A protocol for ongoing systematic scoping reviews of World Trade Center Health research.

BACKGROUND: The World Trade Center (WTC) Health Program ("Program") seeks to assess the inventory, quality, and impact of its funded research in the context of all clinical and translational research involving WTC populations. This paper presents a protocol for ongoing scoping reviews of WTC-related health research. METHODS: Using terms relevant to the September 11 attacks, we will search OVID MEDLINE, PsycINFO, Scopus, Web of Science, CINAHL, and Embase for records of peer-reviewed publications. Title, abstract, and full text screening will be used to exclude records according to a priori criteria. Data abstraction will be performed on all articles that meet inclusion criteria using a standardized query form that was developed in collaboration with NIOSH. A team of reviewers will be trained to abstract data from included articles. Articles will be double-reviewed, and disagreements will be adjudicated. RESULTS: We will summarize existing research involving WTC populations. The summary will assess the extent, nature, and signals of impact of WTC-related health research. CONCLUSIONS: Our review will lay the groundwork for additional study of research impact by identifying population, clinical, and translational topics that can be assessed through future focused reviews. It will also support planning activities by Program policy makers and stakeholders as they work to achieve the Program's research goals. SYSTEMATIC REVIEW REGISTRATION: This publication serves as documentation of the protocol.

Building Public Health Emergency Preparedness, Response, and Recovery Capabilities Through Disaster Citizen Science: Perspectives From Local Health Department, Academic, and Community Representatives.

CONTEXT: Disaster citizen is the use of scientific methods by the public to address preparedness, response, or recovery needs. Disaster citizen science applications with public health relevance are growing in academic and community sectors, but integration with public health emergency preparedness, response, and recovery (PHEPRR) agencies is limited. OBJECTIVE: We examined how local health departments (LHDs) and community-based organizations have used citizen science to build public health preparedness and response (PHEP) capabilities. The purpose of this study is to help LHDs make use of citizen science to support PHEPRR. DESIGN: We conducted semistructured telephone interviews (n = 55) with LHD, academic, and community representatives engaged or interested in citizen science. We used inductive and deductive methods to code and analyze interview transcripts. SETTING: US and international community-based organizations and US LHDs. PARTICIPANTS: Participants included 18 LHD representatives reflecting diversity in geographic regions and population sizes served and 31 disaster citizen science project leaders and 6 citizen science thought leaders. MAIN OUTCOMES: We identified challenges LHDs and academic and community partners face in using citizen science for PHEPRR as well as strategies to facilitate implementation. RESULTS: Academic and community-led disaster citizen science activities aligned with many PHEP capabilities including community preparedness, community recovery, public health surveillance and epidemiological investigation, and volunteer management. All participant groups discussed challenges related to resources, volunteer management, collaborations, research quality, and institutional acceptance of citizen science. The LHD representatives noted unique barriers due to legal and regulatory constraints and their role in using citizen science data to inform public health decisions. Strategies to increase institutional acceptance included enhancing policy support for citizen science, increasing volunteer management support, developing best practices for research quality, strengthening collaborations, and adopting lessons learned from relevant PHEPRR activities. CONCLUSIONS: There are challenges to overcome in building PHEPRR capacity for disaster citizen science but also opportunities for LHDs to leverage the growing body of work, knowledge, and resources in academic and community sectors.

Public Health Readiness for Citizen Science: Health Department Experiences.

OBJECTIVE: The aim of this study was to examine the experiences of US health departments with citizen science. DESIGN: In 2019, we conducted a national survey of 272 local health department (LHD) representatives about knowledge and attitudes, readiness, experiences, and barriers related to citizen science (response rate = 45%). SETTING: LHDs in the United States in 2019. PARTICIPANTS: LHD representatives. MAIN OUTCOME MEASURES: Knowledge and attitudes, readiness, experiences, and barriers related to citizen science. RESULTS: Sixty-two percent of respondents reported LHD experience with citizen science in areas such as health promotion, emergency preparedness, and environmental health. LHDs in large jurisdictions (78%) were more likely to report staff familiarity with citizen science than small (51%) and medium (59%) jurisdictions ( P = .01). Although 64% reported readiness for citizen science, only 32% reported readiness for community-led activities. We found that LHDs use citizen science more for community engagement activities, such as public education, than data collection activities. Respondents indicated that staff education and training in citizen science methods, funding, and partners with relevant expertise were priority needs. CONCLUSION: LHDs have leveraged citizen science for community engagement, but barriers to technical uses remain.

