Unbalanced Response Research Articles

Effect of the antimicrobial peptide LL-37 on Toll-like receptors 2-, 3- and 4-triggered expression of IL-6, IL-8 and CXCL10 in human gingival fibroblasts

The antimicrobial peptide LL-37 is known to have a potent LPS-neutralizing activity in monocytes and macrophages. Recently, LL-37 in gingival crevicular fluids is suggested to be the major protective factor preventing infection of periodontogenic pathogens. In this study, we tried to address the effect of LL-37 on proinflammatory responses of human gingival fibroblasts (HGFs) stimulated with Toll-like receptor (TLR)-stimulant microbial compounds. LL-37 potently suppressed LPS-induced gene expression of IL6, IL8 and CXCL10 and intracellular signaling events, degradation of IRAK-1 and IκBα and phosphorylation of p38 MAPK and IRF3, indicating that the LPS-neutralizing activity is also exerted in HGFs. LL-37 also suppressed the expression of IL6, IL8 and CXCL10 induced by the TLR3 ligand poly(I:C). LL-37 modestly attenuated the expression of IL6 and IL8 induced by the TLR2/TLR1 ligand Pam 3CSK 4, but did not affect the expression induced by the TLR2/TLR6 ligand MALP-2. Interestingly, LL-37 rather upregulated the expression of IL6, IL8 and CXCL10 induced by another TLR2/TLR6 ligand FSL-1. Thus, the regulatory effect of LL-37 is differently exerted towards proinflammatory responses of HGFs induced by different microbial stimuli, which may lead to unbalanced proinflammatory responses of the gingival tissue to infection of oral microbes.

REGRESI LOGISTIK UNIVARIAT DENGAN DATA RESPON TIDAK SEIMBANG

In binary logistic regression problem it is common for the two classes to be imbalanced. One case is very rare compared to the other. This paper focus on determining Maximum Likelihood Estimator on univariate logistic regression for infinitely unbalanced data response. By finding the differential of log-likelihood equation that is resulted, its maximum depend on points given through their average . Thus we can substitute each given with or substituting all given with one . If we use normal distribution for given then the slope can be determined by simple formula where and each an average and variance for which . Keywords : Logistic Regression, MLE, Infinitely Unbalanced Data Response

A probiotic dairy product containing L. gasseri CECT5714 and L. coryniformis CECT5711 induces immunological changes in children suffering from allergy

The increase in the prevalence of allergic diseases in children has been attributed to an unbalanced immune response probably due to environmental factors. The immunoregulatory properties of probiotic bacteria could balance the disequilibrium in the immune response causing the allergic response. The aim of this study was to evaluate the immunological effects of the consumption of a dairy product containing two probiotic strains in children suffering from allergy. A double-blinded, randomized, control comparative study was performed with 44 allergic children. Children were randomly distributed in two groups, a control Yogurt and a Probiotic group. Both groups daily consumed 200 ml of a dairy fermented product for 3 months. The Yogurt group consumed a conventional yogurt, whereas the Probiotic group consumed a similar dairy product where Lactobacillus bulgaricus was substituted by a mixture of Lactobacillus gasseri CECT5714 and Lactobacillus coryniformis CECT5711 (at least 10(6) cfu/g each strain). Intestinal and immunological parameters were measured in fecal and blood samples. The consumption of the probiotic product induced a significant decrease in the level of IgE in plasma (p = 0.03) and an increase in CD4(+)/CD25(+) T regulatory cells (p = 0.01). The decrease in IgE was accompanied by a significant increase in mucosal IgA (p = 0.01). However, changes in other effector cells potentially involved in allergic reactions such as eosinophiles, basophiles or other IgE+ cells were not detected. The consumption of the probiotic product also induced significant changes in innate response as a significant increase in natural killer cells was detected (p = 0.03). The daily consumption of a probiotic product containing L. gasseri CECT5714 and L. coryniformis CECT5711 for 3 months induces, in allergic children, beneficial effects on immune parameters involved in the allergic response such as a reduction of IgE in plasma and an increase in regulatory T cells. The probiotic product also enhanced innate and specific immune parameters that may improve the general health status of children.

