Assessment of Institutional Implementation Research Capacity of the National Institutes of Health D43 Network.

Implementation science enhances the efficient practice of solutions from research to real-world application. Low- and lower- to middle-income countries may benefit significantly from implementation research given their limited resources. The National Institutes of Health Fogarty International Center D43 network consists of partnerships between foreign and U.S.-based institutions and aims to strengthen global health research. This paper assesses the D43 network's implementation research focus and training capacity. A survey was distributed to 387 program directors of ongoing and completed D43 projects. Preliminary results show 51.7% of respondents describe "increasing implementation research capacity" as a "high priority." Only 24.8% of faculty in implementation science received formal training, and 60.3% of D43 programs lacked an implementation research training program. Results show there is an increasing need for implementation research but that more can be done to develop implementation research capacity and training. The low response rate of 18% is a limitation of this study.

Gender neutral HPV vaccination programs: Reconsidering policies to expand cancer prevention globally.

Human papillomavirus (HPV) infection is responsible for many cancers in both women and men. Cervical cancer, caused by HPV, is the fourth most common cancer among women worldwide, even though it is one of the most preventable cancers. Prevention efforts include HPV vaccination, however these programs remain nascent in many countries. In 2020 the World Health Assembly adopted the Global Strategy for cervical cancer elimination including a goal to fully vaccinate 90% of girls with the HPV vaccine by the age of 15. However, very few countries have reached even 70% coverage. Increased vaccine availability in the future may allow the opportunity to vaccinate more people. This could add to the feasibility of introducing gender-neutral HPV vaccination programs. Adopting a gender-neutral HPV vaccine approach will reduce HPV infections transmitted among the population, combat misinformation, minimize vaccine-related stigma, and promote gender equity. We propose approaching programmatic research through a gender-neutral lens to reduce HPV infections and cancers and promote gender equality. In order to design more effective policies and programs, a better understanding of the perspectives of clients, clinicians, community leaders, and policy-makers is needed. A clear, multi-level understanding of these stakeholders' views will facilitate the development of target policy and programs aimed at addressing common barriers and optimizing uptake. Given the benefit of developing gender-neutral HPV vaccination programs to eliminate cervical cancer and address other HPV associated cancers, we must build knowledge through implementation research around this topic to inform policy-makers and funders for future policy shifts.

Assessing the interrelationship between stigma, social influence, and cervical cancer prevention in an urban underserved setting: An exploratory study.

In the US, incidence and mortality from cervical cancer disproportionately affects racial/ethnic minorities and low-income women. Despite affordable access to primary and secondary prevention measures at Federally Qualified Health Centers (FQHCs), Human Papillomavirus (HPV) vaccination and screening rates are low, suggesting the presence of non-financial barriers to uptake in this population. This explanatory sequential mixed-methods study sought to explore factors that influence the acceptability of cervical cancer prevention services among parents and legal guardians of vaccine-eligible girls attending an urban FQHC and to assess social influences related to cervical cancer prevention. Participants included eight mothers, one father, and two grandparents/legal guardians. Nine participants self-identified as Black/Afro-Caribbean, or African American, two as Latinx, and one as Native American. The quantitative data suggested discordance between participants' cervical cancer prevention knowledge and their practices. Most indicated that their daughters had received the HPV vaccine but were unsure about HPV transmission modes. Qualitative data revealed that participants were comfortable disclosing information on HPV infection and vaccination status, and most women were likely to share information related to cervical cancer testing and diagnosis. Few comments indicated personal stigma on the part of participants, but there was frequent expression of perceived public stigma (shaming and blaming women), gender differences (men are indifferent to risk), and distrust of the healthcare system. Findings highlight several concepts including the disharmony between knowledge and practice, prevalent perceived public stigma, cumbersome attitudes on the part of men regarding HPV and cervical cancer, and distrust of the healthcare system.

Stigma and cervical cancer prevention: A scoping review of the U.S. literature.

