR) methods provide the necessary framework and tools for large urban communities to investigate feto-infant mortality problems. Adapted from the Periods of Risk model developed by Dr. Brian McCarthy, the six-stage PPOR approach includes epidemiologic methods to be used in conjunction with community planning processes. Stage 2 of the PPOR approach has three major analytic parts: Analytic Preparation, which involves acquiring, preparing, and assessing vital records files; Phase 1 Analysis, which identifies local opportunity gaps; and Phase 2 Analyses, which investigate the opportunity gaps to determine likely causes of feto-infant mortality and to suggest appropriate actions. This article describes the first two analytic parts of PPOR, including methods, innovative aspects, rationale, limitations, and a community example. In Analytic Preparation, study files are acquired and prepared and data quality is assessed. In Phase 1 Analysis, feto-infant mortality is estimated for four distinct perinatal risk periods defined by both birthweight and age at death. These mutually exclusive risk periods are labeled Maternal Health and Prematurity, Maternal Care, Newborn Care, and Infant Health to suggest primary areas of prevention. Disparities within the study community are identified by comparing geographic areas, subpopulations, and time periods. Excess mortality numbers and rates are estimated by comparing the study population to an optimal reference population. This excess mortality is described as the opportunity gap because it indicates where communities have the potential to make improvement.

Impact of pre-conception health care: evaluation of a social determinants focused intervention.

The purpose of this study was to evaluate the outcomes of the social determinants component of a multiple determinants model of pre- and inter-conception care. Health department vital statistics and infectious disease data on birth and factors influencing birth outcomes were analyzed for participants in a program designed to mitigate the effects of social class and stress in contrast to a matched comparison group and other relevant populations. The program showed promising results related to reducing infant mortality and reducing other high-risk factors for poor birth outcomes, including low birth weight and sexually transmitted disease. Social determinant interventions, designed to mitigate the impact of social class and stress, should be considered with efforts to reduce infant mortality, particularly the disparities associated with infant mortality. Additional research should be conducted to refine replicable social determinant focused interventions and confirm and generalize these results.

A community-centered model of the academic health department and implications for assessment.

The academic health department, also referred to as the teaching health department, is receiving increased attention as an organizational structure to enhance public health workforce development. Traditionally, academic institutions have been viewed by major funders, and reported in the literature, to be the innovators of these partnerships, in part to extend the academic institution's education role in the workplace. However, the role of the local health department as innovator is emerging with implications beyond workforce development. This report illustrates how a local agency-initiated community-centered approach to an academic health department enhances the core public health function of assessment, a frequently underdeveloped function at the local level. This agency-initiated, community-centered academic health department model builds assessment capacity through a partnership that integrates academic research and public health surveillance capacity to provide comprehensive assessment, including community assessment, community-based participatory research, data analysis, and program evaluation. This organizational structure, focused on systems approaches to building community capacity rather than focusing on disease categories or high-risk populations, illustrates how a local health department can substantially enhance its assessment capacity using available resources.

Application of economic impact analysis to a local public health agency and its "Academic Health Department".

Public health systems are stressed by increasing demands and inadequate resources. This study was designed to demonstrate how economic impact analysis can estimate the economic value of a local public health system's infrastructure as well as the economic assets of an "Academic Health Department" model. This study involved the secondary analysis of publicly available data on health department finances and employment using proprietary software specifically designed to assess economic impacts. The health department's impact on the local community was estimated at over 100 million dollars, exceeding the economic impact of other recently studied local industries with no additional costs to local taxpayers.

A model for training pediatricians to expand mental health services in the community practice setting.

A model of training pediatricians in mental health diagnosis and intervention was developed to increase the pediatrician's competency in dealing with the increasing number of children with these problems. The model consisted of a pediatric psychiatrist working in collaboration with community pediatricians and training pediatricians in mental health interview and evaluation techniques, recognition and diagnosis of behavioral and mental disorders, and intervention and treatment. Following implementation of this model, the community pediatricians demonstrated an increase in mental health diagnoses in their practices. This model represents one approach in preparing pediatricians to respond to the increasing number of children with mental health and behavioral problems.

The health status of southern children: a neglected regional disparity.

