Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B

<p>Abstract</p> <p>Background</p> <p>Nontypeable <it>Haemophilus influenzae </it>(NTHi) is an important respiratory pathogen implicated as an infectious trigger in chronic obstructive pulmonary disease, but its molecular interaction with human lung epithelial cells remains unclear. Herein, we tested that the hypothesis that NTHi induces the expression of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) via activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B in pulmonary alveolar epithelial cells.</p> <p>Methods</p> <p>Human alveolar epithelial A549 cells were infected with different concentrations of NTHi. The phosphorylation of p38 MAPK was detected by Western blot analysis, the DNA binding activity of NF-kappa B was assessed by electrophoretic mobility shift assay (EMSA), and the expressions of COX-1 and 2 mRNA and PGE2 protein were measured by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. The roles of Toll-like receptor (TLR) 2 and TLR4, well known NTHi recognizing receptor in lung epithelial cell and gram-negative bacteria receptor, respectively, on the NTHi-induced COX-2 expression were investigated in the HEK293 cells overexpressing TLR2 and TLR4 <it>in vitro </it>and in the mouse model of NTHi-induced pneumonia by using TLR2 and TLR4 knock-out mice <it>in vivo</it>. In addition, the role of p38 MAPK and NF-kappa B on the NTHi-induced COX-2 and PGE2 expression was investigated by using their specific chemical inhibitors.</p> <p>Results</p> <p>NTHi induced COX-2 mRNA expression in a dose-dependent manner, but not COX-1 mRNA expression in A549 cells. The enhanced expression of PGE2 by NTHi infection was significantly decreased by pre-treatment of COX-2 specific inhibitor, but not by COX-1 inhibitor. NTHi induced COX-2 expression was mediated by TLR2 in the epithelial cell <it>in vitro </it>and in the lungs of mice <it>in vivo</it>. NTHi induced phosphorylation of p38 MAPK and up-regulated DNA binding activity of NF-kappa B. Moreover, the expressions of COX-2 and PGE2 were significantly inhibited by specific inhibitors of p38 MAPK and NF-kappa B. However, NTHi-induced DNA binding activity of NF-kappa B was not affected by the inhibition of p38 MAPK.</p> <p>Conclusion</p> <p>NTHi induces COX-2 and PGE2 expression in a p38 MAPK and NF-kappa B-dependent manner through TLR2 in lung epithelial cells <it>in vitro </it>and lung tissues <it>in vivo</it>. The full understanding of the role of endogenous anti-inflammatory PGE2 and its regulation will bring new insight to the resolution of inflammation in pulmonary bacterial infections.</p

Laxative activities of Mareya micrantha (Benth.) Müll. Arg. (Euphorbiaceae) leaf aqueous extract in rats

<p>Abstract</p> <p>Background</p> <p><it>Mareya micrantha </it>(Benth.) Müll. Arg. (Euphorbiaceae) is a shrub that is commonly used in Côte d'Ivoire (West Africa) for the treatment of constipation and as an ocytocic drug. The present study was carried out to investigate the laxative activity of <it>Mareya micrantha </it>in albino's Wistar rats.</p> <p>Methods</p> <p>Rats were divided in 5 groups of 5 animals each, first group as control, second group served as standard (sodium picosulfate) while group 3, 4 and 5 were treated with leaf aqueous extract of <it>Mareya micrantha </it>at doses of 100, 200 and 400 mg/kg body weight (b.w.), <it>per os </it>respectively. The laxative activity was determined based on the weight of the faeces matter. The effects of the leaves aqueous extract of <it>Mareya micrantha </it>and castor oil were also evaluated on intestinal transit, intestinal fluid accumulation and ions secretion.</p> <p>Results</p> <p>Phytochemicals screening of the extract revealed the presence of flavonoids, alkaloids, tannins, polyphenols, sterols and polyterpenes. The aqueous extract of <it>Mareya micrantha </it>applied orally (100, 200 and 400 mg/kg; <it>p.o</it>.), produced significant laxative activity and reduced loperamide induced constipation in dose dependant manner. The effect of the extract at 200 and 400 mg/kg (<it>p.o</it>.) was similar to that of reference drug sodium picosulfate (5 mg/kg, <it>p.o</it>). The same doses of the extract (200 and 400 mg/kg, <it>p.o</it>.) produced a significant increase (p < 0.01) of intestinal transit in comparison with castor oil (2 mL) (p < 0.01). Moreover, the extract induced a significant enteropooling and excretion of Cl^-, Na⁺, K⁺and Ca²⁺in the intestinal fluid (p < 0.01).</p> <p>Conclusions</p> <p>The results showed that the aqueous extract of <it>Mareya micrantha </it>has a significant laxative activity and supports its traditional use in herbal medicine.</p

