Unbalanced Response Research Articles

A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection.

Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-κB. We found that the modulating effect is primarily restricted to the less abundant β-isoform (hβAT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of hβAT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or hβAT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with hβAT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.

Interleukin-26 is overexpressed in human sepsis and contributes to inflammation, organ injury, and mortality in murine sepsis

BackgroundSepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown.MethodsSerum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined.ResultsOn the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1β, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity.ConclusionsSeptic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.

The Transcriptional and Protein Profile From Human Infected Neuroprogenitor Cells Is Strongly Correlated to Zika Virus Microcephaly Cytokines Phenotype Evidencing a Persistent Inflammation in the CNS.

Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/β, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.

Cannabinoid CB2 Receptor Functional Variation (Q63R) Is Associated with Multiple Sclerosis in Iranian Subjects.

The cannabinoid system has been identified as a critical endogenous regulator of immune homeostasis through immunomodulatory actions. This system is one of the main regulatory systems of the central nervous system (CNS). Variations in the cannabinoid CB2 receptor gene (CNR2) could affect intracellular signaling and reduce system function, which has been associated with an unbalanced immune response and increased risk of a variety of autoimmune inflammatory disorders. The present study investigated the relationship between CNR2 rs35761398 (Q63R) functional variation and multiple sclerosis (MS). A total of 100 Iranian MS patients and 100 healthy controls were enrolled in the study and genotyped through TaqMan assay. The co-dominant, dominant, recessive, over-dominant, and additive inheritance models were analyzed using SNPStats software. A significant genetic association was observed between Q63R polymorphism and MS. The dominant model was accepted as the best inheritance model to fit the data (OR 2.70, 95% CI 1.47-4.97, p = 0.001). The data implied the involvement of the CNR2 gene in susceptibility to MS in Iranian patients.

Adaptive hybrid control of unbalanced vibrations of a rotor/active magnetic bearing system with coupling misalignment using low cost instrumentation

An adaptive hybrid controller is proposed for reducing the unbalanced vibration response of a flexible rotor/active magnetic bearing system. It is observed that conventional adaptive feedforward controller (AFFC) normally used in the active noise control is very sensitive in performance for changes in rotor spin frequencies. Although frequency updating is a part of its architecture, a small practical variation in the rotor spin frequency can reduce its effectiveness drastically. A smart combination of adaptive notch filter and Goertzel filter is proposed for the frequency estimation. During changes of the rotor spin frequency, fundamental harmonics of the flexible rotor are excited. By using hybrid controllers that combine feedback control and AFFC, the amplitude of these fundamental harmonics is reduced significantly. By applying the multi-harmonic hybrid control, the multiple harmonics generated due to coupling misalignment are compensated efficiently. Fourier transform of the control signal is further used to detect the presence of the coupling misalignment.

Unbalanced Vibration Response Reduction of Rotor Using Active Magnetic Actuator Based on PD Control

An active control method based on the proportional-derivative (PD) feedback control strategy using an active magnetic actuator (AMA) is proposed for suppressing rotor vibration caused by rotor unbalance. The control current of the AMA is adjusted according to the real-time displacement of the rotor through the PD feedback algorithm to produce an electromagnetic force to reach the vibration response reduction of the unbalanced rotor. The motion equation of the rotor-bearing AMA system is established and transformed into a state equation for designing a control strategy based on the PD feedback. Finally, the test rig is set up and the verifications of simulation and experiment are carried out. The simulation and experimental results show the effectiveness of the proposed method for the suppression of the rotor unbalance vibration.