Translational Impacts of World Trade Center Health Program Research: A Mixed Methods Study.

The World Trade Center (WTC) Health Program (hereafter Program) provides medical monitoring and treatment for its Members: the responders and survivors who were at the WTC and related sites or located within the New York City disaster area during and after the terrorist attacks of September 11, 2001. Scientific research supported by the Program provides an evidence base for the health monitoring and clinical care of Members. In this article, the authors describe the findings and recommendations of a four-year study of the Program's research portfolio and its translational impact. They present results from a mixed methods assessment that integrates (1) a scoping review of nearly 1,000 peer-reviewed publications and thousands of pages of grey literature that reference research related to the health effects of 9/11, (2) stakeholder perspectives gathered through focus groups and interviews, and (3) a review of Program documentation. The study is intended to guide planning by Program leadership as it aims to maximize the impacts of Program research and achieve its goal of translating research into care for those affected by the attacks on 9/11.

Development of the National Institute for Occupational Safety and Health Worker Well-Being Questionnaire.

OBJECTIVE: This article describes development of the National Institute for Occupational Safety and Health (NIOSH) Worker Well-Being Questionnaire (WellBQ). METHODS: The NIOSH WellBQ was developed through literature reviews and expert panel recommendations. We drew from a representative sample of the civilian, noninstitutionalized, US working population to pilot the questionnaire. Psychometric analyses were performed on data from 975 respondents to finalize items and optimize the NIOSH WellBQ's psychometric properties. RESULTS: The final questionnaire consists of 16 scales, 5 indices, and 31 single items across 5 domains: (1) work evaluation and experience; (2) workplace policies and culture; (3) workplace physical environment and safety climate; (4) health status; and (5) home, community, and society (experiences and activities outside of work). The instrument demonstrated adequate reliability and validity. CONCLUSIONS: The NIOSH WellBQ is a reliable and valid instrument that comprehensively measures worker well-being.

Impact of World Trade Center-Related Health Research: An Application of the NIEHS Translational Framework.

The World Trade Center Health Program (WTCHP) has a research mission to identify physical and mental health conditions that may be related to the 9/11 terrorist attacks as well as effective diagnostic procedures and treatments for WTC-related health conditions. The ability of the WTCHP to serve its members and realize positive impacts on all of its stakeholders depends on effective translation of research findings. As part of an ongoing assessment of the translational impact of World Trade Center (WTC)-related research, we applied the National Institute of Environmental Health Sciences (NIEHS) translational framework to two case studies: WTC-related research on post-traumatic stress disorder (PTSD) and cancer. We conducted a review of 9/11 health-related research in the peer-reviewed literature through October 2017, grey literature, and WTCHP program documentation. We mapped peer-reviewed studies in the literature to the NIEHS framework and used WTCHP program documentation and grey literature to find evidence of translation of research into clinical practice and policy. Using the NIEHS framework, we identified numerous translational milestones and bridges, as well as areas of opportunity, within each case study. This application demonstrates the utility of the NIEHS framework for documenting progress toward public health impact and for setting future research goals.

Enhancing community preparedness: an inventory and analysis of disaster citizen science activities.