How Much Does Malaria Vector Control Quality Matter: The Epidemiological Impact of Holed Nets and Inadequate Indoor Residual Spraying

BACKGROUND: Insecticide treated nets (ITN) and indoor residual spraying (IRS) are the two pillars of malaria vector control in Africa, but both interventions are beset by quality and coverage concerns. Data from three control programs were used to investigate the impact of: 1) the physical deterioration of ITNs, and 2) inadequate IRS spray coverage, on their respective protective effectiveness. METHODS: Malaria indicator surveys were carried out in 2009 and 2010 in Bioko Island, mainland Equatorial Guinea and Malawi to monitor infection with P. falciparum in children, mosquito net use, net condition and spray status of houses. Nets were classified by their condition. The association between infection and quality and coverage of interventions was investigated. RESULTS: There was reduced odds of infection with P. falciparum in children sleeping under ITNs that were intact (Odds ratio (OR): 0.65, 95% CI: 0.55-0.77 and OR: 0.81, 95% CI: 0.56-1.18 in Equatorial Guinea and in Malawi respectively), but the protective effect became less with increasingly worse condition of the net. There was evidence for a linear trend in infection per category increase in deterioration of nets. In Equatorial Guinea IRS offered protection to those in sprayed and unsprayed houses alike when neighbourhood spray coverage was high (≥80%) compared to those living in areas of low IRS coverage (<20%), regardless of whether the house they lived in was sprayed or not (adjusted OR = 0.54, 95% CI 0.33-0.89). ITNs provided only personal protection, offering no protection to non users. Although similar effects were seen in Malawi, the evidence was much weaker than in Equatorial Guinea. CONCLUSIONS: Universal coverage strategies should consider policies for repair and replacement of holed nets and promote the care of nets by their owners. IRS programs should ensure high spray coverage since inadequate coverage gives little or no protection at all

The Effect of Climate Fluctuation on Chimpanzee Birth Sex Ratio

Climate and weather conditions, such as the North Atlantic Oscillation, precipitation and temperature influence the birth sex ratio (BSR) of various higher latitude species, including deer, elephant seals or northern human populations. Although, tropical regions show only little variation in temperature, climate and weather conditions can fluctuate with consequences for phenology and food resource availability. Here, we evaluate, whether the BSR of chimpanzees, inhabiting African tropical forests, is affected by climate fluctuations as well. Additionally, we evaluate, if variation in consumption of a key food resource with high nutritional value, Coula edulis nuts, is linked to both climate fluctuations and variation in BSR. We use long-term data from two study groups located in Taï National Park, Côte d'Ivoire to assess the influence of local weather conditions and the global climate driver El Niño Southern Oscillation (ENSO) on offspring sex. Côte d'Ivoire has experienced considerable climate variation over the last decades, with increasing temperature and declining precipitation. For both groups we find very similar time windows around the month of conception, in which offspring sex is well predicted by ENSO, with more males following low ENSO values, corresponding to periods of high rainfall. Furthermore, we find that the time spent cracking and feeding on Coula nuts is strongly influenced by climate conditions. Although, some of our analysis suggest that a higher proportion of males is born after periods with higher nut consumption frequency, we cannot conclude decisively at this point that nut consumption may influence shifts in BSR. All results combined suggest that also chimpanzees may experience climate related shifts in offspring sex ratios as response to climate fluctuation

Combining indoor residual spraying and insecticide-treated nets for malaria control in Africa: a review of possible outcomes and an outline of suggestions for the future

Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are currently the preferred methods of malaria vector control. In many cases, these methods are used together in the same households, especially to suppress transmission in holoendemic and hyperendemic scenarios. Though widespread, there has been limited evidence suggesting that such co-application confers greater protective benefits than either ITNs or IRS when used alone. Since both methods are insecticide-based and intradomicilliary, this article hypothesises that outcomes of their combination would depend on effects of the candidate active ingredients on mosquitoes that enter or those that attempt to enter houses. It is suggested here that enhanced household level protection can be achieved if the ITNs and IRS have divergent yet complementary properties, e.g. highly deterrent IRS compounds coupled with highly toxic ITNs. To ensure that the problem of insecticide resistance is avoided, the ITNs and IRS products should preferably be of different insecticide classes, e.g. pyrethroid-based nets combined with organophosphate or carbamate based IRS. The overall community benefits would however depend also on other factors such as proportion of people covered by the interventions and the behaviour of vector species. This article concludes by emphasizing the need for basic and operational research, including mathematical modelling to evaluate IRS/ITN combinations in comparison to IRS alone or ITNs alone

