Noninfectious Inflammation Research Articles

MICROBIOME AND UVEITIDES. A REVIEW.

Microorganisms inhabiting all surfaces of mucous membranes and skin and forming a complex ecosystem with the host is called microbiota. The term microbiome is used for the aggregate genome of microbiota. The microbiota plays important role in the mechanisms of number of physiological and pathological processes, especially of the hosts immune system. The origin and course of autoimmune diseases not only of the digestive tract, but also of the distant organs, including the eye, are significantly influenced by intestinal microbiota. The role of microbiota and its changes (dysbiosis) in the etiopathogenesis of uveitis has so far been studied mainly in experimental models. Reduction of severity of non-infectious intraocular inflammation in germ-free mice or in conventional mice treated with broad-spectrum antibiotics was observed in both the induced experimental autoimmune uveitis model (EAU) and the spontaneous R161H model. Studies have confirmed that autoreactive T cell activation occurs in the intestinal wall in the absence of retinal antigen. Recent experiments focused on the effect of probiotic administration on the composition of intestinal microbiota and on the course of autoimmune uveitis. Our study group demonstrated significant prophylactic effect of the administration of the probiotic Escherichia coli Nissle 1917 on the intensity of inflammation in EAU. To date, only a few studies have been published investigating intestinal dysbiosis in patients with uveitis (e.g., in Behcets disease or Vogt-Koyanagi-Harada syndrome). The results of preclinical studies will be presumably used in clinical practice, mainly in the sense of prophylaxis and therapy, such as change in the lifestyle, diet and especially the therapeutic use of probiotics or the transfer of faecal microbiota.

Treatment of noninfectious uveitis.

Uveitis is a broad term that refers to a large group of eye disorders categorized by intraocular inflammation, a leading cause of visual impairment. Historically, treatment of noninfectious uveitis has depended on corticosteroid drugs. Owing to the myriad of side effects caused by corticosteroids, immunomodulatory therapy has become the preferred treatment for chronic noninfectious intraocular inflammation. Recently, biological response modifiers have established a new era in uveitis therapy, with the range of targets continuing to expand. In this review, we aimed to convey up-to-date information on the treatment of noninfectious uveitis to the general ophthalmologist.

Inflammation expressed by elevated Galectin-3 and telomere shortening is enhanced in preterm labor

Preterm birth is the leading cause of neonatal morbidity and mortality. The precise biological signals and mechanisms that determine human parturition, term or preterm, continue to be poorly understood. Multiple theories exist, among which are enhanced oxidative stress, non-infectious inflammation, and telomere shortening leading to fetal amnion and chorion senescence. Galectin-3 (Gal-3) is involved in cell growth, differentiation, inflammation and fibrosis. We evaluated changes in two common pathways of stress and inflammation: telomere homeostasis and Gal-3 at the levels of maternal serum and placental samples from women with spontaneous preterm birth (SPTB) in comparison to those with uncomplicated (normal) term pregnancies (NTP).

994. Comparison of Lactate, Procalcitonin and a Gene Signature Assay Alone or in Combination to Differentiate Sepsis from Non-infectious Systemic Inflammation in ICU Patients