IMMUNOMODULATION, IMMUNOSTIMULATION AND EXTRACORPOREAL BLOOD PURIFICATION IN SEPSIS: POTENTIALLY BENEFICIAL TECHNIQUES IN CARDIAC SURGERY

Sepsis is a potentially life-threatening state caused by an infection and an inadequate, dysregulated host immune response. Focusing on cardiac surgery, the prevalence of sepsis is low, after procedures situated between 0.39% and 2.5%. Nevertheless, the current life-expectancy of septic patients are poor, mortality varying from 65% to 79%.Pathophysiology and immunopathology of sepsis is still unclear. Actually we consider sepsis as a dynamic process with two different sides. Both immune hyperactivity and immune suppression are presented during the progression. Although immunomodulation is not a fresh idea in the treatment of sepsis. Currently the diagnosis of sepsis is based on clinical signs. The biomarkers and molecular diagnostic tools are insufficient.The actual concept of immunopathophysiology in sepsis is based on the idea of a dynamic parallel immune response, both pro- and antiinflammatory processes are presented from the beginning. Equilibrium may be the key in the immune response of sepsis. Immune system tries to maintain the homeostatic environment during sepsis via pro- and antiinflammatory processes. In case of an unbalanced, dysregulated and radical (in both directions) response mortality become frightfully high. Infectional source control, adequate antibiotic therapy and organ support are the three corner stones in the treatment of sepsis since the definition of sepsis born.In our review we would like to add a detailed overview on two promising modalities of immunomodulation: (1) extracorporeal blood purification; (2) immunostimulation.The purposeof present article is to give an up-to-date, comprehensive review on the utilization of extracorporeal blood purification techniques and immunostimulation in septic patient after cardiac surgery.

The IRE1-XBP1 axis controls the tumorigenic properties of macrophages Jeffrey J. Rodvold, Alyssa Batista, Alyssa Lew, Takao Iwawaki, Gonzalo Almanza, and Maurizio Zanetti. Moores Cancer Center, UCSD, La Jolla, CA 92093-0815

Abstract Macrophages are major facilitators of tumorigenicity in mice and humans. However, a general unifying mechanism for how macrophages insert themselves into the tumorigenic process is still missing. We hypothesized that the dysregulation of macrophages could originate from an unbalanced unfolded protein response (UPR). Indeed, the transcriptional profile of tumor-infiltrating CD11b+Gr1− macrophages in experimentally induced (B16.F10) or spontaneously-arising (APC) tumors in mice, shows that they express features of a generalized UPR with concomitant upregulation of IL-23 and Arginase1 relative to spleen and bone marrow myeloid cells. This defines a mixed pro-inflammatory/immune suppressive phenotype (IIS) also described in human cancers. These effects were largely attenuated in B16.F10 tumors grown in TLR4 −/− mice except for the upregulation of Arg1. Using IRE-1 (4μ8c) and PERK (GSK2656157) specific small molecule inhibitors we also determined that macrophages with the UPR/IIS phenotype undergo an IRE1-dependent upregulation of PD-L1. Under similar experimental conditions the ablation of either Ern1 (IRE1) or Xbp1 in macrophages also prevented the upregulation of PD-L1. Finally, the survival of mice implanted with B16.F10 tumor cells was significantly prolonged in mice with Ern1−/− macrophages over that in fl/fl control mice. A prolonged survival in mice with Xbp1−/− macrophages was not significant. These results demonstrate the central role of the IRE1-XBP1 axis in the pro-inflammatory/immune suppressive characteristics of intratumoral macrophages, and their tumor promoting effects overall. They also point to the benefit of modulating the IRE1- XBP1 axis in the tumor microenvironment.

Higher Number of Night Shifts Associates with Good Perception of Work Capacity and Optimal Lung Function but Correlates with Increased Oxidative Damage and Telomere Attrition.

