Tan et al.  demonstrated that hMPV induces an impaired allo-stimulatory function of dendritic cells, consequently causing a poor production of inflammatory cytokines. In contrast, Guerrero- Plata et al.  showed that hMPV-infected moDCs did not significantly inhibit T cell proliferation. They also demonstrated that RSV and hMPV differentially activate human DCs. Both viruses were able to mature moDCs characterized by an up- regulation of antigen-presenting and co-stimulatory molecules, however, only RSV-infected moDCs led to impaired T cell activation. This finding has also been observed by de Graaff et al.  including data demonstrating a failure for T cell activated by RSV-DC to produce IFN-c. hMPV is a major respiratory pathogen in infants and inthe elderly as well as RSV, two genetically distinct members of the Paramyxoviridae family that cause indistinguishable clinical symptoms. However, data dis- cussed previously, demonstrate a difference intheimmuneresponse. It is interesting that, unlike RSV, hMPV did not stimulate the production of inflammatory cytokines, hMPV- infected DC were able to stimulate T cells  but did elicit identical inflammatory symptoms of similar  or milder severity . A critical question raised by these studies is the different properties of hMPV isolates used to infect and replicate into APCs. In tissue culture, growth of hMPV is slow and requires the addition of trypsin to the media to efficiently propagate the virus [1,4]. This difficulty and the adaptation of the virus strain invitro may explain the paradigm of the results obtained by Guerrero- Plata et al. and Tan et al. in their studies.
We also showed that M2-2 deletion led to the induction of pro- inflammatory and antiviral mediators by hMPV (Fig. 2). By investigating the nuclear translocation of regulatory transcription factors, we found that M2-2 inhibited the activation of p65 and IRF-7, while M2-2 was not involved in IRF-3 activation. IRF-7 is a MyD88-interacting protein and gets activated by TLR9 agonist or DNA virus infection [30,32,42]. In addition to MyD88- activated IRF-7, Banos-Lara et.al., has recently demonstrated that MDA5/IRF-3 pathway also played a role in IRF-7 expression in hMPV-infected mice bone marrow-derived DC (BMDC) . We think that M2-2 likely suppressed IRF-7 activation by targeting MyD88, at least at the early time points p.i., but not by regulating IRF-3 activation for three reasons: First, IRF-7 activation by hMPV occurred earlier than IRF-3 activation. Second, IRF-39s nuclear translocation was not affected by M2-2 (Fig. 3). Third, M2-2 interacted with MyD88 (Fig. 5). Enhanced IRF-7 activation by M2-2 deletion at early time p.i. was also consistent to increased induction of IFN-a by M2-2 deletion (Fig. 2B). Since TRIF did not play a major role in hMPV-induced cytokine/chemokine secretion (Fig. S2), MyD88/TRIF pathway might play a minimal role in IRF-3 activation at 15 h p.i. Although MDA5-dependent pathway is critical for IRF-3 activation by hMPV in BMDC , and we have previously shown that MAVS, a downstream adaptor of MDA5, is a target of M2-2 in airway epithelial cells , we did not observe the change in IRF-3 activation by M2-2 (Fig. 3C). Unaffected IRF-3 activation by M2-2 deletion in moDC suggested that MDA5-MAVS may not be important for IRF-3 activation inhuman DC, or the targeting effect of M2-2 on MAVS is cell type- dependent. Since IRF-7 is an IFN-inducible protein , greater IRF-7 expression and consequent enhanced nuclear translocation of IRF-7 at a late time point p.i. might also result from IFN signaling pathway, which was likely to be activated by IFN induction at early time points p.i. Therefore, M2-2-inhibited IRF- 7 activation at 15 h p.i. might result from suppressed MyD88/ IRF-7 and/or IFN signaling pathways.
Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating theinflammatoryresponse. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immuneresponse to viral infection, following treatment of airway epithelial cells with IFN c and influenza virus. The synergism also occurred when the cells were treated with IFN c and a viral replication mimicker (dsRNA) both invitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn’t affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFkB sites, western blot analysis indicated that the combined treatment of IFN c and dsRNA significantly augmented NFkB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN c and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFkB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.
calculated from the cumulative mortality of G. mellonella on day 2 due to P. aeruginosa septicaemia (Jarosz, 1994). Overnight broth cultures of the bacterial pathogen were microbiologically standardized by the agar colony count, and a cell suspension of the required density (about 0,3x10 2 in 2 µl for pupae) was prepared in saline W (Weevers, 1966) a physiological salt solution for Lepidoptera. During the 24 h post- immunization, pupae of G. mellonella treated with an immunosuppressant were challenged with twelve to fifteen lethal viable cells of the insect bacterial parasite. The insects that had been immunized with the P. aeruginosa LPS but not given the immunosuppressant were also challenged with a multifold lethal dose of living cells of P. aeruginosa. The onset of the disease was observed then and mortality due to Pseudomonas saepticaemia was recorded daily.
sensitive to cathepsin B inhibition and to the blockade of phagocytosis. These findings agree with the activation of cathepsin B by b-glucans  and with the inhibitory effect of cytochalasin D on cytokine production in DC stimulated with particulate b- glucans reported by Rosas et al. , who concluded that inhibition of cytoskeletal assembly by cytochalasins impides the contact with particles. A study addressing caspase recruitment domain- containing protein (CARD)9 by dectin-1 signaling showed that it is possible to distinguish signals downstream Syk such as activation of p38 MAPK, which can occur inthe absence of cytokine production, and signals dependent on Syk/CARD9/NF-kB associated with cytokine production . In other words, the dectin-1 route can promote CARD9 phagosomal translocation and enhance TLR-induced cytokine production even though dectin-1 signaling is insufficient to drive cytokine production. As it has been reported that phagosomal degradation increases TLR access to ligands , it seems likely that a similar mechanism may be operative following zymosan phagocytosis, thus agreeing with the recognition of Aspergillus conidia by dectin-1 in acidified phagolysosomes .
As the multinomial model is non-linear, the marginal effect of the treatment in a DID model is not the marginal impact of the interaction between time and treatment, but the difference of the cross-differences, as described by Puhani (2012). The results of Table 7 (in terms of marginal effects) show that the BVJ has a significant effect on the probability studying and working at the same time, but not on the other outcome variables. The estimated marginal effects mean that the probability of a youngster studying and working increases by 4.2 percentage points with the BVJ, compared with a baseline of 30% inthe control group in 2006. The estimated coefficients for the categories ‘studying only’ and ‘working only’ were negative but not statistically significant. It seems, therefore, that treated adolescents do not quit their jobs to study because of the program, but do both activities at the same time. This raises questions about the long run impacts of the program, since the quality of the night classes is notoriously low in Brazil.
All bronchoscopies were performed trans-orally by one very experienced bronchoscopist who is a board-certified Clinical Specialist in Respiratory Medicine (Smith, M.E.) with the subject in supine position. We utilized a slightly modified version of a previously published endotoxin exposure protocol [1,21]. Briefly, ketobemidonhydroklorid (2.5 to 7.5 mg depending on clinical conditions) was given as pre-medication, followed by a nebulized local anaesthesia sprayed into the oropharynx (xylocaine 10 mg/ dose, 362 doses). Additional local anaesthesia was given as needed through the bronchoscope (xylocaine 20 mg/mL, up to 14 mL). Endobronchial photographs were taken bilaterally during B.I and B.II to ensure that the BAL sampling was performed inthe same bronchial segments that had been exposed to endotoxin or vehicle. The following procedures were applied for B.I: A balloon-tipped catheter was inserted through the bronchoscope, placed in a bronchial segment (either right middle lobe or lingula) and inflated with air to seal off the chosen segment proximally before challenge. The instillation of vehicle (10 mL of 0.9% phosphate- buffered saline, PBS) and inflation of a small volume of air (10 mL) into the bronchial segment was then conducted. The broncho- scope was subsequently retracted and transferred to the corre- sponding segment inthe contra-lateral lung. The sealing off- procedure was followed by instillation of endotoxin (USP reference standard endotoxin from Eschericia coli 0113: H10, from USP, Rockville, MD, USA) and inflation of air (10 mL). Endotoxin was given in a dose proven both efficacious and clinically safe (4 ng/kg diluted with PBS up to 10 mL of fluid) . Finally, the bronchoscope was subsequently retracted and the head end of the operating table was immediately elevated 30 u with the subject in place during one hour (h) to minimize spread of instilled fluid from the challenged segments.
cell count and levels of cortisol was found in patients who did not suffer from IRIS. This correlation was suggested to indicate a more controlled clinical response of the HIV-infected patients (27). The results showed that plasma cortisol concentrations were similar before and after ART in all the patients studied. It was suggested that patients experiencing IRIS could present an inadequate HPA axis response (1). Previous reports have suggested an intra-adrenal shift from DHEAS towards the cortisol production during critical illness (28-30), as could be the case of HIV infected patients who suffered IRIS. It has been proposed that an exacerbated proinflammatory response could result from the suppression of the HPA axis and of adrenal failure or reflect glucocorticoid tissue resistance as well (31,32). This clinical disorder is known as critical illness-related corticosteroid insufficiency resulting from an inadequate corticosteroid production or action for such severe disease (32,33). In agreement with the previous idea, patients with adrenal insufficiency could present an altered regulation of theimmune system, which has been linked to IRIS (34). The fact that plasma levels of DHEA-S, which are mainly of adrenal origin, did not significantly change in non-IRIS-P after ART, but rather decreased more than 20% in IRIS-P with respect to values before treatment, could reflect a more impaired adrenal function in IRIS-P than in non-IRIS-P. These results are consistent with
Neutrophils were rare compared with the other cells analysed in this study and were present at similar num- bers in all types of lesions. Several studies have evalu- ated neutrophils in leishmaniasis, especially inthe early phase of the disease. However, some of the reports are controversial. For example, neutrophils may contribute to protection from the disease, but may also be important for the immunopathology (Müller et al. 2001, Aga et al. 2002, Laskay et al. 2003, von Stebut 2007, Afonso et al. 2008, Daboul 2010). Some studies have suggested that Leishmania can use neutrophils to invade macrophages
Trip time includes en route time for a two-way voyage, standstill time and loading, unloading and non operational time. In this study we assume that average standstill time for loading, unloading and non operating time is 3,5 days per voyage for a tanker with the deadweight up to 100 000 t Time en route is determined by the length of a lane and vessel effective velocity. The term ―effective velocity‖ implies the fact that a vessel spends certain amount of time on waiting for improvement in weather, vessel ice scrabbling in heavy conditions etc. Both length of route and effective velocity depend on current ice conditions and weather that may differ from one trip to another. Methods of simulation modeling and statistical data are appropriative to estimate enroute time for a particular lane.
I think we can answer this question inthe positive: Yes, He can, because He is the most perfect being and His omnipotence is absolutely unlimited. A very important premise underlying the answer to the last question is that the risk is not so great, or even that it is very small. It is so because the nature and mechanism of the created world ensure with a very high proba- bility that all purposes intended by God will be attained without his causal action inthe processes occurring inthe world. The emergence of life inthe universe is almost inevitable, because the universe is large and old enough, and biochemical mechanisms are very effective. The emergence of sentient beings was also almost inevitable because of longstanding and countless mutations and adaptations of living organisms to their environment. All this was very probable and hence in a sense necessary (inevitable). The great advantage of the non-deterministic world is its own creativity, which is possible because of the chance events happening in a way restricted only by the laws of nature. Thus, if one evolutionary path fails another one is opened. Perhaps a mutation suitable for the growth and development of a given species happened by chance and enabled it to survive in hard con- ditions and further develop. Elasticity and redundancy are very typical for the world of chance, but because of these properties, this world has a large number of possibilities and abilities to develop and regenerate after various natural catastrophes (Łukasiewicz 2006).
proliferative responses of a variety of immune cell types [18–19] inresponse to microbial and self-antigens [20–21]. Previous studies analyzing the role of Tregs in IRIS conducted using a cross- sectional study design did not show any differences in their levels between IRIS and non-IRIS cases [22–23]. However, Seddiki et al., reported that the suppressive ability of Tregs in M.avium IRIS cases was lower than that observed in non-IRIS cases . The clinical resemblance of IRIS to paradoxical reactions, or a hyperactive immune system, suggests that the balance between immune activation and regulation is disturbed early on during ART. Using a prospective longitudinal study design we focused on the dynamics of Tregs following ART initiation and tested the hypothesis that (all-cause) IRIS results from a relative delay inthe reconstitution of FOXP3 positive T regulatory cells. In addition, we assessed whether baseline plasma cytokines could predict the occurrence of IRIS after initiation of ART. The results from this study argue against a significant role for Treg levels, either proportions or absolute numbers, as predictors of the development of IRIS.
Variation in serum cortisol levels and antibody titers in cattle were obtained exclusively from diets and stress conditions employed. Baseline cortisol levels at the beginning of the experiment (day 0) were near the 3.29-µg/dL reference value for Zebu cattle and 3.68 µg/dL for the Nelore breed (20-22). In addition, blood samples from day 0 were not positive for rabies, indicating that animals had no prior contact with the rabies virus or vaccine. Finally, selenium from paddock forage did not affect the results, since its value comprised only half of the 0.1 mg/kg concentration recommended by the National Research Council (NRC) to supply beef cattle needs (23).
which involve hypoxia-inducible factor 1 (HIF-1) (2,6).The HIF-1 is a local regulator especially related to angiogenesis but is also receiving prominence by modulating osteoclastogenesis and osteoclastic activity (9,10). HIF1A gene encodes the alpha subunit of transcription factor HIF- 1α, which regulates oxygen dependent gene transcription (4,7). Inthe hypoxia signaling pathway HIF-1 α plays a major role. This factor is O2-sensitive, and inthe presence of O2, HIF-1 α is hydrolysed and degraded. During hypoxia, HIF1A is stabilized and translocated to the nucleus where it induces transcription of hypoxia-regulated genes, particularly associated with increased angiogenesis (10). However, it has been reported that HIF-1α is also involved inthe regulation of the osteoclastogenesis and osteoclast activation (2,6,9,10).
The samples were remelted on the surface with the electric arc with the use of the FALTIG 315AC/DC apparatus. The single remelting was applied. The treatment parameters were used: amperage of the electric arc I = 100 A, speed of the electrode movement v=200 mm/min. As the plasma formative gas, the argon was used. The treatment has been conducted at the depart- ment of Foundry and Welding of Rzeszow University of Tech- nology. After the remelting, there has been the conventional tempering done 1x1 hour in a temperature of 200°C for the steel C90 and 2x2 hours inthe temperature of 560 °C for the steel HS 6- 5-2. Parameters of tempering (temperature, time and multiplicity) of the tested steels were selected according to the standard PN-EN ISO 4957:2002U. The microhardeness measurements were made with the Hanemanna objective mph 100. The load used was 0,064 N, the operating time of the load was 10 s. Metallographic tests were conducted on the optical microscope - Neophot 2 and Tesla BS-340 electronic scanning microscope.
DNA-binding activity starting 10 minutes after the injection of flagellin. Such immediate response supports the hypothesis that cardiac inflammation was a direct consequence of flagellin-heart interactions rather than an indirect effect due to the remote generation of inflammatory mediators. Furthermore, NF-kB activation occurred at very low concentrations of flagellin, as indicated by a threshold-inducing dose of 10 ng/mouse (0.4 m g/ kg), which are clinically relevant, given that plasma levels of free circulating flagellin between 2 and 16 m g/l have been detected in humans with septic shock . Overall, these findings indicate that the heart is equipped to immediately recognize circulating flagellin with high sensitivity, implying that this bacterial protein may represent a particularly critical danger signal in this organ.
Tobacco, alcohol, and betel quid are the main causes of squamous cell cancers of the upper aerodigestive tract. These substances can cause multifocal carcinogenesis leading to multiple synchronous or metachronous cancers of the oesophagus, head and neck region, and lungs (‘ield cancerisation’). Globally there are several million people who have survived either head and neck squamous cell cancer (HNSCC) or lung cancer (LC). HNSCC and LC survivors are at increased risk of developing second primary malignancies, including second primary cancers of the oesophagus. The risk of second primary oesophageal squamous cell cancer (OSCC) ranges from 8-30% in HNSCC patients. LC and HNSCC survivors should be ofered endoscopic surveillance of the oesophagus. Lugol chromoendoscopy is the traditional and best evaluated screening method to detect early squamous cell neoplasias of the oesophagus. More recently, narrow band imaging combined with magnifying endoscopy has been established as an alternative screening method in Asia. Low-dose chest computed tomography (CT) is the best evidence- based screening technique to detect (second primary) LC and to reduce LC-related mortality. Low-dose chest CT screening is therefore recommended in OSCC, HNSCC, and LC survivors. In addition, OSCC survivors should undergo periodic pharyngolaryngoscopy for early detection of second primary HNSCC. Secondary prevention aims at quitting smoking, betel quid chewing, and alcohol consumption. As ield cancerisation involves the oesophagus, the bronchi, and the head and neck region, the patients at risk are best surveilled and managed by an interdisciplinary team.
Human neurocysticercosis (NC) is caused by the establishment of Taenia solium larvae inthe central nervous system. NC is a severe disease still affecting the population in develop- ing countries of Latin America, Asia, and Africa. While great improvements have been made on NC diagnosis, treatment, and prevention, the management of patients affected by extraparenchymal parasites remains a challenge. The development of a T. solium NC experimental model in pigs that will allow the evaluation of new therapeutic alternatives is herein presented. Activated oncospheres (either 500 or 1000) were surgically implanted inthe cerebral subarachnoid space of piglets. The clinical status and the level of serum anti- bodies inthe animals were evaluated for a 4-month period after implantation. The animals were sacrificed, cysticerci were counted during necropsy, and both the macroscopic and microscopic characteristics of cysts were described. Based on the number of established cysticerci, infection efficiency ranged from 3.6% (1000 oncospheres) to 5.4% (500 onco- spheres). Most parasites were caseous or calcified (38/63, 60.3%) and were surrounded by an exacerbated inflammatoryresponse with lymphocyte infiltration and increased inflamma- tory markers. The infection elicited specific antibodies but no neurological signs. This novel experimental model of NC provides a useful tool to evaluate new cysticidal and anti-inflam- matory approaches and it should improve the management of severe NC patients, refrac- tory to the current treatments.
Axisymmetric geometry of the investigated processes, allows considering one half of the billet, reducing calculation time this way. To carry out the simulation processes, DEFORM software was used. The billet material was considered as a plastic with the strain hardening defined on fig. 4. The mesh of the billet was fine enough to take into account all the asperities of the interface. As well as die, container and punch were treated as a rigid.