Cervical cancer is preventable through HPV vaccination and screening however, uptake falls below national targets. A scoping review was conducted to describe stigmas related to HPV infection and vaccination and cervical cancer and screening in the US. Results were organized into the domains proposed by Stangl and colleagues' Health Stigma and Discrimination Framework. Common drivers of stigma were fear of social judgement and rejection, self-blame, and shame. Positive facilitators included social norms that provided motivation to receive HPV vaccination and screening. Gender and social norms were notable negative facilitators of stigma. HPV infection and cervical cancer resulted in stigma marking through the belief that both result from incautious behavior-either multiple sexual partners or failing to get screening. Stereotyping and prejudice were stigma practices attributed to HPV infection and cervical cancer through these same behaviors. Stigma experiences related to HPV infection, cervical cancer, and abnormal screening results included altered self-image based on perceived/anticipated stigma, as well as discrimination. This review advances understanding of the multiple dimensions of stigma associated with these outcomes in the US population. Three areas warrant additional consideration. Future studies should 1) assess how stigma dimensions affect uptake of cervical cancer preventions efforts; 2) focus on US women most affected by cervical cancer incidence and mortality to identify potential differences in these dimensions and tailor interventions accordingly; 3) include women from geographic areas of the US with high rates of cervical cancer to adapt interventions that address potential regional variations in resources and need.

Evaluating the implementation of cervical cancer screening programs in low-resource settings globally: a systematized review.

PURPOSE: Cervical cancer disproportionately burdens low-resource populations where access to quality screening services is limited. A greater understanding of sustainable approaches to implement cervical cancer screening services is needed. METHODS: We conducted a systematized literature review of evaluations from cervical cancer screening programs implemented in resource-limited settings globally that included a formal evaluation and intention of program sustainment over time. We categorized the included studies using the continuum of implementation research framework which categorizes studies progressively from "implementation light" to more implementation intensive. RESULTS: Fifty-one of 13,330 initially identified papers were reviewed with most study sites in low-resource settings of middle-income countries (94.1%) ,while 9.8% were in low-income countries. Across all studies, visual inspection of the cervix with acetic acid (58.8%) was the most prevalent screening method followed by cytology testing (39.2%). Demand-side (client and community) considerations were reported in 86.3% of the articles, while 68.6% focused scientific inquiry on the supply side (health service). Eighteen articles (35.3%) were categorized as "Informing Scale-up" along the continuum of implementation research. CONCLUSIONS: The number of cervical cancer screening implementation reports is limited globally, especially in low-income countries. The 18 papers we classified as Informing Scale-up provide critical insights for developing programs relevant to implementation outcomes. We recommend that program managers report lessons learnt to build collective implementation knowledge for cervical cancer screening services, globally.

Eliminating Deaths From Cervical Cancer-Report of a Panel at the 7th Annual Symposium on Global Cancer Research, a Satellite Meeting at the Consortium of Universities for Global Health 10th Annual Meeting.

This is a summary of the presentations addressing approaches and achievements to reach the goal of eliminating cervical cancer as a global public health problem that were delivered at the 7th Annual Symposium on Global Cancer Research at the 10th Annual Consortium of Universities for Global Health Meeting in March 2019. Dr Princess Nothemba Simelela, Assistant Director-General for Family, Women, Children and Adolescents, World Health Organization, gave an introduction to the World Health Organization-led Cervical Cancer Elimination Initiative and the emerging conceptual framework and targets that will shape the global 2020 to 2030 strategy. Subsequent presentations shared experiences from national programs in Rwanda (Agnes Binagwaho), Latin America (Patricia J. Garcia), and Senegal (Babacar Gueye and J. Andrew Dykens. Successes in intensified human papillomavirus vaccination and screening with follow-up treatment of early and advanced lesions detected are highlighted as well as the challenges and obstacles in achieving and maintaining high coverage in Africa and Latin America. With strong political leadership, commitment of national stakeholders, and the use of proven and cost-effective approaches to human papillomavirus vaccination, screening, and treatment, the vision of a world free of cervical cancer and saving women's lives every year by preventing deaths from cervical cancer will be achievable in the next generation in all countries.