Sleep deprivation and the consequent circadian clock disruption has become an emergent health question being associated with premature aging and earlier chronic diseases onset. Night-shift work leads to circadian clock misalignment, which is linked to several age-related diseases. However, mechanisms of this association are not well understood. Aim of this study is to explore in night-shift workers early indicators of oxidative stress response and biological aging [oxidized/methylated DNA bases and leukocytes telomere length (LTL)] and late indicators of functional aging [lung function measurements (FEV1 and FVC)] in relation to personal evaluation of work capacity, measured by work ability index (WAI). One hundred fifty-five hospital workers were studied within the framework of a cross-sectional study. We collected physiological, pathological, and occupational history including pack-years, alcohol consumption, physical activity, and night shifts, together with blood and urine samples. Relationships were appraised by univariate and multivariate ordered-logistic regression models. We found that workers with good and excellent WAI present higher FEV1 (p< 0.01) and number of night-work shifts (p<0.05), but they reveal higher urinary levels of 8-oxoGua (p<0.01) and shorter LTL (p<0.05). We confirmed that higher work ability was prevalent among chronological younger workers (p<0.05), who have also a significant reduced number of diseases, particularly chronic (p<0.01) and musculoskeletal diseases (p<0.01). The new findings which stem from our work are that subjects with the highest work ability perception may have more demanding and burdensome tasks; they in fact present the highest number of night-shift work and produce unbalanced oxidative stress response that might induce premature aging.

OXiris® Use in Septic Shock: Experience of Two French Centres

Background: Sepsis is a dysregulated host response to an infection and can result in organ dysfunctions and death. Extracorporeal blood purification techniques aim to improve the prognosis of these patients by modulating the unbalanced immune response. This study reports our experience with the use of the oXiris® membrane for septic shock patients requiring continuous renal replacement therapy (CRRT). Summary: Thirty-one patients were diagnosed with septic shock and underwent CRRT with the oXiris® membrane between 2014 and 2019. We compared the observed hospital mortality with that predicted by the Simplified Acute Physiology Score II (SAPS II). Change in the Sequential Organ Failure Assessment (SOFA) score and of the main clinical and biological parameters over time were analyzed. Hospital mortality was lower than predicted for the most severe patients (60 vs. 91% for the [74–87] SAPS II quartile and 70 vs. 98% for the [87–163] SAPS II quartile, p < 0.02). There was no significant improvement in the SOFA score from 0h to 48 h. An 88% relative decrease in norepinephrine infusion was observed (median at 0 h was 1.69 [0.52–2.45] µg/kg/min; at 48 h it was 0.20 [0.09–1.14] µg/kg/min, p = 0.002). Lactataemia and pH were significantly improved over time. Patients with intra-abdominal sepsis as well as those with Gram-negative bacilli (GNB) infections seemed to benefit the most from the therapy. Key Messages: CRRT with the oXiris® haemofilter resulted in higher observed survival than predicted by a severity score (SAPS II) for the most severe patients. Haemodynamic status and lactataemia appeared to improve, especially in intra-abdominal sepsis and GNB infections.

Both knock-down and overexpression of Rap2a small GTPase in macrophages result in impairment of NF-κB activity and inflammatory gene expression

Small Ras GTPases are key molecules that regulate a variety of cellular responses in different cell types. Rap1 plays important functions in the regulation of macrophage biology during inflammation triggered by toll-like receptors (TLRs). However, despite sharing a relatively high degree of similarity with Rap1, no studies concerning Rap2 in macrophages and innate immunity have been reported yet. In this work, we show that either way alterations in the levels of Rap2a hampers proper macrophages response to TLR stimulation. Rap2a is activated by LPS in macrophages, and although putative activator TLR-inducible Ras guanine exchange factor RasGEF1b was sufficient to induce, it was not fully required for Rap2a activation. Silencing of Rap2a impaired LPS-induced production of IL-6 cytokine and KC/Cxcl1 chemokine, and also NF-κB activity as measured by reporter gene studies. Surprisingly, overexpression of Rap2a did also lead to marked inhibition of NF-κB activation induced by LPS, Pam3CSK4 and downstream TLR signaling molecules. We also found that Rap2a can inhibit the LPS-induced phosphorylation of the NF-κB subunit p65 at serine 536. Collectively, our data suggest that expression levels of Rap2a in macrophages might be tightly regulated to avoid unbalanced immune response. Our results implicate Rap2a in TLR-mediated responses by contributing to balanced NF-κB activity status in macrophages.