BACKGROUND: Disaster citizen science, or the use of scientific principles and methods by "non-professional" scientists or volunteers, may be a promising way to enhance public health emergency preparedness (PHEP) and build community resilience. However, little research has focused on understanding this emerging field and its implications for PHEP. To address research gaps, this paper: (1) assesses the state of disaster citizen science by developing an inventory of disaster citizen science projects; (2) identifies different models of disaster citizen science; and (3) assesses their relevance for PHEP. METHODS: We searched the English-language peer-reviewed and grey literature for disaster citizen science projects with no time period specified. Following searches, a team of three reviewers applied inclusion/exclusion criteria that defined eligible disasters and citizen science activities. Reviewers extracted the following elements from each project: project name and description; lead and partner entities; geographic setting; start and end dates; type of disaster; disaster phase; citizen science model; and technologies used. RESULTS: A final set of 209 projects, covering the time period 1953-2017, were included in the inventory. Projects were classified across five citizen science models: distributed or volunteer sensing (n = 19; 9%); contributory (n = 98; 47%); distributed intelligence (n = 52; 25%); collaborative research (n = 32; 15%); and collegial research (n = 8; 4%). Overall, projects were conducted across all disaster phases and most frequently for earthquakes, floods, and hurricanes. Although activities occurred globally, 40% of projects were set in the U.S. Academic, government, technology, and advocacy organizations were the most prevalent lead entities. Although a range of technologies were used, 77% of projects (n = 161) required an internet-connected device. These characteristics varied across citizen science models revealing important implications for applications of disaster citizen science, enhancement of disaster response capabilities, and sustainability of activities over time. CONCLUSIONS: By increasing engagement in research, disaster citizen science may empower communities to take collective action, improve system response capabilities, and generate relevant data to mitigate adverse health impacts. The project inventory established a baseline for future research to capitalize on opportunities, address limitations, and help disaster citizen science achieve its potential.

Injury and Illness Surveillance of U.S. Agricultural Workers: Assessment of Recommendations and Actions.

Agriculture remains one of America's oldest and most valued industries, but is also one of the most hazardous, with farmworkers experiencing high rates of injuries and illnesses. The National Institute for Occupational Safety and Health's (NIOSH) Agriculture, Forestry and Fishing (AgFF) Program provides leadership to prevent harm to workers in the three named sectors. Since its inception, the AgFF Program has spearheaded numerous surveillance initiatives to understand the magnitude of injuries and illnesses among agricultural worker populations, identify vulnerable groups, and evaluate the effectiveness of intervention measures. In 2012, the program underwent a review from an independent panel convened to evaluate progress in program relevance and impact. While the panel offered a number of recommendations for improving surveillance, it provided little guidance on how to prioritize and achieve the recommendations. In 2015, NIOSH asked the RAND Corporation to assess options for action in response to panel recommendations. The goal of this study is to provide NIOSH with a practical assessment of the feasibility and desirability of carrying out actions to meet surveillance-related panel recommendations, given current AgFF Program resources and priorities. The authors conducted literature reviews and targeted interviews to detail how actions could be implemented and identify barriers to their achievement. For each action, the authors applied criteria relevant to assessing feasibility (costs, partnership engagement, information availability and accessibility, policy barriers, timelines) and desirability (relevance to program priorities, information quality, and impact). Overall, the study identifies a number of actions that balanced both feasibility and desirability for NIOSH to consider as it determines the direction of the AgFF Program.

Fugitive Chemicals and Environmental Justice: A Model for Environmental Monitoring Following Climate-Related Disasters.

The combination of population growth in areas of mixed (residential, commercial, and industrial) land use along U.S. waterfronts and the increasing frequency of devastating hurricanes and storm surges has led to community fears of widespread toxic chemical contamination resulting from accidental industrial or small business releases, particularly in the aftermath of an extreme weather event, such as a hurricane. Industrial waterfront communities, which are frequently environmental justice communities, contain numerous toxic chemical sources located in close proximity to residential housing, schools, daycare centers, playgrounds, and healthcare centers. Despite the longstanding concerns of community activists and researchers about the potential for "fugitive" chemicals to be released into floodwaters, there has been little coordinated research or action to develop environmental monitoring programs for disaster-affected communities. In the aftermath of Superstorm Sandy, a community-academic partnership was formed between the New York City Environmental Justice Alliance, UPROSE, The LifeLine Group, and the RAND Corporation. The collaboration, known as Grassroots Research to Action in Sunset Park (GRASP) has focused on identifying possible sources of chemical contamination, modeling the potential for chemical release into community areas and resulting exposure risks, and proactively developing actions for mitigating or preventing adverse community impacts. Through our ongoing work, we have identified barriers and drivers for community-based environmental monitoring, and in doing so, we have developed a framework to overcome challenges. In this article, we describe this framework, which can be used by waterfront communities bracing to deal with the effects of future devastating weather disasters.