Cervical cancer screening decentralized policy adaptation: an African rural-context-specific systematic literature review.

BACKGROUND: Worldwide, nearly 570,000 women are diagnosed with cervical cancer each year, with 85% of new cases in low- and middle-income countries. The African continent is home to 35 of 40 countries with the highest cervical cancer mortality rates. In 2014, a partnership involving a rural region of Senegal, West Africa, was facing cervical cancer screening service sustainability barriers and began adapting regional-level policy to address implementation challenges. OBJECTIVE: This manuscript reports the findings of a systematic literature review describing the implementation of decentralized cervical cancer prevention services in Africa, relevant in context to the Senegal partnership. We report barriers and policy-relevant recommendations through Levesque's Patient-Centered Access to Healthcare Framework and discuss the impact of this information on the partnership's approach to shaping Senegal's regional cervical cancer screening policy. METHODS: The systematic review search strategy comprised two complementary sub-searches. We conducted an initial search identifying 4272 articles, then applied inclusion criteria, and ultimately 19 studies were included. Data abstraction focused on implementation barriers categorized with the Levesque framework and by policy relevance. RESULTS: Our findings identified specific demand-side (clients and community) and supply-side (health service-level) barriers to implementation of cervical cancer screening services. We identify the most commonly reported demand- and supply-side barriers and summarize salient policy recommendations discussed within the reviewed literature. CONCLUSIONS: Overall, there is a paucity of published literature regarding barriers to and best practices in implementation of cervical cancer screening services in rural Africa. Many articles in this literature review did describe findings with notable policy implications. The Senegal partnership has consulted this literature when faced with various similar barriers and has developed two principal initiatives to address contextual challenges. Other initiatives implementing cervical cancer visual screening services in decentralized areas may find this contextual reporting of a literature review helpful as a construct for identifying evidence for the purpose of guiding ongoing health service policy adaptation.

Society of Behavioral Medicine position statement: Society of Behavioral Medicine supports oral cancer early detection by all healthcare providers.

In response to the increasing incidence of certain oral and oropharyngeal cancers, the Society of Behavioral Medicine (SBM) calls on healthcare providers and legislators to expand awareness of oral and oropharyngeal cancer risk factors, increase early detection, and support policies that increase utilization of dental services. SBM supports the American Dental Association's 2017 guideline for evaluating potentially malignant oral cavity disorders and makes the following recommendations to healthcare providers and legislators. We encourage healthcare providers and healthcare systems to treat oral exams as a routine part of patient examination; communicate to patients about oral/oropharyngeal cancers and risk factors; encourage HPV vaccination for appropriate patients based on recommendations from the Advisory Committee on Immunization Practices; support avoidance of tobacco use and reduction of alcohol consumption; and follow the current recommendations for evaluating potentially malignant oral cavity lesions. Because greater evidence is needed to inform practice guidelines in the primary care setting, we call for more research in collaborative health and dental services. We encourage legislators to support policies that expand Medicaid to cover adult dental services, increase Medicaid reimbursement for dental services, and require dental care under any modification of, or replacement of, the Affordable Care Act.

Implementing visual cervical cancer screening in Senegal: a cross-sectional study of risk factors and prevalence highlighting service utilization barriers.

BACKGROUND: Senegal ranks 15th in the world in incidence of cervical cancer, the number one cause of cancer mortality among women in this country. The estimated participation rate for cervical cancer screening throughout Senegal is very low (6.9% of women 18-69 years old), especially in rural areas and among older age groups (only 1.9% of women above the age of 40 years). There are no reliable estimates of the prevalence of cervical dysplasia or risk factors for cervical dysplasia specific to rural Senegal. The goals of this study were to estimate the prevalence of cervical dysplasia in a rural region using visual inspection of the cervix with acetic acid (VIA) and to assess risk factors for cervical cancer control. PATIENTS AND METHODS: We conducted a cross-sectional study in which we randomly selected 38 villages across the Kédougou region using a three-stage clustering process. Between October 2013 and March 2014, we collected VIA screening results for women aged 30-50 years and cervical cancer risk factors linked to the screening result. RESULTS: We screened 509 women; 5.6% of the estimated target population (9,041) in the region. The point prevalence of cervical dysplasia (positive VIA test) was 2.10% (95% confidence interval [CI]: 0.99-3.21). Moreover, 287 women completed the cervical cancer risk factor survey (56.4% response rate) and only 38% stated awareness of cervical cancer; 75.9% of the screened women were less than 40 years of age. CONCLUSION: The overall prevalence of dysplasia in this sample was lower than anticipated. Despite both overall awareness and screening uptake being less than expected, our study highlights the need to address challenges in future prevalence estimates. Principally, we identified that the highest-risk women are the ones least likely to seek screening services, thus illustrating a need to fully understand demand-side barriers to accessing health services in this population. Targeted efforts to educate and motivate older women to seek screenings are needed to sustain an effective cervical cancer screening program.

Society of behavioral medicine supports increasing HPV vaccination uptake: an urgent opportunity for cancer prevention.

Human papillomavirus (HPV) vaccine coverage remains low in the USA. The Society for Behavioral Medicine (SBM) supports the goals outlined by Healthy People 2020, the President's Cancer Panel, and the National Vaccine Advisory Committee to increase vaccination coverage among both males and females. SBM makes the following recommendations in support of efforts to reduce structural and other barriers to HPV vaccination services in order to increase rates of series completion. We encourage legislators and other policymakers to improve administration authority, insurance coverage, and reimbursement rates to healthcare providers who make the HPV vaccine available to adolescents; provide instrumental support to fund the development of school curricula on HPV vaccination; and increase public awareness that HPV vaccination can prevent cancer. We urge healthcare providers and healthcare systems to increase the strength, quality, and consistency of HPV vaccination recommendations for all eligible patients; to treat HPV vaccination as a routine preventive service; employ culturally appropriate communication strategies in clinical settings to educate eligible patients, parents, and guardians about the importance, effectiveness, and safety of HPV vaccination; and to strengthen and better coordinate the use of electronic medical records and immunization information systems.

Developing the Evidence Base to Inform Best Practice: A Scoping Study of Breast and Cervical Cancer Reviews in Low- and Middle-Income Countries.

BACKGROUND: Breast and cervical cancers have emerged as major global health challenges and disproportionately lead to excess morbidity and mortality in low- and middle-income countries (LMICs) when compared to high-income countries. The objective of this paper was to highlight key findings, recommendations, and gaps in research and practice identified through a scoping study of recent reviews in breast and cervical cancer in LMICs. METHODS: We conducted a scoping study based on the six-stage framework of Arskey and O'Malley. We searched PubMed, Cochrane Reviews, and CINAHL with the following inclusion criteria: 1) published between 2005-February 2015, 2) focused on breast or cervical cancer 3) focused on LMIC, 4) review article, and 5) published in English. RESULTS: Through our systematic search, 63 out of the 94 identified cervical cancer reviews met our selection criteria and 36 of the 54 in breast cancer. Cervical cancer reviews were more likely to focus upon prevention and screening, while breast cancer reviews were more likely to focus upon treatment and survivorship. Few of the breast cancer reviews referenced research and data from LMICs themselves; cervical cancer reviews were more likely to do so. Most reviews did not include elements of the PRISMA checklist. CONCLUSION: Overall, a limited evidence base supports breast and cervical cancer control in LMICs. Further breast and cervical cancer prevention and control studies are necessary in LMICs.

Polycyclic phenols, estrogens and neuroprotection: a proposed mitochondrial mechanism.

Polycyclic phenols, including the estrogens, have been shown to be potent neuroprotectants in a variety of cellular and animal model systems. Although classical estrogen receptor interactions and consequent responses play a role in certain circumstances, the neuroprotective activity of polycyclic phenols that do not interact with estrogen receptors ERalpha or ERbeta is more likely to be through non-genomic mechanism(s). We propose here that such non-feminizing polycyclic phenols exert their protective effects at least in part by stabilizing mitochondria, preventing apoptotic and/or necrotic forms of cell death that are associated with mitochondrial dysfunction. Consistent with this mitochondrial model and the available data, these compounds protect neurons and other cell types from a wide variety of pathologically relevant stressors.

Oxidative Stress and Aging - Second International Conference. Technologies for assessment and intervention strategies. 2-5 April 2001, Maui, USA.

The study of oxidative contributions to aging has reached sufficient maturity to support the development of interventional strategies designed to forestall or reverse protein cross-linking, oxidation of DNA and lipids, and mitochondrial senescence associated with chronic pathology and aging. Catalytic antioxidants, including combined superoxide dismutase (SOD) and catalase mimics, extend the lifespan of oxidatively compromised animals such as Mn-SOD knockout mice, and will be entering the clinic for radiation-induced dermatitis. Substituted phenacylthiozolium compounds that slow the formation and break extant protein cross-linkages formed via Maillard reactions, restoring vascular compliance in aged animals, and are showing efficacy in clinical trials. Non-feminizing estrogen analogs (eg, 17- alpha estradiol) block cytotoxicity in a host of oxidative stress models and moderate neuronal loss in MCAO stroke models. Efficacy of the polycyclic phenols is synergistically amplified by glutathione supplementation, suggesting that the two function as a redox couple analogous to vitamin E and ascorbate. Finally, discovery of novel small molecules designed to stabilize mitochondrial function during Ca(2+)-induced oxidative stress, such as that occurring during stroke or myocardial ischemia reperfusion, will be accelerated by a proprietary fluorescence resonance energy transfer assay developed at MitoKor. Maintaining mitochondrial function under these circumstances will improve cellular bioenergetic and oxidative status, and hence moderate secondary necrosis and apoptosis.

Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization.

OBJECTIVE: Increased chondrocyte nitric oxide (NO) and peroxynitrite production appears to modulate decreased matrix synthesis and increased mineralization in osteoarthritis (OA). Because NO inhibits mitochondrial respiration, this study was undertaken to directly assess the potential role of chondrocyte mitochondrial oxidative phosphorylation (OXPHOS) in matrix synthesis and mineralization. METHODS: We studied cultured human articular chondrocytes and immortalized costal chondrocytes (TC28 cells). We also assessed the effects of antimycin A and oligomycin (inhibitors of mitochondrial complexes III and V, respectively) on chondrocyte mitochondrial respiration, ATP synthesis, and inorganic pyrophosphate (PPi) generation, and the mineralizing potential of released matrix vesicles (MV). RESULTS: Articular chondrocytes and TC28 cells respired at comparable rates. Peroxynitrite and NO donors markedly suppressed respiration and ATP generation in chondrocytes. Because NO exerts multiple effects on chondrocytes, we investigated the primary functions of mitochondrial respiration and OXPHOS. To do so, we identified minimally cytotoxic doses of antimycin and oligomycin, which both induced intracellular ATP depletion (by 50-80%), attenuated collagen and proteoglycan synthesis, and blocked transforming growth factor beta from increasing intracellular ATP and elaboration of PPi, a critical inhibitor of hydroxyapatite deposition. Antimycin and oligomycin also abrogated the ability of the ATP-hydrolyzing enzyme plasma cell membrane glycoprotein 1 (PC-1) to increase chondrocyte PPi generation. Finally, MV from cells treated with antimycin or oligomycin contained less PPi and precipitated >50% more 45Ca. CONCLUSION: Chondrocyte mitochondrial reserve, as NO-sensitive mitochondrial respiration-mediated ATP production, appears to support matrix synthesis and PPi elaboration and to regulate MV composition and mineralizing activity. NO-induced depression of chondrocyte respiration could modulate matrix loss and secondary cartilage mineralization in OA.

Urinary 8-hydroxydeoxyguanosine excretion as a non-invasive marker of neutrophil activation in animal models of inflammatory bowel disease.

BACKGROUND: Because free radicals contribute to ulcerative colitis and Crohn's disease, assessing oxidative load in vivo could provide a surrogate marker of inflammation and disease status. METHODS: Electrochemical high-performance liquid chromatography was used to study urinary excretion of 8-hydroxydeoxyguanosine (8-OH-dGUA), formed by reaction of hydroxyl radicals with native DNA, in 2,4,6-trinitrobenzene-sulfonic acid (TNBS) and dextran sulfate (DSS) rat models of bowel inflammation. Bowel myeloperoxidase (MPO) and histopathology were also assessed. RESULTS: TNBS enema (75 mg/kg in 50% ethanol) and oral DSS (6% via drinking water) both yielded an inflammatory response reflected by increases in bowel MPO that were significantly correlated with tissue injury. In both models urinary 8-OH-dGUA excretion was significantly correlated with bowel MPO activity and epithelial injury and remained at control levels when neutrophils (PMN) were eliminated, whereas epithelial injury and crypt erosion persisted despite neutropenia. CONCLUSIONS: Urinary 8-OH-dGUA excretion directly reflects PMN activation in vivo, thereby providing a non-invasive surrogate marker for inflammation in these models which is more indicative of PMN activation than either MPO activity, which does not distinguish inactive from active MPO, or epithelial status, which is independent of PMN activation in both models.

Streptococcal cell wall-induced arthritis. Requirements for neutrophils, P-selectin, intercellular adhesion molecule-1, and macrophage-inflammatory protein-2.

Immune arthritis in rat ankle joints was induced by intra-articular injection of streptococcal cell was extract (SCW), followed 21 days later by i.v. injection of SCW. This results in a monoarticular arthritis characterized by an influx of neutrophils and mononuclear cells, a 35-fold increase in urinary excretion of 8-hydroxy-deoxyguanosine (8-OH-dGUA; an index of free radical production), ankle edema, and joint damage/destruction. Neutrophil depletion substantially reduced the intensity of ankle edema. Ab-induced blockade of P-selectin or ICAM-1 also reduced the intensity of ankle edema and the influx of neutrophils. Blockade of TNF-alpha or IL-1 resulted in nearly complete and persistent reduction in ankle edema and profound reductions in the accumulation of neutrophils and mononuclear cells in affected joints. Finally, blocking of macrophage-inflammatory protein-2 reduced ankle edema and neutrophil accumulation during the first 2 days after i.v. challenge with SCW. These data indicate that SCW-induced arthritis is neutrophil dependent and that the recruitment of neutrophils and subsequent joint edema requires ICAM-1, P-selectin, and macrophage-inflammatory protein-2, as well as TNF-alpha and IL-1.

Preservation of phosphagen kinase function during transient hypoxia via enzyme abundance or resistance to oxidative inactivation.

Mammalian lactate dehydrogenase and phosphofructokinase are more susceptible in vitro to superoxide (O2) and hydroxyl (.OH) radicals than pyruvate kinase and glucose-6-phosphate dehydrogenase, suggesting that differential inactivation of regulatory enzymes contributes to the metabolic disintegration in stenoxic tissues during transient hypoxia. Likewise, creatine kinase in smooth muscle from porcine ileum is significantly reduced by hypoxia-reoxygenation ex vivo from 300 (+/- 18.2 SE, n = 8) to 196 U.g wet wt-1 (+/- 16.7, P < 0.001, ANOVA). Conversely, arginine kinase, from the myocardium of Limulus polyphemus, a species that tolerates anoxia for days was 2.9-fold less susceptible to oxidative inactivation. To examine whether preservation of kinase function is related to euryoxic capacity, a combination of non-invasive 31P-NMR spectroscopy and enzyme-linked assays was used to follow ATP and phosphagen status during hypoxia-reoxygenation in porcine ileum smooth muscle, L. polyphemus myocardium, and the myocardium of Argopecten irradians, a scallop species tolerant of hypoxia for only 24 h. Despite wide differences in phylogeny, euryoxic capacity and oxidative vulnerability of the phosphagen kinases, in all three tissues, the phosphagen pool recovered concomitant with ATP during reoxygenation, thereby revealing competent kinase function. In the mammalian tissue, such preservation of kinase function is facilitated by a 2400-fold excess of enzyme activity.