The area under the precision‐recall curve as a performance metric for rare binary events

Abstract Species distribution models are used to study biogeographic patterns and guide decision‐making. The variable quality of these models makes it critical to assess whether a model's outputs are suitable for the intended use, but commonly used evaluation approaches are inappropriate for many ecological contexts. In particular, unrealistically high performance assessments have been associated with models for rare species and predictions over large geographic extents. We evaluated the area under the precision‐recall curve (AUC‐PR) as a performance metric for rare binary events, focusing on the assessment of species distribution models. Precision is the probability that a species is present given a predicted presence, while recall (more commonly called sensitivity) is the probability the model predicts presence in locations where the species has been observed. We simulated species at three levels of prevalence, compared AUC‐PR and the area under the receiver operating characteristic curve (AUC‐ROC) when the geographic extent of predictions was increased and assessed how well each metric reflected a model's utility to guide surveys for new populations. AUC‐PR was robust to species rarity and, unlike AUC‐ROC, not affected by an increasing geographic extent. The major advantages of AUC‐PR arise because it does not incorporate correctly predicted absences and is therefore less prone to exaggerate model performance for unbalanced datasets. AUC‐PR and precision were useful indicators of a model's utility for guiding surveys. We show that AUC‐PR has important advantages for evaluating models of rare species, and its benefits in the context of unbalanced binary responses will make it applicable for other ecological studies. By not considering the true negative quadrant of the confusion matrix, AUC‐PR ameliorates issues that arise when the geographic extent is increased beyond the species’ range or when a large number of background points are used when absence information is unavailable. However, no single metric captures all aspects of performance nor provides an absolute index that can be compared across datasets. Our results indicate AUC‐PR and precision can provide useful and intuitive metrics for evaluating a model's utility for guiding sampling, and can complement other metrics to help delineate a model's appropriate use.

Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils.

The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.

Study on the Dynamic Characteristics of a Rotor Bearing System with Damping Rings Subjected to Base Vibration

In this paper, the influence of base excitation on the rotor-rolling bearings’ supports with rubber damping rings coupling dynamics model was studied. Using the finite-element theory associated with the lumped mass method, the governing differential equations of the coupling system were established. In this model, the rotor was discretized using Timoshenko beam elements, while the supports and ball bearing outer races were modelled as lumped parameter models. The dynamic model was verified by varying compliance (VC) vibration impact analysis, the influence of the rubber damping ring, and the rotor unbalanced response. On this basis, the effect of the dynamic characteristics of the rotor coupling system subjected to base vibration was analysed. The base excitation frequency near the natural frequency of the rotor not only exerts an effect on the rotor vibration in the direction of excitation but also the rotor oscillation in the other directions. The amplitude of the axial trajectory is influenced by the frequencies and amplitudes of the foundation excitation. As the amplitudes of the base excitation increase, the amplitude of the axis trajectory tends to increase linearly, and the speed of growth is different at various base excitation frequencies. The shape of the axial trajectory is mainly affected by the foundation excitation frequencies. As the excitation frequency changes, the axis trajectory becomes complicated, and the combination resonance phenomenon occurs.

Research on Automatic Balance Control of Active Magnetic Bearing‐Rigid Rotor System

In this paper, in order to solve the problem of unbalance vibration of rigid rotor system supported by the active magnetic bearing (AMB), automatic balancing method is applied to suppress the unbalance vibration of the rotor system. Firstly, considering the dynamic and static imbalance of the rotor, the detailed dynamic equations of the AMB‐rigid rotor system are established according to Newton’s second law. Then, in order to rotate the rotor around the inertia axis, the notch filter with phase compensation is used to eliminate the synchronous control current. Finally, the variable‐step fourth‐order Runge–Kutta iteration method is used to solve the unbalanced vibration response of the rotor system in MATLAB simulation. The effects of the rotational speed and phase compensation angle on the unbalanced vibration control are analysed in detail. It is found that the synchronous control currents would increase rapidly with the increase of rotational speed if the unbalance vibration cannot be controlled. When the notch filter with phase shift is used to balance the rotor system automatically, the control current is reduced significantly. It avoids the saturation of the power amplifier and reduces the vibration response of the rotor system. The rotor system can be stabilized over the entire operating speed range by adjusting the compensation phase of the notch filter. The method in the paper is easy to implement, and the research result can provide theoretical support for the unbalance vibration control of AMB‐rotor systems.

Immunological characteristics of peritoneal cavity and intra-abdominal infection

Despite the evolution of aggressive surgical techniques, extensive methods of supportive care and a vast array of anti-microbial options, intra-abdominal infection (IAI) is still a challenging clinical issue. Especially, when progressed IAI with septic complications because of unbalanced immune responses, the prognosis will deteriorated significantly. Recent studies indicate that besides the natural immunological cells, including macrophages and neutrophils, local immunological characteristics of peritoneal cavity should be studied with great attention. Among them, the omentum is considered to be a visceral adipose tissue with unique immune function. The milky spots(MSs) formed by the accumulation of immune cells performs immune surveillance and has a lymph node-like immune function, which is very important for the immune defense of the abdominal cavity. B1 cells and two types of intrinsic lymphocytes(ILC2) in the peritoneal cavity, although belonging to the lymphatic lineage, may play an important role in abdominal infections, especially in the early stages of the disease, due to their rapid responsiveness and acquired immune function. Therefore, paying attention to the immunological characteristics of the peritoneal cavity, and elucidating the changes, functions and regulatory mechanisms of B1 cells and ILC2 around the MSs and their components in the process of IAI, in order to explore the immunomodulation targets of blocking the infection from local to systemic dissemination, may be the key to solving the clinical problem of severe IAI and improving prognosis.

Vibration Analysis of Flexible Rotor with Angular Contact Ball Bearings Using a General Bearing Stiffness Model

The vibration analysis of flexible rotor systems supported by angular contact ball bearings is presented. Vibration analysis of rotor-ball bearing systems has often been performed via simplification of supporting bearings as linear springs with constant stiffness. In this study, an improved model of rotor-ball bearing systems was proposed. It utilizes a general bearing model based on response and time-dependent bearing characteristics. The system equations of motion were established using the finite-element method and numerically solved using the Newmark-β method. The method was used to recalculate the bearing stiffness matrices at every interval of numerical integration as a function of the instantaneous bearing displacements using a separated five-degrees-of-freedom bearing model. The method was verified via comparison with experimental data available in the literature. The extended simulations were conducted to investigate the unbalanced responses of a rotor-ball bearing system using the proposed and conventional methods. Numerical results showed a meaningful discrepancy between the vibrational responses obtained by the proposed model using the response and timedependent bearing stiffness model and the traditional constant-stiffness model.

Immune Functional Assays, From Custom to Standardized Tests for Precision Medicine.

The immune response is a dynamic system that maintains the integrity of the body, and more specifically fight against infections. However, an unbalanced host immune response is highlighted in many diseases. Exacerbated responses lead to autoimmune and allergic diseases, whereas, low or inefficient responses favor opportunistic infections and viral reactivations. Conflicting situations may also occur, such as in sepsis where inflammation and compensatory immunosuppression make it difficult to deploy the appropriate drug treatment. Until the current day, assessing the immune profile of patients remains a challenge. This is especially due to the inter-individual variability—a key feature of the immune system—which hinders precise diagnosis, prognosis, and therapeutic stratification. Our incapacity to practically interpret the host response may contribute to a high morbidity and mortality, such as the annual 6 million worldwide deaths in sepsis alone. Therefore, there is a high and increasing demand to assess patient immune function in routine clinical practice, currently met by Immune Functional Assays. Immune Functional Assays (IFA) hold a plethora of potentials that include the precise diagnosis of infections, as well as prediction of secondary and latent infections. Current available products are devoted to indirect pathogen detection such as Mycobacteria tuberculosis interferon gamma release assays (IGRA). In addition, identifying the status and the underlying factors of immune dysfunction (e.g., in septic patients) may guide immune targeted therapies. Tools to monitor and stratify the immune status are currently being studied but they still have many limitations such as technical standardization, biomarkers relevance, systematic interpretation and need to be simplified, in order to set the boundaries of “healthy,” “ill,” and “critically ill” responses. Thus, the design of new tools that give a comprehensive insight into the immune functionality, at the bedside, and in a timely manner represents a leap toward immunoprofiling of patients.

Altered T-cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities.

Recurrent pregnancy loss (RPL) is a multifactorial disorder of women in reproductive age, which in some cases is caused by immunologic abnormalities. In this study, we aimed to evaluate cellular and molecular components of the immune system like different T-cell subsets and their regulating microRNAs (miRNAs) in RPL women and control group. Fifty RPL and 50 healthy subjects were recruited. Subsets of T cells, including regulatory T (Treg) cells, helper T (Th) 17 cells, exhausted T cells, exhausted Treg cells were evaluated by flow cytometry. Transcription factors of T cells and related miRNA profile were quantified using real-time polymerase chain reaction (RT-PCR). Assessment showed that Treg and exhausted T cells, were decreased in RPL patients (p = 0.009 and 0.02, respectively), while an increase was observed in Th17 and exhausted Treg frequency ( p = 0.013 and 0.0037, respectively). Messenger RNA expression level of T-bet and IRF4 was upregulated in RPL patients ( p = 0.011 and 0.0001, respectively), while Th2- and Treg-related transcription factors, GATA3 and GITR, were downregulated in these patients compared with the healthy subjects ( p = 0.0008 and <0.000, respectively). Treg-associated miRNAs, the miR-106b-25-93 cluster, showed a higher rate in RPL patients ( P = 0.007, 0.001, and 0.029, respectively), however, we observed no significant difference in the expression level of Th17-associated miRNA, mir-326. According to the results, we concluded that unbalanced immune responses and deregulated function of T-cell subsets may lead to reproduction-related failure like a miscarriage. Therefore, evaluation of immune cells and related miRNA profile may serve as prognostic biomarker for the treatment of RPL patients.

Adherence to the Mediterranean Diet and Serum Adiponectin Levels in Pregnancy: Results from a Cohort Study in Normal Weight Caucasian Women.

The Mediterranean Diet (MedDiet) is significantly associated with anti-inflammatory effects and a favorable health outcome. During pregnancy, both inflammatory changes and oxidative balance are essential for a successful outcome, while an unbalanced inflammatory response can be a key mediator of obstetrical syndromes. The aim of this study is to investigate the adherence to MedDiet during pregnancy in the 1st and in the 3rd trimester, and to test whether the adherence was associated with serum adiponectin levels. The study was carried out on 99 normal weight Caucasian women. The adherence to MedDiet was measured by a 13-point Mediterranean scale. The whole sample scored 7.2 ± 1.5, with no difference between first and third trimester (p = 0.7). Critical points were: fruit < 3 servings/day in 77% of the sample, beans < 3 times/week in 89%, fish < 2 times/week in 69%, and nut weekly intake < 30 g in 75%. The serum adiponectin levels significantly decreased from the first to the third trimester (−16% ± 4%, p = 0.008), which confirms a low-grade inflammatory condition associated with advancing gestational age. The women who were in the highest tertile of the adherence to MedDiet had a lower percentage decrease, as compared with those in the lowest tertile (10% ± 11% vs. −34% ± 3%, p = 0.01). Even if in pregnancy the adiponectin levels are strongly influenced by the low-grade inflammation, the adherence to MedDiet may modulate this state.