Expanding the Paradigm of Occupational Safety and Health: A New Framework for Worker Well-Being.

OBJECTIVE: This article describes the National Institute for Occupational Safety and Health's (NIOSH) development of a conceptual framework for worker well-being. While well-being research is growing, there is a need to translate theoretical concepts into practical models for measurement and action. METHODS: Multidisciplinary literature reviews informed development of the worker well-being framework and major domains and subdomains. An expert panel helped prioritize constructs for measurement. RESULTS: The framework includes five domains and 20 subdomains and conceptualizes worker well-being as a subjective and objective phenomenon inclusive of experiences both within and beyond work contexts. CONCLUSION: Well-being is a positive and unifying concept that captures multiple factors that contribute to workers' health and quality of life. This work lays the foundation for larger well-being measurement efforts and will provide tools for NIOSH partners to help workers flourish.

Governing Academic Medical Center Systems: Evaluating and Choosing Among Alternative Governance Approaches.

The ability of academic medical centers (AMCs) to fulfill their triple mission of patient care, medical education, and research is increasingly being threatened by rising financial pressures and resource constraints. Many AMCs are, therefore, looking to expand into academic medical systems, increasing their scale through consolidation or affiliation with other health care systems. As clinical operations grow, though, the need for effective governance becomes even more critical to ensure that the business of patient care does not compromise the rest of the triple mission. Multi-AMC systems, a model in which multiple AMCs are governed by a single body, pose a particular challenge in balancing unity with the needs of component AMCs, and therefore offer lessons for designing AMC governance approaches. This article describes the development and application of a set of criteria to evaluate governance options for one multi-AMC system-the University of California (UC) and its five AMCs. Based on a literature review and key informant interviews, the authors identified criteria for evaluating governance approaches (structures and processes), assessed current governance approaches using the criteria, identified alternative governance options, and assessed each option using the identified criteria. The assessment aided UC in streamlining governance operations to enhance their ability to respond efficiently to change and to act collectively. Although designed for UC and a multi-AMC model, the criteria may provide a systematic way for any AMC to assess the strengths and weaknesses of its governance approaches.

The Promise of Direct-to-Consumer Telehealth for Disaster Response and Recovery.

Telehealth has great promise to improve and even revolutionize emergency response and recovery. Yet telehealth in general, and direct-to-consumer (DTC) telehealth in particular, are underutilized in disasters. Direct-to-consumer telehealth services allow patients to request virtual visits with health care providers, in real-time, via phone or video conferencing (online video or mobile phone applications). Although DTC services for routine primary care are growing rapidly, there is no published literature on the potential application of DTC telehealth to disaster response and recovery because these services are so new. This report presents several potential uses of DTC telehealth across multiple disaster phases (acute response, subacute response, and recovery) while noting the logistical, legal, and policy challenges that must be addressed to allow for expanded use. Uscher-Pines L , Fischer S , Chari R . The promise of direct-to-consumer telehealth for disaster response and recovery. Prehosp Disaster Med. 2016;31(4):454-456.

Youth Resilience Corps: An Innovative Model to Engage Youth in Building Disaster Resilience.

