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.

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.

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.

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.

Regulation of polymorphonuclear leukocyte membrane fluidity: effect of cytoskeletal modification.

We previously demonstrated that the f-actin cytoskeleton modulates oxygen radical production associated with polymorphonuclear leukocyte (PMN) oxidative burst activity. Given the close association of the actin and microtubule cytoskeletons with the plasma membrane and the transmembrane location of the PMN NADPH oxidase, it is likely cytoskeletal change may affect PMN membrane responses, such as cellular anisotropy. Changes in PMN membrane fluidity were therefore examined after PMN activation by the chemoattractant N-formyl-1-methionyl-1-leucyl-1-phenylalanine (fMLP) in the presence or absence of phalloidin or cytochalasin B (CB), agents that stabilize and disrupt f-actin, or taxol and vincristine, which stabilize and disrupt microtubules, respectively. Phalloidin and taxol treatment of PMN significantly decreased whereas CB and vincristine significantly increased membrane fluidity. Activation of PMN by fMLP (10(-6) M) resulted in a significant increase in membrane fluidity that was attenuated by PMN pretreatment with phalloidin or taxol. CB and vincristine pretreatment of PMN did not alter the fMLP response. These data suggest that stabilization of the f-actin or microtubule cytoskeleton may prevent increases in cellular membrane fluidity associated with PMN activation.

Glucose metabolism and hemoglobin reactivity in human red blood cells exposed to the tryptophan metabolites 3-hydroxyanthranilate, quinolinate and picolinate.

Glucose metabolism and hemoglobin reactivity in intact human erythrocytes were assessed in the presence of the tryptophan metabolites, 3-hydroxyanthranilate (3-HAT), quinolinate and picolinate. Of these compounds, only 3-HAT altered red cell oxidative status by inducing, in a dose-dependent manner, formation of methemoglobin and non-functional oxidation products of hemoglobin, and by increasing both net glycolytic flux and flux through the hexose monophosphate shunt. 3-HAT also decreased the normal lactate to pyruvate production ratio with pyruvate accumulating at the expense of lactate. These findings are consistent with the auto-oxidative reactivity of quinolinate, picolinate, and 3-HAT in that only 3-HAT undergoes base-catalyzed auto-oxidation (Dykens et al., Biochem Pharmacol 36: 211-217, 1987). Lactate and pyruvate added to the medium in physiologic concentrations uncoupled oxidative glycolysis from reductive glycolysis, resulting in accumulation of pyruvate in the presence of 3-HAT with little increase in total glycolytic flux. Superoxide dismutase (SOD), which accelerates 3-HAT auto-oxidation in vitro (Dykens et al., Biochem Pharmacol 36: 211-217, 1987), exacerbated HAT-mediated oxidative insult by increasing methemoglobin formation, hexose monophosphate shunt flux, and pyruvate accumulation. Persistence of 3-HAT-induced red cell metabolic responses and oxidative damage in the presence of SOD, DETAPAC (diethylenetriaminepentaacetic acid) and formate suggests that an organic-based radical, perhaps the anthranilyl radical produced during 3-HAT auto-oxidation, is the proximate agent exerting oxidative stress. Slow rates of auto-oxidation indicate that 3-HAT may be useful as a probe of antioxidant mechanisms in normal and diseased red blood cells.

Mechanism of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury.

The neuroexcitotoxin kainate has been used as a selective lesioning agent to model the etiology of a number of neurodegenerative disorders. Although excitotoxins cause susceptible neurons to undergo prolonged or repeated depolarization, the proximate metabolic pathology responsible for neuronal necrosis has remained elusive. We report here that kainate-induced death of cerebellar neurons in culture is prevented by inhibiting the enzyme xanthine oxidase, a cellular source of cytotoxic superoxide radicals (O2-.). Moreover, neurons are also protected from excitotoxin-induced death by the addition to the culture medium of either superoxide dismutase or mannitol, which scavenge superoxide and hydroxyl radicals, respectively, or serine protease inhibitor, which forestalls formation of xanthine oxidase. These findings indicate that excitotoxin-induced neuronal degeneration is mediated by superoxide radicals generated by xanthine oxidase, a mechanism partially analogous to that proposed for tissue damage seen upon reperfusion of ischemic tissues.

Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate.

The oxidative reactivities of four tryptophan metabolites in the kynurenine pathway were examined as a potential mechanism for their reported neurotoxicities and carcinogenicities. Neither quinolinic acid, a neurotoxin, nor its monocarboxylic analogue, picolinic acid, auto-oxidized over a wide pH range. However, 3-hydroxyanthranilic acid (3-HAT), a carcinogen, readily auto-oxidized and the reaction rate increased exponentially with increasing pH. 3-HAT auto-oxidation likely involves two steps: auto-oxidation of 3-HAT to the semiquinoneimine (anthranilyl radical) which oxidizes to the quinoneimine, followed by condensation and oxidation reactions to yield a second carcinogen, cinnabarinic acid. 3-HAT auto-oxidation to cinnabarinate required molecular oxygen and generated superoxide radicals and H2O2. Superoxide dismutase (SOD) accelerated 3-HAT auto-oxidation 4-fold, probably by preventing back reactions between superoxide and either the anthranilyl radical or the quinoneimine formed during the initial step of auto-oxidation. Catalase did not accelerate 3-HAT auto-oxidation, but it did prevent destruction of cinnabarinate by H2O2. Interconversion between oxyhemoglobin and methemoglobin occurred during 3-HAT auto-oxidation, although neither form of hemoglobin altered rates of 3-HAT auto-oxidation. Mn2+, Mn3+ and Fe3+-EDTA did not directly catalyze cinnabarinate formation in the absence of O2, but they did accelerate cinnabarinate formation under aerobic conditions.

Oxygen detoxification in algal-invertebrate symbioses from the Great Barrier Reef.

Examination of 34 species of symbiotic invertebrates in four phyla has confirmed the generality of a direct relationship between chlorophyll concentration and the activities of superoxide dismutase and catalase, two enzymes involved in the detoxification of active oxygen. On a finer scale, activities of these enzymes also depend on the localization of the algal symbions (intracellular or extracellular) and hence on the extent to which photosynthetic O2 actually contacts animal cytoplasm, and on the solar irradiance experienced by the symbionts. Differences in SOD activity among organs of Tridacna crocea are not fully explained by local O2 levels but are further related to organ-specific retes of O2 consumption. This result is discussed in terms of known mechanisms of superoxide radical production in mitochondria and differences in O2 utilization concentrations among various organs in bivalve molluscs.