PURPOSE: Great variations exist in child health outcomes among states in the United States, with southern states consistently ranked among the lowest in the country. Investigation of the geographical distribution of children's health status and the regional factors contributing to these outcomes has been neglected. We attempted to identify the degree to which region of residence may be linked to health outcomes for children with the specific aim of determining whether living in the southern region of the United States is adversely associated with children's health status. METHODS: A child health index (CHI) that ranked each state in the United States was computed by using state-specific composite scores generated from outcome measures for a number of indicators of child health. Five indicators for physical health were chosen (percent low birth weight infants, infant mortality rate, child death rate, teen death rate, and teen birth rates) based on their historic and routine use to define health outcomes in children. Indicators were calculated as rates or percentages. Standard scores were calculated for each state for each health indicator by subtracting the mean of the measures for all states from the observed measure for each state. Indicators related to social and economic status were considered to be variables that impact physical health, as opposed to indicators of physical health, and therefore were not used to generate the composite child health score. These variables were subsequently examined in this study as potential confounding variables. Mapping was used to redefine regional groupings of states, and parametric tests (2-sample t test, analysis of means, and analysis-of-variance F tests) were used to compare the means of the CHI scores for the regional groupings and test for statistical significance. Multiple-regression analysis computed the relationship of region, social and economic indicators, and race to the CHI. Simple linear-regression analyses were used to assess the individual effect of each indicator. RESULTS: A geographic region of contiguous states, characterized by their poor child health outcomes relative to other states and regions of the United States, exists within the "Deep South" (Mississippi, Louisiana, Arkansas, Tennessee, Alabama, Georgia, North Carolina, South Carolina, and Florida). This Deep-South region is statistically different in CHI scores from the US Census Bureau-defined grouping of states in the South. The mean of CHI scores for the Deep-South region was >1 SD below the mean of CHI scores for all states. In contrast, the CHI score means for each of the other 3 regions were all above the overall mean of CHI scores for all states. Regression analysis showed that living in the Deep-South region is a stronger predictor of poor child health outcomes than other consistently collected and reported variables commonly used to predict children's health. CONCLUSIONS: The findings of this study indicate that region of residence in the United States is statistically related to important measures of children's health and may be among the most powerful predictors of child health outcomes and disparities. This clarification of the poorer health status of children living in the Deep South through spatial analysis is an essential first step for developing a better understanding of variations in the health of children. Similar to early epidemiology work linking geographic boundaries to disease, discovering the mechanisms/pathways/causes by which region influences health outcomes is a critical step in addressing disparities and inequities in child health and one that is an important and fertile area for future research. The reasons for these disparities may be complex and synergistically related to various economic, political, social, cultural, and perhaps even environmental (physical) factors in the region. This research will require the use and development of new approaches and applications of spatial analysis to develop insights into the societal, environmental, and historical determinants of child health that have been neglected in previous child health outcomes and policy research. The public policy implications of the findings in this study are substantial. Few, if any, policies identify these children as a high-risk group on the basis of their region of residence. A better understanding of the depth and breadth of disparities in health, education, and other social outcomes among and within regions of the United States is necessary for the generation of policies that enable policy makers to address and mitigate the factors that influence these disparities. Defining and clarifying the regional boundaries is also necessary to better inform public policy decisions related to resource allocation and the prevention and/or mitigation of the effects of region on child health. The identification of the Deep South as a clearly defined subregion of the Census Bureau's regional definition of the South suggests the need to use more culturally and socially relevant boundaries than the Census Bureau regions when analyzing regional data for policy development.

Improved characterization of liver lesions with liver-phase uptake of liver-specific microbubbles: prospective multicenter study.

PURPOSE: To evaluate in a prospective multicenter study whether conventional ultrasonographic (US) characterization of liver lesions can be improved by imaging during the liver-specific phase of SH U 508A uptake in the microbubble-specific agent detection imaging mode. MATERIALS AND METHODS: One hundred forty-two patients with liver lesions underwent conventional gray-scale and color Doppler US and SH U 508A-enhanced US. Two radiologists blindly read digital cine clips and assigned scores for confidence in diagnosis of benignancy or malignancy, diagnosis of specific lesion types, and relative difference in SH U 508A uptake between the lesion and the liver parenchyma (ie, subjective conspicuity score [SCS]). Comparisons were made to see whether the addition of agent detection imaging led to improved diagnostic performance. RESULTS: Receiver operating characteristic analysis revealed improved discrimination of benign and malignant lesions for readers 1 (P =.049) and 2 (P <.001). The number of patients with a correct diagnosis of benignancy or malignancy assigned by readers 1 and 2, respectively, improved from 114 and 113 to 125 and 128 with agent detection imaging (reader 1: P =.027; reader 2: P =.008; McNemar test). Specific diagnoses were made more accurately with agent detection imaging: At McNemar testing, the number of correct lesion type determinations increased from 83 to 92 (P =.022) for reader 1 and from 85 to 99 (P <.001) for reader 2. Both readers assigned high scores for differences in SH U 508A uptake between the liver parenchyma and the lesion for metastases and cholangiocarcinomas and low scores for uptake differences in most of the benign lesions. Hepatocellular carcinomas (HCCs), hemangiomas, and adenomas had more variable uptake differences. Fourteen of 22 hemangiomas were assigned an SCS of less than 50%, and 22 (reader 1) and 15 (reader 2) of 31 HCCs were assigned an SCS of greater than 50%. CONCLUSION: With use of SH U 508A-enhanced agent detection imaging, liver lesion characterization and diagnostic performance are significantly improved.

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.

BACKGROUND: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. OBJECTIVE: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. METHODS: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. RESULTS: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. CONCLUSIONS: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease.

Increased levels of a 40-42 amino-acid peptide called the amyloid beta protein (A beta) and evidence of oxidative damage are early neuropathological markers of Alzheimer's disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from A beta-mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimer's amyloidosis and monitored over time the effects of administering melatonin on brain levels of A beta, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time-dependent elevation of beta-amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.

Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis.

Recent epidemiological, clinical, and experimental data suggest that cholesterol may play a role in Alzheimer's disease (AD). We have recently shown that cholesterolemia has a profound effect in the development and modulation of amyloid pathology in a transgenic model of AD. This review summarizes recent advancements in our understanding of the potential role of cholesterol and the amyloid beta protein in initiating the generation of free radicals and points out their role in a chain of events that causes damage of essential macromolecules in the central nervous system and culminates in neuronal dysfunction and loss. Experimental data links cholesterol and oxidative stress with some neurodegenerative aspects of AD.

The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors.

Exposure of neuronal cells to the Alzheimer's amyloid beta protein (Abeta) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against Abeta-mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against Abeta neurotoxicity. For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b). Abeta-mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin, no neuroprotection against Abeta toxicity was observed when we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structurally unrelated free-radical scavenger phenyl-N-t-butyl nitrone (PBN), were added to Abeta-containing culture media. This study demonstrates that the neuroprotective properties of melatonin against Abeta-mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent.