Seeking research questions from implementers: considerations for leveraging ground actors research needs in the fight against malaria in West Africa.

BACKGROUND: To strengthen the fight against malaria, it is imperative to identify weaknesses and possible solutions in order to improve programmes implementation. This study reports experiences gained from collaboration between decision-makers and researchers from a World Bank project (Malaria and Neglected Tropical Diseases in the Sahel, SM/NTD). The objectives of this paper were to identify bottlenecks in malaria programme implementation as well as related research questions they bring up. METHODS: Questionnaire addressed to National Malaria Control Programme managers and prioritization workshops were used as a medium to identify research questions. The bottlenecks in malaria programme implementation were identified in seven thematic areas namely governance, human resources, drugs, service provision, use of prevention methods, monitoring and evaluation (M and E), and public support or buy-in. The first five priority questions were: (1) compliance with drug doses on the second and third days during the seasonal chemoprevention (SMC) campaigns, (2) the contribution of community-based distributors to the management of severe cases of malaria in children under 5 years, (3) the SMC efficacy, (4) artemisinin-based combination therapy (ACT) tolerance and efficacy according to existing guidelines, and (5) the quality of malaria control at all levels of the health system. RESULTS AND CONCLUSION: This work showed the effectiveness of collaboration between implementers, programmes managers, and researchers in identifying research questions. The responses to these identified research questions of this study may contribute to improving the implementation of malaria control programmes across African countries.

PtxtPME1 and homogalacturonans influence xylem hydraulic properties in poplar.

While the xylem hydraulic properties, such as vulnerability to cavitation (VC), are of paramount importance in drought resistance, their genetic determinants remain unexplored. There is evidence that pectins and their methylation pattern are involved, but the detail of their involvement and the corresponding genes need to be clarified. We analyzed the hydraulic properties of the 35S::PME1 transgenic aspen that ectopically under- or over-express a xylem-abundant pectin methyl esterase, PtxtPME1. We also produced and analyzed 4CL1::PGII transgenic poplars expressing a fungal polygalacturonase, AnPGII, under the control of the Ptxa4CL1 promoter that is active in the developing xylem after xylem cell expansion. Both the 35S::PME1 under- and over-expressing aspen lines developed xylem with lower-specific hydraulic conductivity and lower VC, while the 4CL1::PGII plants developed xylem with a higher VC. These xylem hydraulic changes were associated with modifications in xylem structure or in intervessel pit structure that can result in changes in mechanical behavior of the pit membrane. This study shows that homogalacturonans and their methylation pattern influence xylem hydraulic properties, through its effect on xylem cell expansion and on intervessel pit properties and it show a role for PtxtPME1 in the xylem hydraulic properties.

Nitric oxide synthase evaluation in oral precancerous and cancerous lesions.

Nitric Oxide (NO) has been linked to several cardiovascular, neurological and immunological physiological and pathological functions. Several studies have shown that the eNOS, nNOS and iNOS effects on cancer cell growth and proliferation are related to the upregulation of the Wnt pathway and have a central role during metastasis development. Recent studies suggest that cancer cells undergo metabolic reprogramming, which drives cancer cell growth and progression. The aim of this study was to observe the NOS activity in the pathogenesis of oral precancerous and cancerous lesions. The results showed changes in eNOS activity levels, which increased from healthy oral mucosa to oral squamous cell carcinoma SCC, through different dysplasia levels. The iNOS activity levels increased in precancerous lesions compared to healthy mucosa, where iNOS was absent, while it decreased in SCC lesions. Moreover, a gradual increase of nNOS activity together with the progression of the lesions was also found. These results may suggest how NO could play a critical role during pathogenesis, growth and development of precancerous lesions to cancer degeneration.

Impact of capsaicin on mast cell inflammation.

Mast cells are inflammatory cells, and they are prominent in inflammatory diseases such as allergy and asthma. Mast cells possess high-affinity receptors for IgE (FcERI) and the cross-linking of these receptors is essential to trigger the secretion of granules containing arachidonic acid metabolism (such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4), histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Activation of mast cells provokes the secretion of cytokines and mediators that are responsible for the pathologic reaction of immediate hypersensitivity. Sensory nerve stimulation by irritants and other inflammatory mediators provokes the release of neuropeptides, causing an increase in vascular permeability, plasma extravasation and edema. Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability, effects inhibited by capsaicin. Capsaicin causes release of sensory neuropeptide, catecholamines and vasodilation. Several studies have reported that capsaicin is effective in relief and prevention of migraine headaches, improves digestion, helps to prevent heart disease, and lowers blood cholesterol and blood pressure levels. The findings reported in these studies may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders.

Vascular endothelial growth factor (VEGF), mast cells and inflammation.

Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis, therefore blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases. VEGF, expressed in response to soluble mediators such as cytokines and growth factors, is important in the physiological development of blood vessels as well as development of vessels in tumors. In cancer patients VEGF levels are increased, and the expression of VEGF is associated with poor prognosis in diseases. VEGF is a mediator of angiogenesis and inflammation which are closely integrated processes in a number of physiological and pathological conditions including obesity, psoriasis, autoimmune diseases and tumor. Mast cells can be activated by anti-IgE to release potent mediators of inflammation and can also respond to bacterial or viral antigens, cytokines, growth factors and hormones, leading to differential release of distinct mediators without degranulation. Substance P strongly induces VEGF in mast cells, and IL-33 contributes to the stimulation and release of VEGF in human mast cells in a dose-dependent manner and acts synergistically in combination with Substance P. Here we report a strong link between VEGF and mast cells and we depict their role in inflammation and immunity.

Nitric oxide synthase isoenzyme expression in human oral lichen planus.

The roles of nitric oxide (NO) synthase (NOS) enzyme in pathological mechanisms of the oral cavity are still incompletely understood. The aim of this study was to investigate the expression of the endothelial, neuronal and inducible isoforms of NOS (eNOS, nNOS and iNOS) in oral lichen planus (OLP) development in humans. OLP and healthy oral mucosa biopsies were taken for mRNA and protein analysis of NOS isoenzymes by RT-PCR, western blot and immunohistochemistry. The mRNA and protein levels of eNOS and nNOS were present in all samples, with a significant increase only for eNOS in OLP. The normal oral mucosa exhibited only small amounts of iNOS mRNA and protein, while it showed a significant rise in OLP samples. These results were confirmed by immunohistochemical analysis. Our findings suggest that NO produced by increased eNOS and iNOS expression may have circulatory and immune functions in the development of OLP.

Comparison of beneficial actions of non-steroidal anti-inflammatory drugs to flavonoids.

Inflammation is involved in increasing number of diseases necessitating the development of new, effective and safe treatments. Non steroidal anti-inflammatory drugs (NSAIDs) have been helpful in many instances, but they only inhibit cyclooxygenase (COX), but not the generation or actions of cytokines. Instead, some natural flavonoids have multiple anti-inflammatory effects, including COX inhibition, and a much safer profile. Increasing evidence indicates that inflammation plays a critical role in the pathogenesis of many diseases that also involve mast cells. Consequently, the need for new, effective and safe anti-inflammatory drugs is all the more urgent. Corticosteroids are quite potent, but have many adverse effects such as increased risk of infections, osteoporosis, glaucoma and depression. Biological agents such anti-TNF are useful in certain conditions, such as rheumatoid arthritis and psoriasis, but has been associated with increased risk of infection and leukemia.

Role of vitamins D, E and C in immunity and inflammation.

Inflammatory responses are operationally characterized by pain, redness, heat and swelling at the site of infection and trauma. Mast cells reside near small blood vessels and, when activated, release potent mediators involved in allergy and inflammation. Vitamin D modulates contraction, inflammation and remodeling tissue. Vitamin D deficiency has been linked to multiple diseases and several data have demonstrated a strong relationship between serum vitamin D levels and tissue function. Therapy targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions. Mast cells are activated by oxidized lipoproteins, resulting in increased expression of inflammatory cytokines and suggesting that the reduction of oxidation of low density lipoprotein by vitamin E may also reduce mast cell activation. Vitamin C is also an anti-oxidant well-known as an anti-scurvy agent in humans. Vitamin C inhibits peroxidation of membrane phospholipids and acts as a scavenger of free radicals and is also required for the synthesis of several hormones and neurotransmitters. In humans, vitamin C reduces the duration of common cold symptoms, even if its effect is not clear. Supplementation of vitamin C improves the function of the human immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity. Vitamin C depletion has been correlated with histaminemia which has been shown to damage endothelial-dependent vasodilation. However, the impact of these vitamins on allergy and inflammation is still not well understood.

Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors.

Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made.

Endothelial cells, cholesterol, cytokines, and aging.

It has been reported that high levels of cholesterol and triglycerides are associated with increased risk of developing atherosclerosis and shorter life. In fact, vascular endothelial dysfunction occurs during the human aging process. Accumulation of lipids in vascular endothelium activates leukocytes to produce cytokines and chemokines which recruit macrophages. On the other hand, macrophages augment inflammatory response and secrete vascular endothelial growth factor, a key cytokine that mediates angiogenesis and inflammatory response. In addition, hyperlipidaemia is one of the main risk factors for aging, hypertension and diabetes. Here, we review the interrelationship between endothelial cells, high level of cholesterol, and aging.

IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation.

Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37.

Nutrition and cancer prevention.

Cancer cells invade surrounding tissues and metastasize to distant sites. Diet high in fat is a strong link to, and perhaps causes, a high incidence of tumours. Trans-fatty acid might impair the function and it could be involved in the development of cancer. Cholesterol is also strongly suspected to be involved in the development of tumours, therefore it is important for everyone to eat well, especially for people with cancer to prevent the body tissues from breaking down and helping to rebuild the normal tissue that may have been affected by the treatments. Factors secreted by adipocytes and macrophages such as TNF-alpha and other inflammatory proteins are involved in inflammation in cancer. In addition, MCSF which up-regulates adipocyte tissue is also important for the stimulation of fat cell proliferation and is expressed by human adipocytes. Many cytokines, such as IL-1, IL-6, IL-8, IL-32, IL-33 and MCP-1, are biomarkers for cancer and chronic diseases along with transcription factors NFκB and AP-1; these last two factors are important bioactive substances on the molecular mechanism of the control of genes which in turn affect cellular metabolism. In this paper we revisit the interrelationship between cancer and metabolism.

Adverse reaction to irrigation with povidone-iodine after deep-impacted, lower third molar extraction.

Povidone-iodine is most commonly used worldwide because of its germicidal activity, relatively low irritancy or toxicity and low cost. Frequently, povidone-iodine is used as a topical antiseptic for treating and preventing wound infection. In rare cases skin irritation or iododerma-like eruption could represent possible adverse effects due to the oxidative effects of iodine and allergic hypersensitivity reaction. In this report we describe a case of a massive adverse reaction to the irrigation of surgical wound dehiscence with 10 percent povidone-iodine solution after deep-impacted, lower third molar extraction. This reaction was related to a central neurotrophic reflex involving three trigeminal branches and probably due to peripheral chemical insult of mandible nerve. This adverse reaction determined a severe edema and diffuse skin lesions, involving the whole left side of the face mimicking an iododerma-like eruption. These violent symptoms were solved after 60 days. Furthermore, we report a small permanent skin scar in the zygomatic area and transient alterations of facial sensitivity on the affected side which completely disappeared in 6 months.

Microarray evaluation of gene expression profiles in inflamed and healthy human dental pulp: the role of IL1beta and CD40 in pulp inflammation.

Dental pulp undergoes a number of changes passing from healthy status to inflammation due to deep decay. These changes are regulated by several genes resulting differently expressed in inflamed and healthy dental pulp, and the knowledge of the processes underlying this differential expression is of great relevance in the identification of the pathogenesis of the disease. In this study, the gene expression profile of inflamed and healthy dental pulps were compared by microarray analysis, and data obtained were analyzed by Ingenuity Pathway Analysis (IPA) software. This analysis allows to focus on a variety of genes, typically expressed in inflamed tissues. The comparison analysis showed an increased expression of several genes in inflamed pulp, among which IL1β and CD40 resulted of particular interest. These results indicate that gene expression profile of human dental pulp in different physiological and pathological conditions may become an useful tool for improving our knowledge about processes regulating pulp inflammation.

Role of mast cells in innate and adaptive immunity.

Mast cells play a central role in inflammatory and immediate allergic reactions and are necessary for allergic reactions. Mast cells play a role in the pathophysiology of autoimmune diseases and appear to be especially important in inflamed tissues, because they infiltrate tissues and produce a variety of cytokines. Mast cells are important for both innate and adaptive immunity in tissues that are in close contact with the environment, i.e. the skin, the airways and the lung, and the lining of the intestine. However, there are still many unsolved issues of mast cell functions, including their regulatory mechanism on cell differentiation in bone marrow; for example, the cytokines and transcription factors necessary for their differentiation and expansion, as well as the molecular mechanism underlying basophil migration from the bloodstream to peripheral tissues such as lymph nodes still need to be clarified.

IL-36 a new member of the IL-1 family cytokines.

Interleukin-36 (IL-36) is a pro-inflammatory cytokine which plays an important role in innate and adaptive immunity. IL-36 activates MAPK and NF-kB pathways and is produced by many different cells. This cytokine is a family member of interleukin-1 (IL-1) and plays an important role in the pathophysiology of several diseases. Here we summarise and review the new aspects of this important pro-inflammatory cytokine.