Experimental Chagas’ disease in orchiectomized Calomys callosus infected with the CM strain of Trypanosoma cruzi

The incidence and progression of disorders associated with an unbalanced immune response has among many factors the gender as a contributory factor. The aims of this work were to evaluate the effects of orchiectomy and the immune response during the experimental Trypanosoma cruzi infection. Young adult, male Calomys callous were i.p. inoculated with 1 × 10 5 blood trypomastigotes of the CM strain of T. cruzi and divided in groups: Control, Sham and Castrated. Castrated group displayed significantly lower values for prostate and seminal vesicle weights indicating a drastic drop of testosterone plasmatic levels. Orchiectomized animals also displayed lesser number of blood parasites, enhanced lytic antibody percentage, splenocyte proliferation and NO concentration when compared to its sham and control counterparts, indicating that steroid gonadal ablation actually influences immune response triggering a more efficient cellular and humoral response which led animals to become more resistant against T. cruzi infection.

Non‐atopic intrinsic asthma and the ‘family tree’ of chronic respiratory disease syndromes

We present a scheme below in which the most common forms of inflammatory diseases of the respiratory tract, notably atopic and non-atopic asthma and COPD, are depicted as separate offshoots from a common 'at-risk' pathway underpinned by genotypes related to aberrations in control of host defence and tissue repair mechanisms. We propose that entrance into this pathway is initially programmed by environmental experience during infancy and early childhood, in particular by severe lower respiratory tract infection, and that further progression towards expression of specific disease phenotype(s) is determined by the nature, timing and frequency of additional environmental insults subsequently encountered. At the one extreme, early sensitization of at-risk subjects to aeroallergens can potentially drive rapid progression towards expression of the atopic asthmatic phenotype under the dual onslaught of inflammatory responses to allergens/pathogens. At the opposite end of the spectrum the drip-feed effects of occasional infections on respiratory function(s) are amplified over a longer time frame by inflammation resulting from exposure to tobacco smoke and/or related chemical pollutants. Non-atopic asthma is envisaged to fit between these two extremes, being driven essentially by the downstream effects of respiratory infections alone in at-risk subjects. An important common factor in all three disease phenotypes is that acute exacerbations are typically driven by infections, the host responses to which display a characteristic T-helper type 2-like footprint, which in our view points to underlying genotype(s) which result in unbalanced host responses to respiratory pathogens.

