Gastric cancer is associated with NOS2 -954G/C polymorphism and environmental factors in a Brazilian population

<p>Abstract</p> <p>Background</p> <p>Gastric cancer can progress from a chronic inflammation of the gastric mucosa resulting from <it>Helicobacter pylori </it>infection that activates the inflammatory response of the host. Therefore, polymorphisms in genes involved in the inflammatory response, such as inducible nitric oxide synthase (<it>NOS2</it>), have been implicated in gastric carcinogenesis. The aim of this study was to evaluate the association of <it>NOS2 </it>polymorphisms Ser⁶⁰⁸Leu (rs2297518) in exon 16, -954G/C and -1173C/T, both in the promoter region, with gastric cancer and chronic gastritis and the association of cancer with risk factors such as smoking, alcohol intake and <it>H. pylori </it>infection.</p> <p>Methods</p> <p>We conducted a population-based case-control study in 474 Southeast Brazilian individuals (150 with gastric cancer, 160 with chronic gastritis, and 164 healthy individuals), in which we performed <it>NOS2 </it>genotyping by PCR-RFLP.</p> <p>Results</p> <p>SNP Ser⁶⁰⁸Leu was not associated with risk of chronic gastritis or gastric cancer. The polymorphic allele -1173T was not found in the studied population. However, the frequency of -954GC+CC genotypes was significantly higher (p < 0.01) in the cancer group (48.7%) than in both the gastritis (28.1%) and the control (29.9%) groups. Multivariate logistic regression showed that the <it>NOS2 </it>SNP -954G/C was associated with higher risk of gastric cancer (OR = 1.87; 95% CI = 1.12-3.13). We also observed an association with risk factors such as smoking and alcohol intake in both the gastric cancer (OR = 2.68; 95% CI = 1.58-4.53; OR = 3.60; 95% CI = 2.05-6.32, respectively) and the chronic gastritis (OR = 1.93; 95% CI = 1.19-3.13; OR = 2.79; 95% CI = 1.55-5.02, respectively) groups. This is the first report of increased risk of gastric cancer in association with the -954G/C polymorphism. These findings show that several polymorphisms in the promoter region of the <it>NOS2 </it>gene may contribute to the susceptibility to gastric cancer.</p> <p>Conclusions</p> <p>Polymorphism <it>NOS2 </it>-954 G/C, along with alcohol intake and tobacco smoking, is associated with gastric cancer. However, the <it>NOS2 </it>Ser⁶⁰⁸Leu polymorphism was not associated with gastric carcinogenesis. The <it>NOS2 </it>-1173C/T polymorphism was absent in the studied population.</p

Differential gene expression mediated by 15-hydroxyeicosatetraenoic acid in LPS-stimulated RAW 264.7 cells

<p>Abstract</p> <p>Background</p> <p>Given the immuno-modulatory activity of native haemozoin (Hz), the effects of constitutive Hz components on immune response are of interest. Recently, gene expression changes mediated by HNE and the synthetic analogue of Hz, beta-haematin (BH), were identified and implicated a significant role for lipid peroxidation products in Hz's activity. The study presented herein examines gene expression changes in response to 15(S)-hydroxyeicosatetraenoic acid (HETE) in a model macrophage cell line.</p> <p>Methods</p> <p>LPS-stimulated RAW 264.7 macrophage-like cells were treated with 40 μM 15(S)-HETE for 24 h, and microarray analysis was used to identify global gene expression alterations. Fold changes were calculated relative to LPS-stimulated cells and those genes altered at least 1.8-fold (<it>p </it>value ≤ 0.025) were considered to be differentially expressed. Expression levels of a subset of genes were assessed by qRT-PCR and used to confirm the microarray results.</p> <p>Results</p> <p>Network analysis revealed that altered genes were primarily associated with "lipid metabolism" and "small molecule biochemistry". While several genes associated with PPAR-gamma receptor-mediated signaling were differentially expressed, a number of genes indicated the activation of secondary signaling cascades. Genes related to cytoadherence (cell-cell and cell-matrix), leukocyte extravasation, and inflammatory response were also differentially regulated by treatment, supporting a potential role for 15(S)-HETE in malaria pathogenesis.</p> <p>Conclusion</p> <p>These results add insight and detail to 15-HETE's effects on gene expression in macrophage-like cells. Data indicate that while 15-HETE exerts biological activity and may participate in Hz-mediated immuno-modulation, the gene expression changes are modest relative to those altered by the lipid peroxidation product HNE.</p

Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life.

BACKGROUND: Factors driving inter-individual differences in immune responses upon different types of prenatal malaria exposure (PME) and subsequent risk of malaria in infancy remain poorly understood. In this study, we examined the impact of four types of PME (i.e., maternal peripheral infection and placental acute, chronic, and past infections) on both spontaneous and toll-like receptors (TLRs)-mediated cytokine production in cord blood and how these innate immune responses modulate the risk of malaria during the first year of life. METHODS: We conducted a birth cohort study of 313 mother-child pairs nested within the COSMIC clinical trial (NCT01941264), which was assessing malaria preventive interventions during pregnancy in Burkina Faso. Malaria infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. Supernatant concentrations of 30 cytokines, chemokines, and growth factors induced by stimulation of cord blood with agonists of TLRs 3, 7/8, and 9 were measured by quantitative suspension array technology. Crude concentrations and ratios of TLR-mediated cytokine responses relative to background control were analyzed. RESULTS: Spontaneous production of innate immune biomarkers was significantly reduced in cord blood of infants exposed to malaria, with variation among PME groups, as compared to those from the non-exposed control group. However, following TLR7/8 stimulation, which showed higher induction of cytokines/chemokines/growth factors than TLRs 3 and 9, cord blood cells of infants with evidence of past placental malaria were hyper-responsive in comparison to those of infants not-exposed. In addition, certain biomarkers, which levels were significantly modified depending on the PME category, were independent predictors of either malaria risk (GM-CSF TLR7/8 crude) or protection (IL-12 TLR7/8 ratio and IP-10 TLR3 crude, IL-1RA TLR7/8 ratio) during the first year of life. CONCLUSIONS: These findings indicate that past placental malaria has a profound effect on fetal immune system and that the differential alterations of innate immune responses by PME categories might drive heterogeneity between individuals to clinical malaria susceptibility during the first year of life