Interleukin-9 and mast cells.

Mast cells are granulated hematopoietic cells derived from stem cells that reside in nearly all tissues and are involved in protection of a host from bacterial infection with a protective and pathogenic activity. Mast cells are important for both innate and adaptive immunity in tissues which are in close contact with the environment. These cells express proinflammatory cytokines such as IL-1, IL-6, IL-8 and tumor necrosis factor which are necessary for innate immunity. Mast cells also produce interleukin-9 and enhance mast cell expression of several cytokines including IL-1beta, IL-5, IL-6, IL-9 and IL-13. In addition, IL-9 can induce mast cell production of TGF-beta which can have proinflammatory downstream effects. IL-9 can function as either a positive or a negative regulator of immune responses and can have a detrimental role in allergy and autoimmunity. Furthermore, IL-9 contributes to disease by promoting mast cell expansion and production of IL-13 which in turn contributes to airway hyperresponsiveness. Here, in this editorial we review the interrelationship between IL-9 and mast cells.

Hydraulic efficiency and coordination with xylem resistance to cavitation, leaf function, and growth performance among eight unrelated Populus deltoidesxPopulus nigra hybrids.

Tests were carried out to determine whether variations in the hydraulic architecture of eight Populus deltoides×Populus nigra genotypes could be related to variations in leaf function and growth performance. Measurements were performed in a coppice plantation on 1-year-old shoots under optimal irrigation. Hydraulic architecture was characterized through estimates of hydraulic efficiency (the ratio of conducting sapwood area to leaf area, A(X):A(L); leaf- and xylem-specific hydraulic conductance of defoliated shoots, k(SL) and k(SS), respectively; apparent whole-plant leaf-specific hydraulic conductance, k(plant)) and xylem safety (water potential inducing 50% loss in hydraulic conductance). The eight genotypes spanned a significant range of k(SL) from 2.63 kg s(-1) m(-2) MPa(-1) to 4.18 kg s(-1) m(-2) MPa(-1), variations being mostly driven by k(SS) rather than A(X):A(L). There was a strong trade-off between hydraulic efficiency and xylem safety. Values of k(SL) correlated positively with k(plant), indicating that high-pressure flowmeter (HPFM) measurements of stem hydraulic efficiency accurately reflected whole-plant water transport efficiency of field-grown plants at maximum transpiration rate. No clear relationship could be found between hydraulic efficiency and either net CO(2) assimilation rates, water-use efficiency estimates (intrinsic water-use efficiency and carbon isotope discrimination against (13)C), or stomatal characteristics (stomatal density and stomatal pore area index). Estimates of hydraulic efficiency were negatively associated with relative growth rate. This unusual pattern, combined with the trade-off observed between hydraulic efficiency and xylem safety, provides the rationale for the positive link already reported between relative growth rate and xylem safety among the same eight P. deltoides×P. nigra genotypes.

Cholesterol, cytokines and diseases.

A high level of cholesterol is associated with obesity, cardiovascular diseases and atherosclerosis. Immune response in atherosclerosis is mediated by chemokines which attract monocytes, leading to the innate immune response characterised by the production of cytokines. The immunoregulatory cytokines are an important bridge between innate and adductive immunity. TH1 cytokines are involved as effector T cells in inflammatory response, while TH2 cytokines can be anti-inflammatory such as IL-10 and IL-4. It is well known that statins enhance the production of TH2 cytokines whereas the secretion of TH1 cytokines is suppressed. For this purpose, we studied the significance of anti-inflammatory effect and suppression of inflammation by statins. In this paper we revisited the role of cholesterol and cytokines IL-18, IL-10, IL-12, TNF-α, interferon-γ, and chemokines in inflammatory diseases.

Atherosclerosis: a classic inflammatory disease.

Atherosclerosis is an inflammatory disease due to a diet high in saturated fat, hypercholesterolemia, obesity, hypoglycemia, etc. mainly mediated by the infiltration of macrophage and T cells into the vascular wall. Once the endothelial is damaged monocytes penetrate the tissue and are transformed in scavenger cells. Upon stimulation of Th1 cells, a group of cytokines is released and contributes to the inflammatory response of atherosclerotic tissue. When macrophages proliferate they amplify inflammatory response through the secretion of growth factors and cytokines such as TNF and IL-1. In addition, chemokines such as RANTES and other C-C chemokines are generated, and matrix metalloprotinease 9 (MMP-9) are produced by activated monocytes. However, the immune system in atherosclerosis still remains unclear. Here, in this study we revisited the inter-relationship between atherosclerosis and inflammation.