OBJECTIVE: Despite the growing awareness that youth are not just passive victims of disaster but can contribute to a community's disaster resilience, there have been limited efforts to formally engage youth in strengthening community resilience. The purpose of this brief report was to describe the development of a Youth Resilience Corps, or YRC (ie, a set of tools to engage young people in youth-led community resilience activities) and the findings from a small-scale pilot test. METHODS: The YRC was developed with input from a range of government and nongovernmental stakeholders. We conducted a pilot test with youth in Washington, DC, during summer 2014. Semi-structured focus groups with staff and youth surveys were used to obtain feedback on the YRC tools and to assess what participants learned. RESULTS: Focus groups and youth surveys suggested that the youth understood resilience concepts, and that most youth enjoyed and learned from the components. CONCLUSIONS: The YRC represent an important first step toward engaging youth in building disaster resilience, rather than just focusing on this group as a vulnerable population in need of special attention.

Safety of vaccines used for routine immunization of U.S. children: a systematic review.

BACKGROUND: Concerns about vaccine safety have led some parents to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical for population health. This study systematically reviewed the literature on the safety of routine vaccines recommended for children in the United States. METHODS: Data sources included PubMed, Advisory Committee on Immunization Practices statements, package inserts, existing reviews, manufacturer information packets, and the 2011 Institute of Medicine consensus report on vaccine safety. We augmented the Institute of Medicine report with more recent studies and increased the scope to include more vaccines. Only studies that used active surveillance and had a control mechanism were included. Formulations not used in the United States were excluded. Adverse events and patient and vaccine characteristics were abstracted. Adverse event collection and reporting was evaluated by using the McHarm scale. We were unable to pool results. Strength of evidence was rated as high, moderate, low, or insufficient. RESULTS: Of 20 478 titles identified, 67 were included. Strength of evidence was high for measles/mumps/rubella (MMR) vaccine and febrile seizures; the varicella vaccine was associated with complications in immunodeficient individuals. There is strong evidence that MMR vaccine is not associated with autism. There is moderate evidence that rotavirus vaccines are associated with intussusception. Limitations of the study include that the majority of studies did not investigate or identify risk factors for AEs; and the severity of AEs was inconsistently reported. CONCLUSIONS: We found evidence that some vaccines are associated with serious AEs; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide.

Safety of Vaccines Used for Routine Immunization in the United States.

OBJECTIVES: To conduct a systematic review of the literature on the safety of vaccines recommended for routine immunization of children, adolescents, and adults in the United States as of 2011. DATA SOURCES: We included placebo-controlled clinical trials and cohort studies comparing vaccinated and unvaccinated patients. We also included the following types of post-licensure analyses: case-control studies, self-controlled case series, and multivariate risk factor analyses. We conducted an electronic search of PubMed from inception through August 2013, and reviewed Advisory Committee for Immunization Practices statements, vaccine package inserts, and previously published reviews to identify studies. Scientific Information Packets were requested from vaccine manufacturers. REVIEW METHODS: We reviewed the methodology of the 2011 Institute of Medicine (IOM) consensus report "Adverse Effects of Vaccines: Evidence and Causality" and accepted their findings. We augmented their work with new studies and additional vaccines. For studies not included in the IOM report, we abstracted data on the presence or absence of adverse health outcomes, characteristics of patients, study design, and vaccine description, including brand, potency, dosage, timing, and formulation, where available. We excluded formulations not used in the United States. The McHarm instrument was used to evaluate the quality of adverse events collection and reporting in each study. We were unable to pool results; we rated the overall strength of evidence (SOE) as high, moderate, low, or insufficient by using guidance suggested by the Agency for Healthcare Research and Quality for its Effective Health Care Program. RESULTS: A total of 20,478 titles were identified; after title, abstract, and full-text review, 166 studies were accepted for abstraction. The vast majority of studies either did not investigate or could not identify risk factors for adverse events (AEs) associated with vaccination. Similarly, the severity of AEs was inconsistently reported, as was information that would make independent severity determination possible.SOE was high for the following associations in nonpregnant adults: seasonal influenza vaccine and arthralgia, myalgia, malaise, fever, pain at injection site; 2009 monovalent H1N1 vaccine and Guillain-Barré syndrome (GBS); and a lack of association between influenza and pneumococcal vaccines and cardiovascular events in the elderly. Risk of GBS was estimated at 1.6 excess cases per million persons vaccinated. SOE was high for the following associations in children and adolescents: measles, mumps, rubella (MMR) vaccine and febrile seizures in children under age 5; lack of association between MMR vaccine and autism spectrum disorders; and varicella vaccine and disseminated Oka strain varicella zoster virus with associated complications (i.e., meningitis, encephalitis) in individuals with demonstrated immunodeficiencies. There is moderate SOE that vaccines against rotavirus are associated with intussusception in children; risk was estimated as 1 to 5 cases per 100,000 vaccine doses, depending on brand. Moderate-strength evidence exists regarding human papillomavirus vaccine and a lack of association with onset of juvenile rheumatoid arthritis, type 1 diabetes, and GBS. Moderate-strength evidence shows no association between inactivated influenza vaccine and serious AEs in pregnant women.Evidence was insufficient to make conclusions regarding whether several routinely recommended vaccines are associated with serious conditions such as multiple sclerosis, transverse myelitis, and acute disseminated encephalomyelitis. CONCLUSIONS: There is evidence that some vaccines are associated with serious adverse events; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide. Careful consideration should be given to the investigation of research gaps, including patient risk factors that may be associated with AEs; however, important factors must be taken into account when determining whether studies are warranted, including the severity and frequency of the AE being studied and the challenges of conducting sufficiently powered studies when investigating rare events.

