Corticosteroid Response Research Articles

Assessment of the role of fractional exhaled nitric oxide as a predictor of airway eosinophilia and corticosteroid responsiveness in patients with chronic cough

BackgroundFractional exhaled nitric oxide (FeNO) can be used as a rapid indicator of eosinophilic airway inflammation and steroid responsiveness in patients with bronchial asthma, but this role in chronic cough is still questionable. So, this study was carried out to assess the role FeNO as a predictor of airway eosinophilia and inhaled steroids responsiveness in patients with chronic cough. This prospective study included 70 patients with undiagnosed chronic cough and 20 healthy non-smoker control group. Sputum eosinophils % and FeNO were measured before and after a 4-week treatment trial with high dose inhaled corticosteroids. The optimal cut-off value of FeNO to predict sputum eosinophilia and the responsiveness of cough for corticosteroids were determined.ResultsForty-five patients (64.3%) of the studied 70 patients with chronic cough responded to the 4-week trial of inhaled steroids. In the steroid responder group, FeNO and sputum eosinophils % were significantly higher than in the non-responder group. There was a significant positive correlation between FeNO and sputum eosinophils %. The optimal cut-off value of FeNO to detect airway eosinophilia was 33 ppb (with 65% sensitivity and 80% specificity) The ROC AUC was 0.757 and the optimal cut-off value of FeNO to predict corticosteroids responsiveness was 34.5 ppb (with 85% sensitivity and 90% specificity). The ROC AUC was 0.835.ConclusionFeNO can be used as a rapid and non-invasive diagnostic tool of airway eosinophilic inflammation and as a predictor for steroid responsiveness in patients with chronic cough.

Approach to the patient with acute severe autoimmune hepatitis.

SummaryAutoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.

Risk factors and appropriate therapeutic strategies for thrombotic microangiopathy after allogeneic HSCT

AbstractTransplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, so far, no large cohort study determined the risk factors and the most effective therapeutic strategies for TA-TMA. Thus, the present study aimed to clarify these clinical aspects based on a large multicenter cohort. This retrospective cohort study was performed by the Kyoto Stem Cell Transplantation Group (KSCTG). A total of 2425 patients were enrolled from 14 institutions. All patients were aged ≥16 years, presented with hematological diseases, and received allo-HSCT after the year 2000. TA-TMA was observed in 121 patients (5.0%) on day 35 (median) and was clearly correlated with inferior overall survival (OS) (hazard ratio [HR], 4.93). Pre- and post-HSCT statistically significant risk factors identified by multivariate analyses included poorer performance status (HR, 1.69), HLA mismatch (HR, 2.17), acute graft-versus-host disease (aGVHD; grades 3-4) (HR, 4.02), Aspergillus infection (HR, 2.29), and veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS; HR, 4.47). The response rate and OS significantly better with the continuation or careful reduction of calcineurin inhibitors (CNI) than the conventional treatment strategy of switching from CNI to corticosteroids (response rate, 64.7% vs 20.0%). In summary, we identified the risk factors and the most appropriate therapeutic strategies for TA-TMA. The described treatment strategy could improve the outcomes of patients with TA-TMA in the future.

Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy.

BackgroundDuchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment.Methods and FindingsWe enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in the TNFRSF10A gene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N = 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results.ConclusionWe have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.

A Sputum 6 Gene Expression Signature Predicts Inflammatory Phenotypes and Future Exacerbations of COPD.