BackgroundProcalcitonin (PCT) and serum lactate (L) are measures of bacterial infection and tissue hypoxia, respectively, but also used to discern sepsis from infection negative systemic inflammation (INSI). However, improved tools are needed to enhance this differentiation. A previously validated gene signature assay (SeptiCyte RAPID) and its correlated score (SeptiScore (SS)) has been reported to effectively differentiate sepsis from INSI.ObjectiveTo compare early L, PCT and SS results (alone or in combination) in differentiating sepsis from INSI in adult intensive care unit (ICU) patients (Pt).MethodsData from a previously reported, prospective study (8 sites). Inclusion criteria: (i) ICU admission with ≥ 2 signs of systemic inflammatory response syndrome; (ii) Therapeutic antibiotic administration; (iii) external 3-physician clinical review classifying each Pt as sepsis or INSI with ≥ 2 reviewer agreement; (iv) L, PCT & SS values within 24 hrs of ICU admission; (v) Statistical Analysis; (iv) Area under the receiving operator curve (AUROC), 95% confidence intervals (CI) via generalized linear models for: (i) Each parameter alone (L, PCT, SS); (ii) Combinations (L + PCT, L + SS, PCT + SS, All 3); (iii) AUROC discriminated Sepsis from INSI model: (a) < 0.7 Sub-Optimal; (b) 0.7-0.8 Good; (c) > 0.8 Excellent. Comparisons conducted via paired t-test.Results222 pts, sepsis=113; INSI=109 Similar demographics between groups (NS). Mean age (SD) = 57.9 (17.1) yrs; 58.1% male). Overall mechanically ventilated 60.8% and hospital mortality 17.1%. AUCROC (95% CI) in Table and Figure; AUCROC of L, PCT or SS alone or in combination L, PCT, SS Comparison of Sepsis vs INSI ConclusionL is sub-optimal in discriminating sepsis from INSI. PCT with or without L was acceptable but not as robust as SS. SS alone or in any combination provided superior and significant discrimination between sepsis and INSI. Incorporation of SS into the clinical assessment process for suspected sepsis pts should be evaluated to determine the impact on early detection and Pt management.Disclosures Erkan Hassan, Pharm.D., FCCM, Immunexpress (Consultant) Roy Davis, M.D>, Immunexpress (Consultant)Immunexpress (Consultant, Shareholder) Dayle Sampson, Ph.D., Immunexpress (Employee, Shareholder)

Multimodality Imaging of Large-Vessel Vasculitis, From the AJR Special Series on Inflammation.

Large-vessel vasculitis (LVV) is a noninfectious inflammation of the large vessels, including the aorta and its main branches. Imaging plays an essential role in diagnosing LVV given the challenges of tissue biopsy. This article reviews the types of LVV and the multimodality imaging tools available to establish its diagnosis. The cornerstone of imaging diagnosis is morphologic assessment using gray-scale ultrasound (US), gray-scale US combined with color Doppler US, CTA, or MRA. In the last decade, substantial progress has been made in functional and molecular imaging with FDG PET/CT for the diagnosis of LVV. Investigation is ongoing to develop novel MRA techniques and new PET tracers to assess disease activity and to differentiate the various vasculitides. An algorithm is provided to guide imaging technique selection based on the patient's specific clinical presentation.

Corneal Endothelial Transplantation in Uveitis: Incidence and Risk Factors

To estimate the incidence of corneal endothelial transplantation (CET) and identify risk factors among patients with noninfectious ocular inflammation. Retrospective cohort study. Adult patients attending United States tertiary uveitis care facilities diagnosed with noninfectious ocular inflammation were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Time-to-event analysis was used to estimate the incidence of CET, including penetrating keratoplasty, Descemet stripping endothelial keratoplasty, or Descemet membrane endothelial keratoplasty procedures. The incidence of CET was calculated. Potential risk factors for CET were also evaluated using Cox regression, accounting for correlation between eyes of the same patient. Overall, 14,264 eyes met eligibility criteria for this analysis, with a median follow-upof 1.8eye-years. The Kaplan-Meier estimated incidence of CET within 10 years was 1.10% (95% CI, 0.68%-1.53%). Risk factors for CET included age >60 years vs <40 years (adjusted hazard ratio [aHR], 16.5; 95% CI, 4.70-57.9), anterior uveitis and scleritis vs other types (aHR, 2.97; 95% CI, 1.46-6.05; and aHR, 4.14; 95% CI,1.28-13.4, respectively), topical corticosteroid treatment (aHR, 2.84; 95% CI, 1.32-6.13), cataract surgery (aHR, 4.44; 95% CI, 1.73-11.4), tube shunt surgery (aHR, 11.9; 95% CI, 5.30-26.8), band keratopathy (aHR, 5.12; 95% CI, 2.34-11.2), and hypotony (aHR, 7.38; 95% CI, 3.14-17.4). Duration of uveitis, trabeculectomy, peripheral anterior synechia, and ocular hypertension had no significant association after multivariate adjustment. In patients with ocular inflammation, CET occurred infrequently. Tube shunt surgery, hypotony, band keratopathy, cataract surgery, and anterior segment inflammation were associated with increased risk of undergoing CET; these factors likely are associated with endothelial cell damage.

