mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions.

Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of 'Delay cells' is mediated by N-methyl-d-aspartate receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R)-APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose-response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low doses of mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.

Lessons learned from a review of the development of selected vaccines. National Vaccine Advisory Committee.

BACKGROUND: Although the vaccine research and development network in the United States remains vibrant, its continued success requires maintaining harmonious interaction among its many components. Changing one component is likely to affect the system overall. An examination of case studies of the development of selected vaccines would allow an examination of the network as a whole. This article presents conclusions drawn from the case study review undertaken. OBJECTIVE: Successful development of vaccines is a time-intensive process requiring years of commitment from a network of scientists and a continuum of regulatory and manufacturing entities. We undertook this work to shed light on how well the vaccine development system in the United States performs. METHOD: The National Vaccine Advisory Committee examined the research and development pathways of several vaccines that reached licensure expeditiously (hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccines); some that became licensed only after considerable delay (oral typhoid Ty21a vaccine, varicella vaccine); some that are at the point of imminent or recent licensure (reassortant Rhesus rotavirus vaccine, which was licensed by the Food and Drug Administration on August 30, 1998) or near submission for licensure (intranasal cold adapted influenza vaccine); and one for which clinical development is slow because of hurdles that must be overcome (respiratory syncytial virus vaccines). RESULTS: Some common themes emerged from the reviews of these vaccine "case histories": the expediting influence of a strong scientific base and rationale; the need for firm quantitation of disease burden and clear identification of target populations; the critical role played by individuals or teams who act as "champions" to overcome the inevitable obstacles; availability of relevant animal models, high-quality reagents and standardized assays to measure immune response; the absolute requirement for well designed, meticulously executed clinical trials of vaccine safety, immunogenicity, and efficacy; postlicensure measurements of the public health impact of the vaccine and a track record of the vaccine's safety and acceptance with large-scale use; and the critical need for international collaborations to evaluate vaccines against diseases of global importance that are rare in the United States (eg, typhoid fever). It was clear that the critical step-up from bench scale to pilot lots and then to large-scale production, which depends on a small group of highly trained individuals, is often a particularly vulnerable point in the development process. CONCLUSIONS: One fundamental lesson learned is that within the varied and comprehensive US vaccine development infrastructure, multiple and rather distinct paths can be followed to reach vaccine licensure. The National Vaccine Advisory Committee review process should be conducted periodically in the future to ascertain that the US vaccine development network, which has been enormously productive heretofore and has played a leadership role globally, is adapting appropriately to ensure that new, safe, and efficacious vaccines become available in a timely manner.

Public/private partners. Key factors in creating a strategic alliance for community health.

BACKGROUND: The rapidly evolving American health system creates economic and societal incentives for public and private health organizations to collaborate. Despite the apparent benefits of collaboration, there is a paucity of information available to help local agencies develop partnerships. This study, itself a collaboration between a school of public health (SPH) and a Georgia health district, was undertaken to identify critical factors necessary to successfully initiate and sustain a public/private community health collaboration. METHODS: Professional staff at the SPH conducted 26 standardized interviews involving participants from Cobb and Douglas counties Boards of Health; Promina Northwest (now known as Wellstar), a not-for-profit health system; and community stakeholders. Content analysis of each interview question was performed and comparisons were made both within each group and across groups. RESULTS: Trends were identified in the following key areas: vision of health care for Cobb and Douglas counties, forces driving collaboration, strengths of each organization, critical negotiating issues, and potential community gain resulting from the partnership. CONCLUSION: A shared vision between potential collaborators facilitates communication regarding strategies to achieve common goals. A previous history of working together in limited capacities allowed the partners to develop trust and respect for one another prior to entering negotiations. These factors, when taken in conjunction with each organization's strong leadership and knowledge of the community, build a strong foundation for a successful partnership.

Positioning for partnerships. Assessing public health agency readiness.

BACKGROUND: Public health organizations are redefining their roles and aligning their structures with other components of the evolving American health system. Health departments must proactively and strategically plan how to position themselves for the coming years. Prior to implementing changes in functioning, structure, and/or future strategies, an organization should assess its internal readiness to commit to creating these substantial alterations. METHODS: Using a diagnostic tool developed by study investigators, employees of the Cobb and Douglas Counties Boards of Health were surveyed in order to assess their organizational readiness to enter into a strategic partnership with Promina Northwest, a not-for-profit hospital network in the Atlanta, Georgia area. Frequency distributions were conducted for each categorical variable and data were analyzed in aggregate and by job category. RESULTS: The 122 analyzed questionnaires revealed some significant trends. Respondents ranked the six factors having the greatest impact on an organization's ability to change in the following order: leadership, planning, teamwork, mission, information and operations. Interestingly, this rank ordering parallels the perceived strengths and weaknesses of the health departments as determined by the frequency of the most positive responses. CONCLUSION: Cobb and Douglas Counties Boards of Health have taken many key steps to prepare the organizations for significant proactive changes. Survey results emphasized the need for open channels of communication within the organizations and with the external environment so that effective planning can guide the strategic alignment of the health departments with community partners.

The emergency department in surveillance of attempted suicide: findings and methodologic considerations.

The authors conducted one of the first active, population-based public health surveillance systems for detecting suicide attempts in the United States. Surveillance was conducted in all four hospital emergency departments serving a county suburban to Atlanta, GA, with a population of 426,000. Emergency department staff gathered information from all patients who presented with an intentionally self-inflicted injury (suicide attempt) or with thoughts about self-injury (suicidal ideation). During an 18-month period in 1988 and 1989, 798 suicide attempt-related patients were reported, for a rate of 124.7 per 100,000 county residents per year. Females had a higher attempted suicide rate than males, but males had a higher completed suicide rate. Ingestion of drugs or poison was the most common method of attempted suicide (71.1 percent), and use of firearms was the most common method of completed suicide (69.8 percent). In comparing reported cases with those found by reviewing emergency department log books, the authors found that the case reports were 58 percent complete and that surveillance reporting was highly representative of all cases requiring emergency transport. The authors conclude that emergency department-based surveillance for attempted suicide is feasible. It can provide representative data that may be used to monitor trends in attempted suicide and to define high-risk groups. Such surveillance may also allow timely detection of suicide attempt clusters, facilitating prompt intervention.