BackgroundThe 6 gene expression signature (6GS) predicts inflammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway inflammation are similar, suggesting the 6GS may be useful. This study determines the diagnostic and prognostic ability of 6GS in predicting inflammatory phenotypes and exacerbation risk in COPD.MethodsWe performed 2 studies: a cross-sectional phenotype prediction study in stable COPD (total N=132; n=34 eosinophilic (E)-COPD, n=42 neutrophilic (N)-COPD, n=39 paucigranulocytic (PG)-COPD, n=17 mixed-granulocytic (MG)-COPD) that assessed 6GS ability to discriminate phenotypes (eosinophilia≥3%; neutrophilia≥61%); and a prospective cohort study (total n=54, n=8 E-COPD; n=18 N-COPD; n=20 PG-COPD; n=8 MG-COPD, n=21 exacerbation prone (≥2/year)) that investigated phenotype and exacerbation prediction utility. 6GS was measured by qPCR and evaluated using multiple logistic regression and area under the curve (AUC). Short-term reproducibility (intra-class correlation) and phenotyping method agreement (κ statistic) were assessed.ResultsIn the phenotype prediction study, 6GS could accurately identify and discriminate patients with E-COPD from N-COPD (AUC=96.4%; p<0.0001), PG-COPD (AUC=88.2%; p<0.0001) or MG-COPD (AUC=86.2%; p=0.0001), as well as N-COPD from PG-COPD (AUC=83.6%; p<0.0001) or MG-COPD (AUC=87.4%; p<0.0001) and was reproducible. In the prospective cohort study, 6GS had substantial agreement for neutrophilic inflammation (82%, κ=0.63, p<0.001) and moderate agreement for eosinophilic inflammation (78%, κ=0.42, p<0.001). 6GS could significantly discriminate exacerbation prone patients (AUC=77.2%; p=0.034). Higher IL1B levels were associated with poorer lung function and increased COPD severity.Conclusion6GS can significantly and reproducibly discriminate COPD inflammatory phenotypes and predict exacerbation prone patients and may become a useful molecular diagnostic tool assisting COPD management.

Glucocorticoid Receptor Polymorphisms in Children Undergoing Congenital Heart Surgery with Cardiopulmonary Bypass.

We conducted a candidate gene association study to test the hypothesis that different gene polymorphisms will be associated with corticosteroid responsiveness and study outcomes among children undergoing congenital heart surgery. This is a prospective observational cohort study at a large, tertiary pediatric cardiac center on children undergoing corrective or palliative congenital heart surgery. A total of 83 children were enrolled. DNA was isolated for three polymorphisms of interest namely N363 (rs56149945) and 9β (rs6198) associated with increased sensitivity to corticosteroids and Bcl I (rs41423247) associated with decreased sensitivity to corticosteroids. Duration of inotropic use, low cardiac output scores (LCOS), and vasoactive inotrope scores were examined in relation to these three polymorphisms. Using Kaplan-Meier analysis, heterozygous individuals showed longer transcriptional intermediary factor (TIF) compared with wild type for N363 polymorphism ( p = 0.05). In multivariable Cox regression, heterozygous alleles for 9β polymorphism showed significantly shorter TIF compared with wild type (hazard ratio = 2.04 [1.08-3.87], p = 0.03). The relationship between lower LCOS scores and alleles groups was significant for 9β heterozygous polymorphism only (1.5 [1-2.2], p = 0.01) in comparison to wild type and homozygous. The presence of heterozygote alleles for the increased corticosteroid sensitivity is associated with longer TIF compared with wild type. Conversely, the presence of heterozygous alleles for the decreased sensitivity to corticosteroids is associated with shorter TIF compared with wild type.

Outcome and risk of ocular complications of managing children with chronic anterior uveitis with topical rimexolone 1.

To investigate the efficacy and safety of 1% rimexolone ophthalmic suspension in children with chronic anterior uveitis under real-life conditions in a tertiary center. This is a retrospective longitudinal study. Medical records were analyzed at baseline, 1, 3, 6 and 12months before and after switching to rimexolone for best-corrected visual acuity (BCVA), oral steroid use, number of flares, IOP and anti-glaucoma management. Twenty-four patients (41 eyes) diagnosed with either anterior uveitis (n = 25, 60.0%) or panuveitis (n = 16, 40%) were enrolled. The mean age was 10.5years (4-16years). The number of patients requiring oral prednisolone reduced from 8 patients (32.0%) at baseline to 3 patients (20.0%) at 12months (P < 0.001). Following baseline, the median number of uveitis flares reduced from 2.0 (inter-quartile range (IQR) 1.0-2.75) to 1.0 (IQR 0.0-1.0) compared to the 12months before baseline (P < 0.001). The mean IOP reduced from baseline (22.0 ± 7.3mmHg) to 1month (18.8 ± 8.7mmHg, P = 0.01) and remained stable up to 12months (15.9 ± 5.0mmHg, P < 0.001). Average BCVA, dose of oral prednisolone and anti-glaucoma treatments did not change compared to the baseline. The development for IOP ≥ 30mmHg was associated with a known corticosteroid response [odds ratio (OR) 6.8, P = 0.003] and a dose > 7.5mg/day oral prednisolone (OR 4.4, P = 0.033). Rimexolone 1% ophthalmic suspension is an effective and safe topical steroid for pediatric anterior uveitis.