Atherosclerosis is an inflammatory disease

During the last decades, emerging evidence has shown that atherosclerosis is characterised by a complex endocrine, paracrine and juxtacrine cross-talk between immune and vascular cells as well as several tissues and organs, including the liver, heart, kidney, adipose tissue, adrenal, pancreatic, pituitary and sex glands [1]. Thus, atherosclerosis has to be considered as a “systemic disease”, characterised by arterial inflammatory lesions that mature and modify themselves with disease progression. Atherosclerotic plaques are the battlefield among an unbalanced immune response and lipid accumulation in the intima of arteries. Although the “first event” favouring early lipid deposition within the arterial sub-intimal space has not been identified, the infiltration of low-density lipoproteins (LDL) should be considered as the pivotal step in plaque formation [2]. Oxidative and enzymatic modifications of retained LDL increase the expression of adhesion molecules on endothelial cell surface membrane, thus favouring leukocyte recruitment from the blood stream [3]. Leukocytes recruitment within atherosclerotic plaques is also orchestrated by the chemokine binding to their receptors on cell membrane. This is a redundant system which regulates all inflammatory phases of atherogenesis in both humans and animals [4]. Monocytes have been defined by Weber et al. as the “crucial force” to drive atherogenesis [3]. In vivo monocyte inflammatory functions and differentiation are influenced by the different expression of chemokine receptors, CD14 and CD16. Two different monocyte subsets have been identified. Inflammatory monocyte subset (CXC3CR1 CCR2Ly6CCD14CD16) represents the main population recruited within the plaque from the blood stream and display both phagocytic and proteolytic activities. On the other hand, resident monocyte subset (CXC3CR1 CCR2Ly6CCD14CD16) is the main population involved in the initiation of tissue inflammation, angiogenesis and atheroprogression [3]. Modified LDL are uptaked by scavenger receptors of resident macrophages that differentiate into different inflammatory cell types, such as dendritic cells, foam cells, osteoclastand osteoblast-like cells. These processes are modulated by several cytokines and growth factors (such as receptor activator of nuclear factor [NF]kappaB ligand [RANKL], osteoprotegerin [OPG], tumour necrosis factor [TNF]alpha, granulocyte macrophage-colony stimulating factor [GM-CSF], macrophage-colony-stimulating factor [MCSF] and interleukin [IL]-4). On the other hand, connexins, which mediate gap junction formation between adjacent cells (vascular and immune cells), have been recently shown to playing a crucial role in cell differentiation and growth. Three different connexins (Cx37, Cx40 and Cx43) are differently expressed in macrophage and endothelial cells during atherosclerotic plaque maturation [5]. At this step, the non-specific immune response, mainly characterised by local monocyte/macrophage-mediated inflammatory processes has started. In a second phase, resident inflammatory and vascular cells further produce chemokines for the recruitment of T lymphocytes within the plaque. This induces the deleterious vicious circle of the Semin Immunopathol (2009) 31:1–3 DOI 10.1007/s00281-009-0146-7

The Quality of Guest Comment Cards

This study examines the quality of guest comment cards used by major U.S. lodging chains. To accomplish this objective, guidelines for comment card design were developed through a review of the relevant literature. The guidelines focus on eight issues: (1) return methods, (2) introductory statements, (3) contact information, (4) number of questions, (5) space for open comments, (6) number of response categories for closed-ended questions, (7) balanced versus unbalanced response categories for closed-ended questions, and (8) question wording. Using a sample of 63 lodging chains, the most common deviations from guidelines include a lack of secure return methods, the use of positively biased response categories, and insufficient writing space for open comments. To improve the quality of comment card feedback, these and other limitations should be corrected. Managerial implications and directions for future research are included.

Peripheral cytokine profile in Chilean patients with Crohn’s disease and ulcerative colitis

Crohn's disease (CD) and ulcerative colitis (UC) belong to the group of inflammatory bowel diseases (IBD), with complex ethiopathogenic factors that include an unbalanced immune and inflammatory response to commensal and food antigens. The differential diagnosis between CD and UC is performed using clinical, endoscopic, histopathological, serological and radiological methods; however between 10-15% of IBD patients are diagnosed as "unclassified colitis". Further research into IBD is necessary in order to develop additional diagnostic tools. The aim of this work was to see if the Th1, Th17 or Th2 immune pattern, represented by CD4+ lymphocytes producing IFN-gamma, IL-17 and IL-5 or IL-13, respectively (CD4/IFN-gamma+, CD4/IL-17+,CD4/IL-5+ or, CD4/IL13+), are useful peripheral markers which can be used to differentiate between UC and CD. Peripheral blood samples were taken from IBD patients from the Clinic Hospital of the University of Chile. The percentage of IFN-gamma-, IL-17-, IL-5- or IL-13-expressing CD4+ cells was determined by flow cytometry in phorbol ester- (PMA) and calcymycin-activated blood samples. The percentages of the CD4+ cell populations producing each cytokine were compared between UC and CD. IFN-gamma production by CD4+ lymphocytes was significantly higher in CD compared to UC and the control. The percentage of IL-17-expressing cells was significantly higher in CD patients compared to to the control; however, there were no differences between UC and CD; or between UC and healthy individuals. No significant differences were observed between the different groups as regards the representative Th2 cytokines. This study suggests that, under pathogenic conditions, several immune profiles may be operating, in the development of IBD. Although peripheral IFN-gamma and IL-17 expression, as indicators of the immune pattern, may help in the diagnosis of IBD, other cytokines and adaptive immune markers should be analyzed to allow better differentiation between the two entities.

T helper Type 2 Differentiation is Associated with Induction of Antibacterial Defense Mechanisms in Blood Lymphocytes of Patients with Sarcoidosis

Whereas sarcoidosis is characterized by an excessive inflammatory immune response mainly at the pulmonary site, circulating T lymphocytes poorly respond to antigen challenge. It has been suggested, that the extensive local inflammation might be triggered by bacterial pathogens. Recently, it has been shown that this paradoxically immunological situation likely results from a disequilibrium between effector and regulatory T lymphocytes (Treg). Here, we apply a DNA microarray approach in order to analyze circulating T cells for specific dysregulatory events, which should provide detailed insights in the impairment of cell-mediated immunity. Gene expression profiles were performed from peripheral blood T lymphocytes of untreated patients with pulmonary sarcoidosis (stage I) (n = 3) and a control group consisting of healthy donors (n = 3). Circulating T lymphocytes in sarcoidosis exhibit a specific gene expression pattern of molecules that are primarily involved in immune responses and lymphocyte signalling. Compared to controls patients with sarcoidosis display also alterations in gene expression of molecules with bacteriolytic and chemotactic function. Among others, array analysis resulted in increased transcript levels of Th2 immune response, whereas genes coding for molecules involved in Th1 differentiation are down-regulated. Furthermore, genes encoding proteins representing primordial antimicrobial peptides which may mobilise immunocompetent T cells and other inflammatory cells are up-regulated. This observation supports recent reports suggesting that bacterial antigens play a role in the pathogenesis of sarcoidosis. However, the results of our study indicate an unbalanced immune response towards Th2 in the peripheral blood of patients with sarcoidosis.

Sample Attrition Bias in Randomized Experiments: A Tale of Two Surveys

The randomized trial literature has helped to renew the field of microeconometric policy evaluation by emphasizing identification issues raised by endogenous program participation. Measurement and attrition issues have perhaps received less attention. This paper analyzes the dramatic impact of sample attrition in a large job search experiment. We take advantage of two independent surveys on the same initial sample of 8,000 persons. The first one is a long telephone survey that had a strikingly low and unbalanced response rate of about 50%. The second one is a combination of administrative data and a short telephone survey targeted at those leaving the unemployment registers; this enriched data source has a balanced and much higher response rate (about 80%). With naive estimates that neglect non responses, these two sources yield puzzlingly different results. Using the enriched administrative data as benchmark, we find evidence that estimates from the long telephone survey lack external and internal validity. We turn to existing methods to bound the effects in the presence of sample selection; we extend them to the context of randomization with imperfect compliance. The bounds obtained from the two surveys are compatible but those from the long telephone survey are somewhat uninformative. We conclude on the consequences for data collection strategies.

Nonlinear Numerical Prediction of Gas Foil Bearing Stability and Unbalanced Response

One of the main interests of gas foil bearings lies in their superior rotordynamic characteristics compared with conventional bearings. A numerical investigation on the stability limit and on the unbalanced response of foil bearings is presented in this paper. The main difficulty in modeling the dynamic behavior of such bearings comes from the dry friction that occurs within the foil structure. Indeed, dry friction is highly nonlinear and is strongly influenced by the dynamic amplitude of the pressure field. To deal with these nonlinearities, a structural dynamic model has been developed in a previous work. This model considers the entire corrugated foil and the interactions between the bumps by describing the foil bearing structure as a multiple degrees of freedom system. It allows the determination of the dynamic friction forces at the top and at the bottom of the bumps by simple integration of ordinary differential equations. The dynamic displacements of the entire corrugated sheet are then easily obtained at each time step. The coupling between this structural model and a gas bearing prediction code is presented in this paper and allows performing full nonlinear analyses of a complete foil bearing. The bearing stability is the first investigated problem. The results show that the structural deflection enhances the stability of compliant surface bearings compared with rigid ones. Moreover, when friction is introduced, a new level of stability is reached, revealing the importance of this dissipation mechanism. The second investigated problem is the unbalanced response of foil bearings. The shaft trajectories depict a nonlinear jump in the response of both rigid and foil bearings when the value of the unbalance increases. Again, it is evidenced that the foil bearing can support higher mass unbalance before this undesirable step occurs.

Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice

Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-alpha). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-gamma, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-alpha antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-gamma injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.

Characterization of CD4+CD25+ natural regulatory T cells in the inflammatory infiltrate of human chronic periodontitis

Periodontitis is an infectious disease, where putative periodontopathogens trigger chronic inflammatory and immune responses against periodontal structures, in which an unbalanced host response is also determinant to the disease outcome. It is reasonable to assume that patient susceptibility to periodontal tissue destruction could be determined by the balance between the response against periodontopathogens and regulatory mechanisms of these events mediated by suppressive T cells. In the present study, we identified and characterized natural regulatory T cells (Tregs) in the inflammatory infiltrate of human chronic periodontitis (CP) with emphasis on phenotypic analyses that were carried out to address the participation of Tregs in CP. Results showed that patients with CP presented increased frequency of T lymphocytes and CD4+CD25+ T cells in the inflammatory infiltrate of gingival tissues. These cells exhibited the phenotypic markers of Tregs such as forkhead box p3 (Foxp3), CTLA-4, glucocorticoid-inducible TNFR, CD103, and CD45RO and seemed to be attracted to the inflammation site by the chemokines CCL17 and CCL22, as their expression and its receptor CCR4 were increased in CP patients. Moreover, besides the increased detection of Foxp3 mRNA, diseased tissues presented high expression of the regulatory cytokines IL-10 and TGF-beta. In addition, the inflammatory infiltrate in CP biopsies was composed of CD25+Foxp3+ and CD25+TGF-beta+ cells, thus corroborating the hypothesis of the involvement of Tregs in the pathogenesis of CP. Finally, these results indicate that Tregs are found in the chronic lesions and must be involved in the modulation of local immune response in CP patients.

Dengue vaccine: The current status

Dengue fever is a re-emerging public health problem with two-fifths of the world population being at risk of infection. Since there are no antiviral drugs available against the dengue virus, and vector control programmes have been largely unsuccessful in preventing outbreaks, vaccination seems to be the most viable option for preventing infection. An ideal dengue vaccine should provide long lasting immunity against all four serotypes of the virus. The envelope protein of the virus plays a key role in vaccine development. The present day candidate vaccines includes a live attenuated tetravalent vaccine, intertypic chimaeric vaccines based on live attenuated dengue virus vectors, chimaeric vaccines based on the live attenuated Yellow Fever 17D vector and recombinant vaccines which include vaccines based on flavivirus and non-flavivirus vectors. Tetravalent live attenuated vaccines, intertypic chimaeric vaccines and chimaeric vaccines are being tested in human trials. Recombinant DNA vaccines based on flavivirus and non-flavivirus vectors are being tested in animal trials. Recent studies have shown that the tetravalent formulations may elicit an unbalanced immune response. Research is continuing to find means of obtaining a balanced response to all antigens in the tetravalent formulations.

Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis

Expansion of circulating CD28- T-cells reminiscent of effector memory T-cells (T(EM)) has been reported in Wegener's granulomatosis (WG) recently. To investigate the role of T(EM) in WG, we analyzed the expression of the activating NK-receptor NKG2D and its ligand MIC on circulating T(EM) and in granulomatous lesions, respectively. NKG2D was anomalously expressed and preferentially detected on circulating CD4+CD28- T(EM) in WG. Compared to healthy controls, T(EM) display a more activated phenotype potentially favoring unbalanced proinflammatory responses in WG. Cluster-like formations of "Wegener's autoantigen" PR3 were surrounded by NKG2D+ and NKG2D-ligand MIC+ cells in WG-granulomata, but not in disease controls. Further, IL-15 - known to drive T(EM) differentiation and proliferation--was also expressed in WG-granulomata. Thus, through acquisition of NK-like "innate" properties, IL-15 stimulated NKG2D+ T(EM) could interact with MIC+ cells within WG-granulomata, thereby sustaining inflammation and autoimmunity and promoting self-perpetuating pathology in WG.

Cytokine Patterns and Lymphocyte Subsets in Patients with Chronic GVHD after Allogeneic Stem Cell Transplantation with Reduced Intensity Conditioning.

Background .Chronic GVHD (cGVHD) is the most common and severe late complication after allogeneic stem cell transplantation (SCT), because of increasing use of matched unrelated donors, peripheral blood stem cells and reduced intensity conditioning (RIC). Impaired immune reconstitution and unbalanced Th1-type or Th2-type immune response with cytokines dysregulation seem to play a key role in the pathogenesis of chronic GVHD (cGVHD).Aims. In order to study the immunologic mechanisms involved in cGVHD, we prospectively evaluated the Th1 (TNF-alpha, IFN-gamma) and Th2 (IL-4, IL-6, IL-10) cytokine patterns and lymphocyte subsets in the setting of allogeneic SCT-RIC.Patients and methods. We assessed by ELISA the serum levels of TNF-alpha, IFN-gamma, IL-4, IL-6, IL-10 and soluble tumor necrosis factor receptors I and II (sTNF-R) in 8 healthy donors and in 19 patients undergoing allogeneic SCT-RIC (13 patients with related and 6 patients with unrelated donor). Serum levels were assessed before transplantation and monthly from second to twelfth month after SCT. Total lymphocytes and their subsets with different co-stimulatory molecules (CD4, CD8, CD19, CD28/3,CD25/4, CD134/4, CD152/3, CD16/56, CD4/45ro, CD4/45ra, CD8/45ro, CD8/45ra) were evaluated by flow cytometry in peripheral blood (PB) monthly after SCT. Cyclosporine A was used as GVHD prophylaxis in all patients from third month until its tapering or until the beginning of the therapy against extensive cGVHD. Wilcoxon test was used for statistical analysis of the data.Results. Twelve out of 19 patients developed cGVHD at a median time of 7 months (range, 6–10); cGVHD was extensive in 8 patients at a median time of 8 months (range, 6–12). The levels of cytokines did not differ significantly in patients pre-SCT and healthy donors. Patients with cGVHD differed from those without cGVHD because of:1.significantly higher levels of TNF-alpha from third to sixth month after SCT (3rd, p=0.003; 4th p=0.001; 5th, p=0.0005; 6th, p=0.01);2.significantly higher levels of sTNF-R II at 6th (p=0.01);3.significantly higher levels of IL-10 (p= 0.004) at 4th month;4.significantly lower number of NK cells in PB from third to sixth month after SCT (3rd, p=0.004; 4th p=0.009; 5th, p=0.0007; 6th, p=0.0003);5.significantly lower number of CD 152/3 cells in PB from third to sixth month after SCT (3rd, p=0.009; 4th p=0.0004; 5th, p=0.0004; 6th, p=0.007);6.significantly lower number of CD 4/25 cells in PB at 4th (p=0.0004) and 5th (p=0.01)Discussion. Our sequential study showed:1.increased levels of Th1 (TNF-alpha) and Th2 (IL-10) cytokines with different kinetics after SCT and before the onset of cGVHD;2.a decrease of NK and T cells with regulatory molecules such as CD152 after SCT and before the onset of cGVHD.These results suggest an overall prevalence of a TNF-alpha oriented response in patients with cGVHD. Defects of immunoregulatory cells could be related to these fluctuating and unbalanced cytokine patterns. However, further studies with more patients are required to support these preliminary results.

Toll-Like Receptors, New Horizons in Sepsis

Sepsis and septic shock, its more severe form, have shown alarming increases in incidence and a persistently high mortality rate, despite technological advancement allowing adequate support of vital functions in intensive care units. Progress in understanding of physiopathology has directed the therapeutic approach, until recently limited to sustaining failing organ systems and combating infectious agents, towards the alterations provoked by an unbalanced systemic inflammatory response and its deleterious effects on cellular function. Less than 10 years ago, the discovery of Toll-Like Receptor proteins, which allow the detection of pathogen molecular patterns, initiate and modulate the immune response, opened up new and exciting possibilities in approaches to sepsis. The elucidation of the transduction pathways triggered by Toll-Like Receptors activation signals exposes promising therapeutic targets. Currently, mechanisms associated within the context of Toll-Like Receptor signalization are identified in the tolerance phenomena described in the past. The description of genetic polymorphisms associated with Toll-Like Receptors, and the different patterns of response to infectious insults have defined high-risk subgroups of imbalanced immune response with greater specificity. A better understanding of the molecular structures involved in the process and the negative-regulation of some of them have opened up possibilities in antagonizing and modulating the response to the inflammatory activation mediated by Toll-Like Receptors. Having understood how the immune system recognizes pathogens and organizes the inflammatory response upon the discovery of Toll-Like Receptors and their signaling pathways, we gained an insight into the possibilities of specific treatment instead of supportive measures for sepsis.

Spinal cord injury induces endoplasmic reticulum stress with different cell‐type dependent response

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are poorly understood. In this study, we show that spinal cord injury (SCI) induces endoplasmic reticulum stress revealed by the activation of an unbalanced unfolded protein response (UPR). Using a weight-drop contusion model of SCI, the UPR activation was characterized by a quick transient phosphorylation of alpha subunit of eukaryotic initiation factor 2 soon restored by the up-regulation of its regulator Gadd34; an effective cleavage/activation of the ATF6alpha transcription factor leading to up-regulation of the canonical UPR target genes Chop, Xbp1 and Grp78; the presence of the processing of Xbp1 mRNA indicative of inositol requiring kinase 1 activation, and a gradual accumulation of C/EBP homologous transcription factor protein (CHOP) with concomitant caspase-12 activation. Interestingly, the subcellular distribution of CHOP was found in the nucleus of neurons and oligodendrocytes but in the cytoplasm of astrocytes. Considering the pro-apoptotic action attributed to this transcription factor, this phenomenon might account for the different susceptibility of cell types to dye after SCI.

Reduction of vibration level in rotordynamics by design optimization

We focus on the reduction of the vibration level of rotors by optimizing the shape of the body. The target is to reduce rotor weight and rotor vibrations leading to higher efficiency and less noise. We consider a finite element discretization of the rotor using a Rayleigh beam model which includes rotary inertia and gyroscopic moments leading to nonself-adjoint systems. We present a general algebraic framework for this case. The mass function is the objective function of the optimization problem and constraints are set on the nonlinear and nonconvex functions of critical speed and unbalanced response. For the numerical solution, algorithms belonging to the class of sequential convex programming are applied for the example of a turbocharger. A remarkable reduction of mass of an initially given prototype could be achieved while significantly reducing the unbalanced response and raising the critical speeds.

On the hollowness ratio effect on the dynamics of a spinning Rayleigh beam

The analytical solutions of a spinning Rayleigh beam with rotatory moment inertia and gyroscopic effect are presented in this paper. The critical speeds can be written analytically in a function of the length-to-radius ratio ( l) defined by the beam's length over its outer radius and the hollowness ratio ( α) defined by the hollow area over the total area of the cross section. The sensitivity analyses show that the critical speed is decreasing with l, but increasing with α. Moreover, α is more sensitive to the critical speeds. The design of a spinning beam should therefore be emphasized more on the hollowness factor. Contrary to common belief, only finite critical speeds exist and the number is independent of the boundary conditions. It increases monotonically with l, but decreases with α. The steady state unbalanced response can therefore be expressed analytically by the finite precessional modes and the corresponding generalized coordinates.