Evaluation of antibody response to Plasmodium falciparum in children according to exposure of Anopheles gambiae s.l or Anopheles funestus vectors

<p>Abstract</p> <p>Background</p> <p>In sub-Saharan areas, malaria transmission was mainly ensured by <it>Anopheles. gambiae </it>s.l. and <it>Anopheles. funestus </it>vectors. The immune response status to <it>Plasmodium falciparum </it>was evaluated in children living in two villages where malaria transmission was ensured by dissimilar species of <it>Anopheles </it>vectors (<it>An. funestus vs An. gambiae </it>s.l.).</p> <p>Methods</p> <p>A multi-disciplinary study was performed in villages located in Northern Senegal. Two villages were selected: Mboula village where transmission is strictly ensured by <it>An. gambiae </it>s.l. and Gankette Balla village which is exposed to several <it>Anopheles </it>species but where <it>An. funestus </it>is the only infected vector found. In each village, a cohort of 150 children aged from one to nine years was followed during one year and IgG response directed to schizont extract was determined by ELISA.</p> <p>Results</p> <p>Similar results of specific IgG responses according to age and <it>P. falciparum </it>infection were observed in both villages. Specific IgG response increased progressively from one-year to 5-year old children and then stayed high in children from five to nine years old. The children with <it>P. falciparum </it>infection had higher specific antibody responses compared to negative infection children, suggesting a strong relationship between production of specific antibodies and malaria transmission, rather than protective immunity. In contrast, higher variation of antibody levels according to malaria transmission periods were found in Mboula compared to Gankette Balla. In Mboula, the peak of malaria transmission was followed by a considerable increase in antibody levels, whereas low and constant anti-malaria IgG response was observed throughout the year in Gankette Balla.</p> <p>Conclusion</p> <p>This study shows that the development of anti-malaria antibody response was profoundly different according to areas where malaria exposure is dependent with different <it>Anopheles </it>species. These results are discussed according to i) the use of immunological tool for the evaluation of malaria transmission and ii) the influence of <it>Anopheles </it>vectors species on the regulation of antibody responses to <it>P. falciparum</it>.</p

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Design and Implementation of a Novel Web-Based E-Learning Tool for Education of Health Professionals on the Antibiotic Vancomycin

BACKGROUND: Traditional approaches to health professional education are being challenged by increased clinical demands and decreased available time. Web-based e-learning tools offer a convenient and effective method of delivering education, particularly across multiple health care facilities. The effectiveness of this model for health professional education needs to be explored in context.OBJECTIVES: The study aimed to (1) determine health professionals' experience and knowledge of clinical use of vancomycin, an antibiotic used for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and (2) describe the design and implementation of a Web-based e-learning tool created to improve knowledge in this area.METHODS: We conducted a study on the design and implementation of a video-enhanced, Web-based e-learning tool between April 2014 and January 2016. A Web-based survey was developed to determine prior experience and knowledge of vancomycin use among nurses, doctors, and pharmacists. The Vancomycin Interactive (VI) involved a series of video clips interspersed with question and answer scenarios, where a correct response allowed for progression. Dramatic tension and humor were used as tools to engage users. Health professionals' knowledge of clinical vancomycin use was obtained from website data; qualitative participant feedback was also collected.RESULTS: From the 577 knowledge survey responses, pharmacists (n=70) answered the greatest number of questions correctly (median score 4/5), followed by doctors (n=271; 3/5) and nurses (n=236; 2/5; P<.001). Survey questions on target trough concentration (75.0%, 433/577) and rate of administration (64.9%, 375/577) were answered most correctly, followed by timing of first level (49%, 283/577), maintenance dose (41.9%, 242/577), and loading dose (38.0%, 219/577). Self-reported "very" and "reasonably" experienced health professionals were also more likely to achieve correct responses. The VI was completed by 163 participants during the study period. The rate of correctly answered VI questions on first attempt was 65% for nurses (n=63), 68% for doctors (n=86), and 82% for pharmacists (n=14; P<.001), reflecting a similar pattern to the knowledge survey. Knowledge gaps were identified for loading dose (39.2% correct on first attempt; 64/163), timing of first trough level (50.3%, 82/163), and subsequent trough levels (47.9%, 78/163). Of the 163 participants, we received qualitative user feedback from 51 participants following completion of the VI. Feedback was predominantly positive with themes of "entertaining," "engaging," and "fun" identified; however, there were some technical issues identified relating to accessibility from different operating systems and browsers.CONCLUSIONS: A novel Web-based e-learning tool was successfully developed combining game design principles and humor to improve user engagement. Knowledge gaps were identified that allowed for targeting of future education strategies. The VI provides an innovative model for delivering Web-based education to busy health professionals in different locations