On call at the mall: a mixed methods study of U.S. medical malls.

BACKGROUND: The decline of the traditional U.S. shopping mall and a focus on more consumer- centered care have created an opportunity for "medical malls". Medical malls are defined as former retail spaces repurposed for healthcare tenants or mixed-use medical/retail facilities.We aimed to describe the current reach of healthcare services in U.S. malls, characterize the medical mall model and emerging trends, and assess the potential of these facilities to serve low-income populations. METHODS: We used a mixed methods approach which included a comprehensive literature review, key informant interviews, and a descriptive analysis of the Directory of Major Malls, an online retail database. RESULTS: Six percent (n = 89) of large, enclosed shopping malls in the U.S. include at least one non-optometry or dental healthcare tenant. We identified a total of 28 medical malls across the U.S., the majority of which opened in the past five years and serve middle or high income populations. Stakeholders felt the key strengths of medical malls were more convenient access including public transportation, greater familiarity for patients, and "one stop shopping" for primary care and specialty services as well as retail needs. CONCLUSIONS: While medical malls currently account for a small fraction of malls in the US, they are a new model for healthcare with significant potential for growth.

Integrating susceptibility into environmental policy: an analysis of the national ambient air quality standard for lead.

Susceptibility to chemical toxins has not been adequately addressed in risk assessment methodologies. As a result, environmental policies may fail to meet their fundamental goal of protecting the public from harm. This study examines how characterization of risk may change when susceptibility is explicitly considered in policy development; in particular we examine the process used by the U.S. Environmental Protection Agency (EPA) to set a National Ambient Air Quality Standard (NAAQS) for lead. To determine a NAAQS, EPA estimated air lead-related decreases in child neurocognitive function through a combination of multiple data elements including concentration-response (CR) functions. In this article, we present alternative scenarios for determining a lead NAAQS using CR functions developed in populations more susceptible to lead toxicity due to socioeconomic disadvantage. The use of CR functions developed in susceptible groups resulted in cognitive decrements greater than original EPA estimates. EPA's analysis suggested that a standard level of 0.15 µg/m(3) would fulfill decision criteria, but by incorporating susceptibility we found that options for the standard could reasonably be extended to lower levels. The use of data developed in susceptible populations would result in the selection of a more protective NAAQS under the same decision framework applied by EPA. Results are used to frame discussion regarding why cumulative risk assessment methodologies are needed to help inform policy development.

Protein kinase C - possible therapeutic target to treat cardiovascular diseases.

Cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and diabetes, are major global health problems and one of the leading causes of death. Thrombosis associated with multiple CVDs such as atherosclerosis and diabetes further increase morbidity by causing myocardial infarction or stroke. The members of Protein Kinase C (PKC) family are serine threonine kinases, abundantly expressed in cells that maintain cardiovascular health. Studies done using pharmacological tools that block wide range of PKCs or specific PKC isoforms and PKC gene knockout animals revealed that these enzymes regulate critical functional responses in cardiovascular cells. Interestingly, PKC isotype activity is context specific and PKC isotypes may have opposing functional roles depending on cell type and cellular environment (eg., cardiomyocytes, platelets). Furthermore, precise structural differences that occur amongst these isoforms have lead to development of compounds that inhibit or activate specific PKC isoforms. Thus, it is feasible to enhance the protective effects of a PKC isoform, while minimizing the damage caused by other members of PKC family. In this review, we summarize the role of each of these PKC isoforms in various cardiovascular diseases. In addition, we detail the specific PKC isoform modulators, their mechanism of action and ability to treat cardiovascular diseases, as evaluated in animal models or human subjects.

Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion.

Protein kinase C-delta (PKC-delta) is expressed in platelets and activated downstream of protease-activated receptors (PARs) and glycoprotein VI (GPVI) receptors. We have previously shown that PKC-delta positively regulates PAR-mediated dense granule secretion, whereas it negatively regulates GPVI-mediated dense granule secretion. We further investigated the mechanism of such differential regulation of dense granule release by PKC-delta in platelets. SH2 domain-containing inositol phosphatase-1 (SHIP-1) is phosphorylated on Y1020, a marker for its activation, upon stimulation of human platelets with PAR agonists SFLLRN and AYPGKF or GPVI agonist convulxin. GPVI-mediated SHIP-1 phosphorylation occurred rapidly at 15 seconds, whereas PAR-mediated phosphorylation was delayed, occurring at 1 minute. Lyn and SHIP-1, but not SHIP-2 or Shc, preferentially associated with PKC-delta on stimulation of platelets with a GPVI agonist, but not with a PAR agonist. In PKC-delta-null murine platelets, convulxin-induced SHIP-1 phosphorylation was inhibited. Furthermore, in Lyn null murine platelets, GPVI-mediated phosphorylations on Y-1020 of SHIP-1 and Y311 of PKC-delta were inhibited. In murine platelets lacking Lyn or SHIP-1, GPVI-mediated dense granule secretions are potentiated, whereas PAR-mediated dense granule secretions are inhibited. Therefore, we conclude that Lyn-mediated phosphorylations of PKC-delta and SHIP-1 and their associations negatively regulate GPVI-mediated dense granule secretion in platelets.

Protein kinase C[delta] differentially regulates platelet functional responses.

OBJECTIVE: Protein Kinase C delta (PKCdelta) is expressed in platelets and activated downstream of protease-activated receptors (PAR)s and glycoprotein VI (GPVI) receptors. The purpose of this study was to investigate the role of PKCdelta in platelets. METHODS AND RESULTS: We evaluated the role of PKCdelta in platelets using two approaches--pharmacological and molecular genetic approach. In human platelets pretreated with isoform selective antagonistic RACK peptide (delta V1-1)TAT, and in the murine platelets lacking PKCdelta, PAR4-mediated dense granule secretion was inhibited, whereas GPVI-mediated dense granule secretion was potentiated. These effects were statistically significant in the absence and presence of thromboxane A2 (TXA2). Furthermore, TXA2 generation was differentially regulated by PKCdelta. However, PKCdelta had a small effect on platelet P-selectin expression. Calcium- and PKC-dependent pathways independently activate fibrinogen receptor in platelets. When calcium pathways are blocked by dimethyl-BAPTA, AYPGKF-induced aggregation in PKCdelta null mouse platelets and in human platelets pretreated with (delta V1-1)TAT, was inhibited. In a FeCl3-induced injury in vivo thrombosis model, PKCdelta-/- mice occluded similar to their wild-type littermates. CONCLUSIONS: Hence, we conclude that PKCdelta differentially regulates platelet functional responses such as dense granule secretion and TXA2 generation downstream of PARs and GPVI receptors, but PKCdelta deficiency does not affect the thrombus formation in vivo.