Human neutrophil (PMN) oxygen radical production and the cytoskeleton.

Electron paramagnetic resonance (EPR) studies were conducted to examine oxygen radical generation following PMN activation by N-formyl-1-methionyl-1-leucyl-1-phenylalanine (fMLP) in the presence or absence of phalloidin and cytochalasin B (CB), agents which stabilize or disrupt f-actin, or taxol and colchicine which stabilize and disrupt microtubule cytoskeletal structures respectively. PMN oxyradical production was monitored using the spin trap 5,5-dimethyl-1-pyrroline n-oxide (DMPO). PMN when unstimulated, treated with phalloidin (10(-6)-10(-8)M), CB (10(-6)-10(-8)M), taxol (10(-6)-10(-8)M), or colchicine (10(-6)-10(-8)M), did not produce a detectable DMPO signal. Stimulation with fMLP (10(-6)M), however, resulted in a significant hydroxyl radical signal which was augmented by PMN treatment with CB (10(-6)-10(-7)M, p < 0.05) and attenuated following PMN treatment with phalloidin (10(-6)-10(-7)M, p < 0.05). Interestingly, colchicine treatment (10(-6)-10(-8)M) significantly attenuated fMLP-mediated oxyradical production, whereas taxol (10(-6)-10(-7)M) significantly increased PMN oxyradical production. These data suggest that stabilization of f-actin and disruption of microtubules attenuates the PMN oxidative burst, whereas disruption of f-actin and stabilization of microtubules increases radical production. These findings suggest cytoskeletal domain-specific contributions to PMN oxidative activity.

Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implications for neurodegeneration.

The evidence is compelling that free radicals, plus increases in free cytosolic Ca2+ and Na+, figure prominently in neuronal death after exposure to glutamate and dicarboxylic excitotoxins such as NMDA and kainate. However, neither the source of these radicals nor the direct connection between Ca2+ mobilization and radical production has been well defined. Electron paramagnetic resonance studies reported here indicate that intact mitochondria isolated from adult rat cerebral cortex and cerebellum generate extremely reactive hydroxyl (.OH) radicals, plus ascorbyl and other carbon-centered radicals when exposed to 2.5 microM Ca2+, 14 mM Na+, plus elevated ADP under normoxic conditions, circumstances that prevail in the cytoplasm of neurons during excitotoxin-induced neurodegeneration. In a feed-forward cycle, exposure of isolated mitochondria to .OH significantly increases subsequent radical production five- to 16-fold (average = 8.8 +/- 1.6 SE, n = 6, p > 0.01) with succinate as substrate, and also selectively impairs function of NADH-CoQ dehydrogenase activity (electron transport complex 1). These effects are also reflected by respiration rates that are reduced 48% with complex 1 substrates, but increased 27% with complex 2 substrate, after .OH exposure. Comparable complex 1 dysfunction is observed in mitochondria isolated from the substantia nigra of Parkinson's disease patients, from platelets of Huntington's disease patients, and from neocortex of Alzheimer's disease patients. Mitochondrial radical production provides a testable model, based on oxyradical toxicity, oxidative enzyme inactivation, and mitochondrial dysfunction, for the final common pathway of neuronal necrosis during excitotoxicity, and in a host of neurodegenerative disorders.