Changing Patterns of Malaria Epidemiology between 2002 and 2010 in Western Kenya: The Fall and Rise of Malaria

The impact of insecticide treated nets (ITNs) on reducing malaria incidence is shown mainly through data collection from health facilities. Routine evaluation of long-term epidemiological and entomological dynamics is currently unavailable. In Kenya, new policies supporting the provision of free ITNs were implemented nationwide in June 2006. To evaluate the impacts of ITNs on malaria transmission, we conducted monthly surveys in three sentinel sites with different transmission intensities in western Kenya from 2002 to 2010.Longitudinal samplings of malaria parasite prevalence in asymptomatic school children and vector abundance in randomly selected houses were undertaken monthly from February 2002. ITN ownership and usage surveys were conducted annually from 2004 to 2010. Asymptomatic malaria parasite prevalence and vector abundances gradually decreased in all three sites from 2002 to 2006, and parasite prevalence reached its lowest level from late 2006 to early 2007. The abundance of the major malaria vectors, Anopheles funestus and An. gambiae, increased about 5-10 folds in all study sites after 2007. However, the resurgence of vectors was highly variable between sites and species. By 2010, asymptomatic parasite prevalence in Kombewa had resurged to levels recorded in 2004/2005, but the resurgence was smaller in magnitude in the other sites. Household ITN ownership was at 50-70% in 2009, but the functional and effective bed net coverage in the population was estimated at 40.3%, 49.4% and 28.2% in 2010 in Iguhu, Kombewa, and Marani, respectively.The resurgence in parasite prevalence and malaria vectors has been observed in two out of three sentinel sites in western Kenya despite a high ownership of ITNs. The likely factors contributing to malaria resurgence include reduced efficacy of ITNs, insecticide resistance in mosquitoes and lack of proper use of ITNs. These factors should be targeted to avoid further resurgence of malaria transmission

Target product profile choices for intra-domiciliary malaria vector control pesticide products: repel or kill?

BACKGROUND\ud \ud The most common pesticide products for controlling malaria-transmitting mosquitoes combine two distinct modes of action: 1) conventional insecticidal activity which kills mosquitoes exposed to the pesticide and 2) deterrence of mosquitoes away from protected humans. While deterrence enhances personal or household protection of long-lasting insecticidal nets and indoor residual sprays, it may also attenuate or even reverse communal protection if it diverts mosquitoes to non-users rather than killing them outright.\ud \ud METHODS\ud \ud A process-explicit model of malaria transmission is described which captures the sequential interaction between deterrent and toxic actions of vector control pesticides and accounts for the distinctive impacts of toxic activities which kill mosquitoes before or after they have fed upon the occupant of a covered house or sleeping space.\ud \ud RESULTS\ud \ud Increasing deterrency increases personal protection but consistently reduces communal protection because deterrent sub-lethal exposure inevitably reduces the proportion subsequently exposed to higher lethal doses. If the high coverage targets of the World Health Organization are achieved, purely toxic products with no deterrence are predicted to generally provide superior protection to non-users and even users, especially where vectors feed exclusively on humans and a substantial amount of transmission occurs outdoors. Remarkably, this is even the case if that product confers no personal protection and only kills mosquitoes after they have fed.\ud \ud CONCLUSIONS\ud \ud Products with purely mosquito-toxic profiles may, therefore, be preferable for programmes with universal coverage targets, rather than those with equivalent toxicity but which also have higher deterrence. However, if purely mosquito-toxic products confer little personal protection because they do not deter mosquitoes and only kill them after they have fed, then they will require aggressive "catch up" campaigns, with behaviour change communication strategies that emphasize the communal nature of protection, to achieve high coverage rapidly

Malaria infection and disease in an area with pyrethroid-resistant vectors in southern Benin

