Role of MyD88-adaptor-like gene polymorphism rs8177374 in modulation of malaria severity in the Pakistani population

Abstract Introduction: The present study was designed to investigate the association between rs8177374 polymorphism and malaria symptoms due to exposure of Plasmodium vivax and Plasmodium falciparum. Materials and methods: A total of 454 samples were included in the study (228 malaria patients and 226 healthy individuals). Malaria patients, divided into P. vivax and P. falciparum groups on the basis of the causative species of Plasmodium, were categorized into mild and severe on the basis of clinical outcomes according to WHO criteria. Healthy individuals were used as controls. Allele specific PCR based strategy was used for the identification of rs8177374 SNP. Results: MyD88-adaptor-like gene polymorphism was associated with susceptibility to malaria (p < 0.001). C allele frequency (0.74) was higher in the population compared to T allele frequency (0.26). CT genotype increased the susceptibility of malaria (OR: 2.661; 95% CI: 1.722-4.113) and was positively associated with mild malaria (OR: 5.609; 95% CI: 3.479-9.044, p = 0.00). On the other hand, CC genotype was associated with severe malaria (OR: 3.116; 95% CI: 1.560-6.224, p = 0.00). P. vivax infection rate was higher in CT genotype carriers compared to other genotypes (OR: 3.616; 95% CI: 2.219-5.894, p < 0.001). Conclusion: MyD88-adaptor-like/TIR domain containing adaptor protein polymorphism for single nucleotide polymorphism rs8177374 is related with the susceptibility of malaria.

Minimally traumatic alveolar ridge augmentation with a tunnel injectable thermo-sensitive alginate scaffold

Injectable bone substitutes and techniques have been developed for use in minimally invasive procedures for bone augmentation. Objective : To develop a novel injectable thermo-sensitive alginate hydrogel (TSAH) as a scaffold to induce bone regeneration, using a minimally invasive tunnelling technique. Material and Methods : An injectable TSAH was prepared from a copolymer solution of 8.0 wt% Poly(N-isopropylacrylamide) (PNIPAAm) and 8.0 wt% AAlg-g-PNIPAAm. In vitro properties of the material, such as its microstructure and the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2), were investigated. Then, with the subperiosteal tunnelling technique, this material, carrying rhBMP-2, was injected under the labial periosteum of the maxillary anterior alveolar ridge in a rabbit model. New bone formation was evaluated by means of X-ray, micro-computed tomography (micro-CT), fluorescence labelling, histological study, and immunohistochemistry study. Results : The material exhibited good injectability and thermo-irreversible properties. SEM showed an interconnected porous microstructure of the TSAH. The result of ALP activity indicated sustained delivery of BMP-2 from the TSAH from days 3 to 15. In a rabbit model, both TSAH and TSAH/rhBMP-2 induced alveolar ridge augmentation. The percentage of mineralised tissue in the TSAH/rhBMP-2 group (41.6±3.79%) was significantly higher than in the TSAH group (31.3±7.21%; p<0.05). The density of the regenerating tissue was higher in the TSAH/rhBMP-2 group than in the other groups (TSAH group, positive control, blank control; p<0.05). Conclusions : The TSAH provided convenient handling properties for clinical application. To some extent, TSAH could induce ridge augmentation and mineral deposition, which can be enhanced when combined with rhBMP-2 for a minimally invasive tunnelling injection. .

Potential biomarkers for the clinical prognosis of severe dengue

Currently, several assays can confirm acute dengue infection at the point-of-care. However, none of these assays can predict the severity of the disease symptoms. A prognosis test that predicts the likelihood of a dengue patient to develop a severe form of the disease could permit more efficient patient triage and treatment. We hypothesise that mRNA expression of apoptosis and innate immune response-related genes will be differentially regulated during the early stages of dengue and might predict the clinical outcome. Aiming to identify biomarkers for dengue prognosis, we extracted mRNA from the peripheral blood mononuclear cells of mild and severe dengue patients during the febrile stage of the disease to measure the expression levels of selected genes by quantitative polymerase chain reaction. The selected candidate biomarkers were previously identified by our group as differentially expressed in microarray studies. We verified that the mRNA coding for CFD, MAGED1, PSMB9, PRDX4 and FCGR3B were differentially expressed between patients who developed clinical symptoms associated with the mild type of dengue and patients who showed clinical symptoms associated with severe dengue. We suggest that this gene expression panel could putatively serve as biomarkers for the clinical prognosis of dengue haemorrhagic fever.

O polimorfismo do antagonista do receptor da interleucina-1 (IL1RN) como fator contribuinte para gravidade da cardite reumática em brasileiros / Interleukin-1 receptor antagonist gene (IL1RN) polymorphism as a contributing factor for the severity of rheumatic carditis in a brazilian cohort

A febre reumática (FR) é uma doença imuno-mediada, na qual citoquinas pró-inflamatórias têm um importante papel. Uma produção exacerbada de interleucina-1 (IL-1) parece ser um evento precoce entre as anormalidades imunológicas observadas na FR. O antagonista do receptor de IL-1 (IL1-RA) é um inibidor competitivo endógeno do receptor da IL-1. A razão IL-1RA/IL-1 é importante na determinação da intensidade e duração da resposta inflamatória. O alelo 2 (A2) do gene codificador do IL1-RA (IL1RN) tem sido relacionado a um número de doenças inflamatórias e autoimunes, bem como a uma maior resistência a infecções. Considerando que a FR é uma doença inflamatória autoimune desencadeada por uma infecção bacteriana, nós avaliamos o polimorfismo do IL1RN com o intuito de determinar possível relevância na susceptibilidade à FR e suas manifestações clínicas. O genótipo de 84 pacientes com FR e 84 controles pareados por raça foram determinados através da análise do número de repetições em tandem de 86pb no segundo íntron do IL1RN. O DNA foi extraído de leucócitos de sangue periférico e amplificado com sondas específicas. Dados sobre as manifestações clínicas da FR foram obtidos através de questionários padronizados e extensa revisão de prontuários. Cardite foi definida como sopro cardíaco novo auscultado por médico treinado com a correspondente regurgitação ou estenose valvar ao ecocardiograma. Cardite foi definida como grave na presença de insuficiência cardíaca congestiva ou da indicação de cirurgia cardíaca. A associação estatística entre genótipos, FR e suas variações clínicas foram determinadas. A presença do alelo 1 (A1) e do genótipo A1/A1 foram menos freqüentemente encontradas entre pacientes com cardite severa quando comparado a pacientes sem esta manifestação (OR= 0.11, p=0.031; OR= 0.092, p=0.017)...

Rheumatic fever (RF) is an immune-mediated disease in which proinflammatory cytokines play an important role. Exacerbated Interleukin-1 (IL- 1) production seems to be an early event in the immunological abnormalities that are observed in RF. The Interleukin-1 receptor antagonist (IL-1ra) is an endogenous competitive inhibitor of IL-1. The IL-1ra/IL-1 ratio is important in evaluating the intensity and duration of the inflammatory response. The second allele (A2) for the IL-1ra gene (IL1RN) has been related to a number of inflammatory and autoimmune diseases as well as to a greater resistance to infections. Considering that RF is an inflammatory autoimmune disease that is triggered by a bacterial infection, we have evaluated the IL1RN polymorphism and its possible relevance to the susceptibility to RF and its clinical manifestations. The genotypes of 84 RF patients (Jones criteria) and 84 normal race-matched controls were determined through the analysis of the number of 86-bp tandem repeats in the second intron of IL1RN. The DNA was extracted from peripheral-blood leukocytes and amplified with specific primers. Clinical manifestations of RF were obtained through a standardized questionnaire and an extensive chart review. Carditis was defined as new onset cardiac murmur that was perceived by a trained physician with corresponding valvae regurgitation or stenosis on echocardiogram. Carditis was classified as severe in the presence of congestive heart failure or upon the indication for cardiac surgery. The statistical association among the genotypes, RF and its clinical variations was determined. The presence of allele 1 and the genotype A1/A1 were found less frequently among patients with severe carditis when compared to patients without this manifestation (OR= 0.11, p=0.031; OR= 0.092, p=0.017). Neither allele 1 nor allele 2 were associated with the presence of RF (p=0.188; p=0.106), overall carditis (p=0.578 and p=0.767), polyarthritis (p=0.343 and p=0.313) and chorea (p=0.654 and p=0.633). In conclusion, for this Brazilian cohort, the polymorphism of the IL-1ra gene is a relevant factor for rheumatic heart disease severity.

Interleukin-2 receptor serum concentrations in normal pregnancy and pre-eclampsia

The purpose of this research was to assess interleukin-2 receptor serum levels in normal pregnancy and pre-eclampsia. Sera from 90 healthy pregnant women (30 for each trimester), 30 with pre-eclampsia and a group of 30 healthy non-pregnant were analyzed. Soluble interleukin-2 receptor was measured by specific double antibody enzymatic immunoassay (ELISA). Results were: 267.5 +/- 12.3 (mean +/- s.e.m) pg/mL in the uncomplicated first trimester sample, 300.9 +/- 14.5 pg/mL in the second trimester and 248.8 +/- 12.5 pg/mL in the third. The non-pregnant control group had 443.7 +/- 39.6 pg/mL, significantly different from normal pregnancy in all trimesters (p < 0.001). The concentration in pre-eclamptic patients was 382.2 +/- 24.2 pg/mL, with p < 0.01 with regard to the normal third trimester group. The conclusion is that interleukin-2 receptor serum levels diminish in normal pregnancy and rise in preeclampsia. The first finding seems to be a protective mechanism to the fetal allograft. The latter, point to increased cellular activity.