Epidural fever.

Epidural analgesia (EPA) is the most effective method of intrapartum pain relief and is considered to be very safe. Recently, it has been used in up to 34% of parturients with EPA and is also associated with maternal temperature elevations during labor. The mechanism of this epidural-associated fever remains incompletely understood. The most likely etiology seems to be non-infectious inflammation caused by an epidural catheter. However, some authors deny this association. They theorize it is caused by selection bias only, as EPA is more often required by women with more painful and prolonged or more complicated labor, where temperature elevation is due to other causes. They point out that in some studies, fever was correlated to EPA only with concurrent placental inflammation. Maternal fever, despite the cause, either infectious or non-infectious origin, carries important clinical and public health implications. Further research that evaluates maternal epidural status and its influence on maternal or neonatal fever could improve sepsis evaluation and lead to worldwide decrease of unnecessary antibio-tic exposure.

Biologic Therapies and Small Molecules for the Management of Non-Infectious Scleritis: A Narrative Review.

Scleritis refers to a wide spectrum of ocular conditions ranging from mild to sight-threatening scleral inflammation that may compromise visual function and threaten the anatomical integrity of the ocular globe. Most aggressive forms like necrotizing or posterior scleritis are often difficult-to-treat cases, refractory to conventional treatment. The association with systemic diseases, namely rheumatoid arthritis, Sjögren syndrome, granulomatosis with polyangiitis, and relapsing polychondritis, may have prognostic implications as well. A better understanding of the pathogenesis of ocular inflammatory diseases have paved the way to more effective and targeted treatment approaches. In this regard, a growing body of evidence supports the potential role of biologic agents in the management of non-infectious scleral inflammation, either idiopathic or in a background of immune-mediated systemic disorders. Biologic agents such as anti-tumor necrosis factor agents, interleukin-1 and interleukin-6 inhibitors as well as CD20 blockade have displayed promising results. More specifically, several studies have reported their ability to control scleral inflammation, reduce the overall scleritis relapses, and allow a glucocorticoid-sparing effect while being generally well tolerated. Anecdotal reports have also been described with other biologic agents including abatacept, ustekinumab, daclizumab, and alemtuzumab as well as targeted small molecules such as tofacitinib. Further studies are warranted to fully elucidate the role of biologic agents in non-infectious scleritis and investigate specific areas with the aim to administer treatments in the context of personalized medicine. This review summarizes the available data regarding clinical trials, small pilot studies, and real-life experience of the last two decades reporting the use of biologic agents in the management of non-infectious scleritis.

Assessment of Imaging Findings in Inflammatory Breast Disease by Ultrasound

Abstract Background: Inflammatory breast disorders include a wide array of underlying causes, ranging from common benign infection, noninfectious inflammation and inflammation resulting from underlying breast malignancy. Mastitis refers to inflammation of the breast parenchyma, often presenting with pain, heat and redness that may be a debilitating illness with prolonged morbidity. It may also present with a wide array of other nonspecific symptoms, which may lead to delayed diagnosis and inappropriate treatment. Aim of Study: To discuss imaging findings in inflammatory breast disease by ultrasound. Patients and Methods: This was a prospective study which was carried out at Ain Shams University Hospitals; the study was conducted on 100 women with inflammatory breast diseases referred to the Radiology Department and Surgical Outpatient's Clinics. Results: Echogenic edematous fat lobules of the studied group show that; 30 (30.0%) were negative and 70 (70%) were positive, interstitial edema; 24 (24.0%) were negative and 76 (76%) were positive, defined collections; 68 (68.0%) were negative and 32 (32%) were positive. Lymph node enlargement; 54 (54.0%) were negative and 46 (46.0%) were positive. There was lymph node enlargement for only 45 (31 cases show reactive lymph nodes oval in shape with preserved shape and hilum and 14 cases show suspicious lymph nodes with cortical thickening and eccentric hilum). Follow-up by u/s and histopathology of the studied group show that 93 (93.0%) were resolved and 7 (7.0%) were IDC by histopathology. Conclusion: Ultrasound plays a fundamental role in the diagnostic work up of mastitis patients. An ideal ultrasound should ensure an accurate diagnosis, guide for interventional procedures whenever necessary and should be used to monitor adequate management by short term follow-up studies along the course of therapy.

Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patients in the early post-traumatic period

In polytrauma patients who survive the primary insult, the imbalance between the pro- and anti-inflammatory processes seems to be responsible for life-threatening complications such as sepsis or multiple organ dysfunction syndrome. Measurement of C-reactive protein (CRP) and procalcitonin (PCT) is a standard way for differentiating between infectious (bacterial) and non-infectious inflammation. Monitoring of immune cell functions, like leukocyte anti-sedimentation rate (LAR) can also be useful to diagnose infectious complications. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known immunomodulatory and anti-inflammatory effects. The aim of our study was to determine the changes of PACAP38 levels in polytrauma patients in the early post-traumatic period in intensive care unit and analyse possible correlation of its level with conventional (CRP, PCT) and unconventional (LAR) laboratory parameters. Twenty polytrauma patients were enrolled. Blood samples were taken daily for five days. We observed significant correlation between PACAP38 and CRP levels on day 4 and 5 as well as between PACAP38 and LAR levels all of the days. This could be due to the anti-inflammatory and cytoprotective functions of PACAP38 as part of an endogenous response to the trauma induced systemic inflammatory response syndrome. These significant correlations could have clinical importance in monitoring the dynamic balance of pro- and anti-inflammatory processes in case of polytraumatic patients.

Contact dermatitis: etiology, pathophysiology, clinical features and diagnostics

Ernesta Pranskaitytė1, Laura Malinauskienė1 1 Clinic of Chest Diseases, Immunology and Allergology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania Abstract Background. Contact dermatitis (CD) is a common skin disease with an increasing prevalence. It is a non-infectious skin inflammation that occurs after contact with an allergen or irritant. Based on pathophysiological mechanism, CD is divided into allergic CD (ACD) and irritant CD (ICD). ACD and ICD can co-exist due to the use of both the allergens and irritants, which leads to impaired skin barrier and promotes the development of CD. CD usually manifests as erythema, oedema, papules, pustules, and itchy skin. CD is diagnosed from a medical history, symptoms, and by performing patch testing. Dermatitis can be prevented by identifying and avoiding CD causing substances. Aim: to review an aetiology, risk factors, pathophysiology, diagnostics, clinical features of CD, ACD and ICD comorbidity. Methods: the review of literature was conducted using „PubMed“ and „UpToDate“ databases, using the keywords “Contact dermatitis”, “Allergic contact dermatitis”, “Contact allergy”, “Irritant contact dermatitis”, “Irritants”, “Allergens”. Keywords: contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, allergens, irritants.

Klotho and calciprotein particles as therapeutic targets against accelerated ageing.

The klotho gene, named after a Greek goddess who spins the thread of life, was identified as a putative ‘ageing-suppressor’ gene. Klotho-deficient mice exhibit complex ageing-like phenotypes including hypogonadism, arteriosclerosis (vascular calcification), cardiac hypertrophy, osteopenia, sarcopenia, frailty, and premature death. Klotho protein functions as the obligate co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate intake. Thus, Klotho-deficient mice suffer not only from accelerated ageing but also from phosphate retention due to impaired phosphate excretion. Importantly, restoration of the phosphate balance by placing Klotho-deficient mice on low phosphate diet rescued them from premature ageing, leading us to the notion that phosphate accelerates ageing. Because the extracellular fluid is super-saturated in terms of phosphate and calcium ions, an increase in the phosphate concentration can trigger precipitation of calcium-phosphate. In the blood, calcium-phosphate precipitated upon increase in the blood phosphate concentration is adsorbed by serum protein fetuin-A to form colloidal nanoparticles called calciprotein particles (CPPs). In the urine, CPPs appear in the renal tubular fluid when FGF23 increases phosphate load excreted per nephron. CPPs can induce cell damage, ectopic calcification, and inflammatory responses. CPPs in the blood can induce arteriosclerosis and non-infectious chronic inflammation, whereas CPPs in the urine can induce renal tubular damage and interstitial inflammation/fibrosis. Thus, we propose that CPPs behave like a pathogen that accelerates ageing and should be regarded as a novel therapeutic target against age-related disorders including chronic kidney disease.