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate baseline data on malaria before the evaluation of new vector control strategies in an area of pyrethroid-resistance of vectors. The burden of malaria was estimated in terms of infection (prevalence and parasite density) and of clinical episodes.</p> <p>Methods</p> <p>Between December 2007 and December 2008 in the health district of Ouidah - Kpomassè - Tori Bossito (southern Benin), a descriptive epidemiological survey of malaria was conducted. From 28 selected villages, seven were randomized from which a total of 440 children aged 0 to 5 years were randomly selected. Clinical and parasitological information was obtained by active case detection of malaria episodes carried out during eight periods of six consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic infection. Entomological information was also collected. The ownership, the use and the correct use of long-lasting insecticide-treated nets (LLINs) were checked over weekly-survey by unannounced visits at home in the late evening.</p> <p>Results</p> <p>Mean parasite density in asymptomatic children was 586 <it>P. falciparum </it>asexual forms per μL of blood (95%CI 504-680). Pyrogenic parasite cut-off was estimated 2,000 <it>P. falciparum </it>asexual blood forms per μL. The clinical incidence of malaria was 1.5 episodes per child per year (95%CI 1.2-1.9). Parasitological and clinical variables did not vary with season. <it>Anopheles gambiae </it><it>s.l</it>. was the principal vector closely followed by <it>Anopheles funestus</it>. Entomological inoculation rate was 5.3 (95%CI 1.1-25.9) infective bites per human per year. Frequency of the L1014F <it>kdr </it>(West) allele was around 50%. Annual prevalence rate of <it>Plasmodium falciparum </it>asymptomatic infection was 21.8% (95%CI 19.1-24.4) and increased according to age. Mean rates of ownership and use of LLINs were 92% and 70% respectively. The only correct use of LLINs (63%) conferred 26% individual protection against only infection (OR = 0.74 (95%IC 0.62-0.87), p = 0.005).</p> <p>Conclusion</p> <p>The health district of Ouidah-Kpomassè-Tori Bossito is a mesoendemic area with a moderate level of pyrethroid-resistance of vectors. The used LLINs rate was high and only the correct use of LLINs was found to reduce malaria infection without influencing malaria morbidity.</p

Monitoring mosquitoes in urban Dar es Salaam: Evaluation of resting boxes, window exit traps, CDC light traps, Ifakara tent traps and human landing catches

Ifakara tent traps (ITT) are currently the only sufficiently sensitive, safe, affordable and practical method for routine monitoring host-seeking mosquito densities in Dar es Salaam. However, it is not clear whether ITT catches represent indoors or outdoors biting densities. ITT do not yield samples of resting, fed mosquitoes for blood meal analysis. Outdoors mosquito sampling methods, namely human landing catch (HLC), ITT (Design B) and resting boxes (RB) were conducted in parallel with indoors sampling using HLC, Centers for Disease Control and Prevention miniature light traps (LT) and RB as well as window exit traps (WET) in urban Dar es Salaam, rotating them thirteen times through a 3 × 3 Latin Square experimental design replicated in four blocks of three houses. This study was conducted between 6th May and 2rd July 2008, during the main rainy season when mosquito biting densities reach their annual peak. The mean sensitivities of indoor RB, outdoor RB, WET, LT, ITT (Design B) and HLC placed outdoor relative to HLC placed indoor were 0.01, 0.005, 0.036, 0.052, 0.374, and 1.294 for Anopheles gambiae sensu lato (96% An. gambiae s.s and 4% An. arabiensis), respectively, and 0.017, 0.053, 0.125, 0.423, 0.372 and 1.140 for Culex spp, respectively. The ITT (Design B) catches correlated slightly better to indoor HLC (r(2) = 0.619, P < 0.001, r(2) = 0.231, P = 0.001) than outdoor HLC (r(2) = 0.423, P < 0.001, r(2) = 0.228, P = 0.001) for An. gambiae s.l. and Culex spp respectively but the taxonomic composition of mosquitoes caught by ITT does not match those of the indoor HLC (χ(2) = 607.408, degrees of freedom = 18, P < 0.001). The proportion of An. gambiae caught indoors was unaffected by the use of an LLIN in that house. The RB, WET and LT are poor methods for surveillance of malaria vector densities in urban Dar es Salaam compared to ITT and HLC but there is still uncertainty over whether the ITT best reflects indoor or outdoor biting densities. The particular LLIN evaluated here failed to significantly reduce house entry by An. gambiae s.l. suggesting a negligible repellence effect

Lung epithelium as a sentinel and effector system in pneumonia – molecular mechanisms of pathogen recognition and signal transduction

Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and lung epithelium comprises a large surface between host and environment and is attacked as a primary target during lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the lung epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics