Retention of flowable composite resins in comparison to pit and fissure sealants: a systematic review and meta-analysis.

Despite the worldwide decline in dental caries, pit and fissure caries remains a cause of concern, and application of pit and fissure sealants is an important preventive measure. Due to the high wear rate of conventional unfilled sealants, various other materials have been tested for fissure sealing. The present meta-analysis was conducted to compare the effectiveness of flowable composite resins as a fissure sealant to that of conventional pit and fissure sealants. A literature search was performed in MEDLINE, Cochrane Database of Systematic Reviews, and Google Scholar. Clinical trials comparing the efficacy of flowable composite resins as fissure sealants to that of conventional pit and fissure sealants on permanent teeth with a follow-up of 12 or 24 months were included in this meta-analysis. The retention rates of the 2 groups were evaluated with a random-effects model using Cochrane Reviews software (Cochrane RevMan, version 5.3). Seven studies were included in the final review. Flowable composite resins proved to be a significantly better fissure-sealing material after 1 year of follow-up (odds ratio = 0.47; 95% CI = 0.22-1.01; P = 0.05; degree of inconsistency [I2] = 59%). The retention rates of flowable composite resins at the end of 2 years were similar to those of conventional pit and fissure sealants (odds ratio = 0.71; 95% CI = 0.13-3.95; P = 0.70; I2 = 85%). Flowable composite resins proved to be a superior alternative to conventional sealants after 1 year of follow-up; however, no such difference between the 2 groups was observed after 2 years of follow-up. Further longitudinal studies should be conducted to evaluate the long-term retention and efficacy of flowable composite resins in fissure sealing.

Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn's Disease and Determines Their Capacity to Suppress Th1 Cells.

Background and Aims: The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. Methods: Tissues and cells derived from Crohn's disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. Results: A significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses. Conclusion: We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.

Early induction of interleukin-10 limits antigen-specific CD4⁺ T cell expansion, function, and secondary recall responses during persistent phagosomal infection.

Diverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4(+) T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4(+) T cells during persistent Ehrlichia muris infection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistent Ehrlichia infection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4(+) T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4(+) T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4(+) T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4(+) T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4(+) T cells may provide a basis to induce a protective immune response against persistent infections.

Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection.

There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1(-/-)-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2(-/-)-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.

Genetic association, seasonal infections and autoimmune basis of narcolepsy.

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

Allergenicity assessment of osmotin, a pathogenesis-related protein, used for transgenic crops.

Genetic engineering can enhance abiotic stress tolerance of plants, thereby increasing productivity. The present study investigates allergenicity of osmotin protein used for developing transgenic crops. Bioinformatic analysis of osmotin was performed using SDAP and Farrp allergen databases. Osmotin was cloned in pET22b+ vector, purified to homogeneity, and analyzed for digestibility, heat stability, and IgE binding using atopic patients' sera. Osmotin showed 40-92% and 48-75% homology with allergens in SDAP and Farrp databases, respectively. These cross-reactive allergens were from apple, tomato, peach, capsicum, kiwi fruit, and cypress. Osmotin was resistant to pepsin digestion and heat treatment at 90 °C for 1 h. Osmotin protein showed dose-dependent inhibition with pooled patients' sera. It showed significant IgE binding with 22 of 117 patients' sera who were sensitized to tomato and apple, thus indicating cross-reactivity among tomato, apple, and osmotin allergens. In conclusion, osmotin was identified as a potential allergen and showed cross-reactivity with tomato and apple allergens.

A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

The role of costimulatory molecules in allergic disease and asthma.

The prevalence of allergic diseases has increased rapidly in recent years. It is well established that the deleterious allergic response is initiated by T-cell recognition of major histocompatibility class II-peptide complexes at the surface of antigen-presenting cells. While this first signal gives antigen specificity to the adaptive immune response, a second nonspecific costimulatory signal is required by T cells to become fully activated. This signal is provided by interactions between antigen-presenting cells and T cells through molecules borne at the surfaces of the two cell types. Depending on the type of molecules involved, this secondary signal can promote the development of an inflammatory allergic reaction or may favor immune regulation. Several molecules of the B7 family (CD80, CD86, PD-1, ICOS, CTLA-4) and tumor necrosis factor receptor family (OX40, CD30, 4-1BB, Fas, CD27, CD40) play an important role in delivering costimulatory signals in early and late phases of allergic response. Therefore, costimulatory molecules involved in promotion or prevention of allergic immune responses are potential targets for the development of novel therapeutic approaches. This review aims to recapitulate our current understanding of the relationship between allergic diseases and costimulatory molecules.

Safety assessment of leaf curl virus resistant tomato developed using viral derived sequences.

Genetic engineering of food crops has significantly influenced the agricultural productivity over the past two decades. It has proved a valuable tool, offering crops with higher yields, improved nutritional quality, resistance against pesticides, herbicides and tolerance against abiotic stresses. However, the safety assessment of genetically engineered (GE) crops is prerequisite before introduction into human food chain. The present study was aimed to assess the toxicity and allergenicity of leaf curl virus resistant GE tomato compared to its wild-type species. Balb/c mice fed with genetically engineered or wild-type tomato did not show significant differences in growth, body weight (P > 0.05) and food consumption when compared with control mice. Values for serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase, urea and cholesterol were comparable in GE and wild-type tomato fed mice. Mice immunized with GE or wild-type tomato extract showed low IgE response. Lung histology of ovalbumin fed mice showed bronchoconstriction with eosinophilic infiltration whereas GE or wild-type tomato showed no cellular infiltration with normal airways. Genetically engineered and wild-type tomato sensitized mice demonstrated similar IL-4 release in splenic cell culture supernatant. GE and wild tomato extract on ELISA showed comparable IgE binding (P > 0.05) with food allergic patients' sera. In conclusion, genetically engineered tomato showed no toxicity in mice and allergenicity is similar to the wild-type tomato.

Safety assessment of bacterial choline oxidase protein introduced in transgenic crops for tolerance against abiotic stress.

Genetically modified crops have resistance to abiotic stress by introduction of choline oxidase protein. In the present study, the safety of choline oxidase protein derived from Arthrobacter globiformis was assessed for toxicity and allergenicity. The protein was stable at 90 degrees C for 1 h. Toxicity studies of choline oxidase in mice showed no significant difference (p > 0.05) from control in terms of growth, body weight, food consumption, and blood biochemical indices. Histology of gut tissue of mice fed protein showed normal gastric mucosal lining and villi in jejunum and ileum sections. Specific IgE in serum and IL-4 release in splenic culture supernatant were low in choline oxidase treated mice, comparable to control. Intravenous challenge with choline oxidase did not induce any adverse reaction, unlike ovalbumin group mice. Histology of lung tissues from choline oxidase sensitized mice showed normal airways, whereas ovalbumin-sensitized mice showed inflamed airways with eosinophilic infiltration and bronchoconstriction. ELISA carried out with food allergic patients' sera revealed no significant IgE affinity with choline oxidase. Also, choline oxidase did not show any symptoms of toxicity and allergenicity in mice.