Attention should be paid to the treatment of traumatic pancreatitis

Traumatic pancreatitis(TP) is an acute non-infectious inflammation secondary to pancreatic injury.TP can be masked by analgesia or other organ damage after pancreatic injury. So it is difficult to diagnosis in the early stage, easy to missed and misdiagnosis, subsequently prone to infection of pancreatic necrosis (IPN).At present, the treatment of TP is advocated as a step-by-step treatment strategy, which takes minimally invasive surgery as the guidance and takes into account of the principles of multiple injury treatment, inflammation control, infection and necrosis clearance, which runs through the two important links of pancreatic injury and IPN management.

Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2

BackgroundInflammatory bowel disease is defined as chronic noninfectious inflammation of the gastrointestinal tract, including ulcerative colitis and Crohn’s disease. Its incidence and predominance have increased globally, with no effective agents for preventing its recurrence or treatment until now. AimThe current study aimed to investigate the possible role of canagliflozin (CANA), a sodium-glucose co-transporter-2 inhibitor (SGLT-2), to prevent and treat acetic acid (AA)-induced colitis in a rat model. MethodsColitis was induced in male Wistar rats by intrarectal instillation of 1 ml of 4% (v/v) AA. Rats were treated orally with either CANA (30 mg/kg/day, p.o.) for 10 days before or after colitis induction or sulfasalazine (360 mg/kg/day, p.o.) for 10 days before colitis induction. ResultsAA resulted in a significant increase in disease activity index, colonic weight over length ratio, colon macroscopic damage score, and histological signs of colitis. All of these effects were significantly decreased by CANA administration. Additionally, CANA markedly inhibited AA-induced oxidative stress and inflammatory responses by significantly reducing the up-regulated levels in malondialdehyde, total nitrite, NF-κB, interleukin-1β, and TNF-α, and significantly increasing the down-regulated levels in reduced glutathione, superoxide dismutase, and interleukin-10. CANA significantly inhibited caspase-3 level while rescued survivin expression in colons. Finally, CANA reduced the elevated levels of pyruvic acid and G6PDH activity, as well as the levels of p22phox and NOX2 in the AA-induced colitis. ConclusionOur findings provide novel evidence that CANA has protective and therapeutic effects against AA-induced colitis by the impact of its antioxidant, anti-inflammatory, and anti-apoptotic effects.

Macrophage-like iPS-derived Suppressor Cells Reduce Th1-mediated Immune Response to a Retinal Antigen

ABSTRACT Purpose To investigate the immunotherapeutic effects of macrophage-like induced pluripotent stem (iPS) cell-derived suppressor cells (SCs) in ocular immune response and experimental autoimmune uveoretinitis (EAU). Methods The genes of Oct3/4, Sox2, Klf4, and c-Myc were transferred to B cells enriched from the spleen cells of C57BL/6 mice by using retrovirus vectors. Transferred B cells were cultured for 17 days to obtain colonies of iPS cells. Through additional steps, iPS-SCs were induced. An antigen-specific T cell proliferation assay was performed with CD4+ T cells collected from draining lymph nodes of the mice immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide and co-cultured with iPS-SCs. Cytokine concentrations in the culture supernatant were examined. Mice were immunized with hIRBP peptide to induce EAU. The iPS-SCs were administered into the mice one day before the induction of EAU. Results The iPS-SCs decreased hIRBP-specific T cell proliferation depending on the number of cells. Productions of tumor necrosis factor-α and interferon-γ were significantly decreased; however, transforming growth factor-β1, nitric oxide, interleukin (IL)-13, IL-17A, and IL-17 F levels were elevated in the supernatant when the collected T cells were co-cultured with iPS-SCs. The iPS-SCs had immunosuppressant effects even without cell-to-cell contact, and their effects were non-specific to the antigen preloaded on iPS-SCs. EAU was significantly milder in the mice administered iPS-SCs prior to immunization. Conclusions Macrophage-like iPS-SCs reduced Th1 immune response to a retinal antigen and Th1-mediated EAU in mice. These results showed the possibility of the application of iPS technology to the treatment of noninfectious ocular inflammation, endogenous uveitis, in the future.

Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice.

Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.

Glucocorticoid (GC) Induced Cytokine Expression in CD4+ T Cells Is a Candidate Biomarker for Clinical Steroid Response in Patients with Immune Thrombocytopenia

IntroductionWhen a group of patients with Immune thrombocytopenia (ITP) (Bristol, UK) were asked to help prioritise research questions they identified glucocorticoid (GC) side effects, relapses and a trial and error approach to ITP treatment as the most impactful problems from their perspective. Although high dose GCs remain the most common first line treatment for adults with ITP and are recommended in guidelines, side effects are very common, with a survey reporting 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects (Brown et al, BMC Blood disorders, 2012; 12:2). Heterogeneous responses and high relapse rates are also significant problems; approximately 20% of patients with ITP are refractory to GCs, so-called steroid-resistant (SR) individuals, and only approximately 20% of patients maintain long term remission. There is currently no way to predict the success of GC treatment prior to administration. Consequently, there is an unmet need for a clinically validated biomarker of clinical GC responsiveness. This would help personalise treatments, ensuring GCs are only given to patients likely to benefit, whilst more efficacious treatments are given earlier to those expected to be SR.Immune cells can be isolated from patients' peripheral blood and cultured in vitro to examine their responses to GCs. Different CD4+ T cell subsets have differential responses to GC treatment, and we have recently shown that CD4+ T cells expressing the cytokine interleukin (IL)-17 (so-called Th17 cells) are GC resistant (Schewitz-Bowers et al, PNAS, 2015, 112(30):4080-5). The expression of the anti-inflammatory cytokine IL-10 has previously been reported to be impaired in T cells from SR asthma patients (Xystrakis et al, J. Clin. Invest., 2006, 116:146-155), and in the most pro-inflammatory subtypes of Th17 cells (Ramesh et al, J. Exp. Med., 2014, 211(1):89-104). We therefore hypothesized that poor clinical response to GCs can be predicted by analyzing the expression of IL-17 and IL-10 in patients' CD4+ T cells exposed to GCs in vitro .MethodsFollowing informed written consent, peripheral blood was drawn from patients with ITP requiring first line steroid treatment registered at University Hospitals Bristol, UK. Of these, 22 demonstrated complete response to steroid treatment with platelet count rising >100 x109/L within 2 weeks of treatment (steroid sensitive, SS) and 10 were refractory to treatment with a platelet count remaining <30x109/L following 2 weeks of treatment (steroid resistant, SR). Blood samples from patients with non-infectious intraocular inflammation (uveitis: an autoimmune condition treated with steroids) were also taken as a control disease cohort (SS n=14, SR n=21). CD4+ T cells were isolated and activated via the T cell receptor with anti-CD3/anti-CD28 T cell activation beads in the presence or absence of the synthetic GC Dexamethasone (Dex). After 96 hours of culture, intracellular cytokine expression of IL-10 and IL-17 was examined by multiparameter flow cytometry.ResultsCD4+ T cells isolated from clinically SR ITP patients showed higher expression of IL-17 and lower expression of IL-10, resulting in a reduced IL-10:IL-17 ratio when activated with anti-CD3/anti-CD28 beads in the presence of Dex (Figure 1A), compared to clinically SS patients (p=0.0015). Similar results were found in patients with uveitis (aCD3/aCD28+Dex SS vs SR p=0.0044), corroborating this finding (Figure 1B).ConclusionThese data suggest that CD4+ T cells are important mediators of clinical response to steroid treatment and that the cytokine signature of CD4+ T cells may form the basis of a laboratory biomarker to help predict clinical response to GC treatment for patients with ITP as well as those with other autoimmune conditions. This would aid clinical decisions for patients, potentially maximizing treatment efficacy while minimizing side-effects. [Display omitted] DisclosuresBradbury:Novartis: Consultancy, Other: Travel support; Amgen: Other: Conference attendence; BMS Pfizer: Consultancy, Honoraria, Speakers Bureau; Bayer: Other: Conference attendence. Lee:EMD Serono: Consultancy; University of Bristol: Patents & Royalties: International Patent Application No: PCT/GB2014/053804 / US Patent application No. 61/919,404 (A biomarker and companion therapeutic for steroid refractory diseases); Nanomerics: Consultancy; Roche: Consultancy, Research Funding.

Molecular Changes on Maternal-Fetal Interface in Placental Abruption-A Systematic Review.

Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious after-effects and a marked risk of maternal and fetal mortality. Despite the fact that numerous placental abruption risk factors are known, the pathophysiology of this issue is multifactorial and not entirely clear. The aim of this review was to examine the current state of knowledge concerning the molecular changes on the maternal–fetal interface occurring in placental abruption. Only original research articles describing studies published in English until the 15 March 2021 were considered eligible. Reviews, book chapters, case studies, conference papers and opinions were excluded. The systematic literature search of PubMed/MEDLINE and Scopus databases identified 708 articles, 22 of which were analyzed. The available evidence indicates that the disruption of the immunological processes on the maternal–fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic non-infectious inflammation and augmented immunological cytotoxic response were found to be present in placental abruption samples in the reviewed studies. Various molecules participate in this process, with only a few being examined. More advanced research is needed to fully explain this complicated process.

Involvement of chronic inflammation via monocyte chemoattractant protein-1 in uraemic cardiomyopathy: a human biopsy study.

AimsPatients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms‐like tyrosine kinase‐1 (Flt‐1) is correlated with renal function, and PlGF/Flt‐1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples.Methods and resultsThe clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P < 0.001). The number of infiltrated CD68‐positive macrophages in the myocardium and expression of monocyte chemoattractant protein‐1 (MCP‐1) in cardiomyocytes were significantly greater in the UCM group than in the other groups (P < 0.001, respectively). Furthermore, while the serum level of soluble form of Flt‐1, an endogenous inhibitor of PlGF, in the UCM group was lower compared with that in the DCM group (P < 0.001), the serum levels of PlGF and PlGF/soluble form of Flt‐1 ratio and plasma level of MCP‐1 in the UCM group were higher than those in the DCM group (P < 0.001, respectively).ConclusionsThese results suggest that activated PlGF/Flt‐1 signalling and subsequent macrophage‐mediated chronic non‐infectious inflammation via MCP‐1 in the myocardium are involved in the pathogenesis of UCM.

Ailevi Akdeniz Ateşi tanılı çocuklarda gecikmiş atrial ileti zamanı

Introduction: Familial Mediterranean Fever (FMF) is a disease with recurrent fever, characterized by painful, noninfectious inflammation of the serous membranes. It mostly affects Armenians, Turks, Arabs and Jews. Prolonged inflammation in FMF may lead to atrial fibrosis which can cause the deterioration of atrial conduction time and refractory periods of atrial myocardium.In the present study we aimed to assess atrial conduction time in children with FMF.Methods: The study included 36, children diagnosed with FMF(17 males/19 females, 13 (7-15) years) and 20 control(7 males/13 females, 11 (9-16) years) cases in our Pediatric Outpatient Clinic between October 2015 and October 2016. Tissue Doppler Echocardiography (TDE) measurements of intra-and interatrial electromechanical delay were done. P wave dispersion (Pdisp) was calculated from the 12-lead electrocardiogram.Results: Inter-atrial (Lateral PA– Tricuspid PA) and Intra-left (Lateral PA-Septal PA) atrial electromechanical delay were significantly longer in FMF patients (P&amp;lt;0.001,respectively). (PA: the time range between the beginning of the P wave in the surface electrocardiogram and the beginning of the tissue Doppler late diastolic wave A). Also, P-wave dispersion (Pdisp) were significantly higher in FMF patients( p= 0.002).Conclusions: This study shows that atrial electromechanical delay and Pdisp are prolonged in children with FMF. We recommend that atrial conduction time be measured for children diagnosed with FMF.