Leukocyte MOrphology and CORticosteroids Response in SEPtic Patients (MOCORSEP)

Leukocyte MOrphology and CORticosteroids Response in SEPtic Patients (MOCORSEP)

P205 CONCORDANCE OF CHANGES IN EXHALED NITRIC OXIDE, ACQ7, ASTHMA SYMPTOMS AND LUNG FUNCTION

The domains of asthma, symptoms, lung function, asthma control, and airway inflammation may change discordantly. A corticosteroid response study provided an opportunity to study these domains.

Mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium

COPD is characterized by chronic lung inflammation and irreversible lung tissue damage. Inhaled noxious gases, including cigarette smoke, are the major risk factor for COPD. Inhaled smoke first encounters the epithelial lining of the lungs, causing oxidative stress and mitochondrial dysfunction. We investigated whether a mitochondrial defect may contribute to increased lung epithelial pro-inflammatory responses, impaired epithelial repair and reduced corticosteroid sensitivity as observed in COPD. We used wild-type alveolar epithelial cells A549 and mitochondrial DNA-depleted A549 cells (A549 Rho-0) and studied pro-inflammatory responses using (multiplex) ELISA as well as epithelial barrier function and repair (real-time impedance measurements), in the presence and absence of the inhaled corticosteroid budesonide. We observed that A549 Rho-0 cells secrete higher levels of pro-inflammatory cytokines than wild-type A549 cells and display impaired repair upon wounding. Budesonide strongly suppressed the production of neutrophil attractant CXCL8, and promoted epithelial integrity in A549 wild-type cells, while A549 Rho-0 cells displayed reduced corticosteroid sensitivity compared to wild-type cells. The reduced corticosteroid responsiveness may be mediated by glycolytic reprogramming, specifically glycolysis-associated PI3K signaling, as PI3K inhibitor LY294002 restored the sensitivity of CXCL8 secretion to corticosteroids in A549 Rho-0 cells. In conclusion, mitochondrial defects may lead to increased lung epithelial pro-inflammatory responses, reduced epithelial repair and reduced corticosteroid responsiveness in lung epithelium, thus potentially contributing to the pathogenesis of COPD.

Development and initial validation of the Asthma Severity Scoring System (ASSESS)

Tools for quantification of asthma severity are limited. We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. ASSESS scores ranged from 0 to 20 (8.78± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

The 2016-2019 ImmunoTOX Assessment Board Report: Results from a Descriptive Real-Life Study of a Collaborative Management of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

Background: Although immunotherapy is globally better tolerated than chemotherapy, immune checkpoint inhibitors may be associated with immune-related adverse events (irAEs) characterized by their diversity, unpredictability, and corticosteroid responsiveness. We investigate the ImmunoTOX meeting's activities, a multidisciplinary real life and case-by-case approach to manage irAEs, to capture the salient medical needs in the management immunological toxicities. Methods: The ImmunoTOX assessment board is an academic, multidisciplinary group of oncologists and organ specialists that was set up in April 2016 at Gustave Roussy cancer centre in France. It meets every two weeks to discuss the case-by-case management of patients presenting with irAEs. This report describes ImmunoTOX's meeting activities between April 6th, 2016, and January 2nd, 2019. Findings: Over the 32 months of study period, 398 requests concerning 356 patients were submitted to the ImmunoTOX board. The most common tumour types of patients were thoracic cancers (n=105, 29%), skin cancers (n=82, 23%), and renal carcinomas (n=28, 8%). The requests most frequently asked were causal link between immunotherapy and adverse event, (n=148, 37%), the possibility for retreatment after hold due to previous adverse event (n=109, 27%), the clinical management of complex situation (n=100, 25%), and the initiation of immunotherapy in patients with pre-existing comorbidities (n=41, 10%). The ImmunoTOX board found a relationship between immunotherapy and adverse event in 273 (77%) of the 356 patients. The organ systems most frequently involved by irAEs were the lung (n=58, 21%), gastrointestinal tract (n=36, 13%), liver or biliary tract (n=33, 12%), musculoskeletal system (n=27, 10%) and nervous system (n=23, 8%). The retreatment by immunotherapy after holding due to previous adverse event and the initiation of immunotherapy in patients with pre-existing autoimmune comorbidities, were assessed as precaution for use and not formally contraindication in 65% and 93% of the cases, respectively. Interpretation: The medical needs in the management of immune-related adverse events involve five salient organ systems, namely the lung, gastrointestinal, liver and biliary tract, musculoskeletal and nervous systems. Retreatment after holding due to previous adverse events and immunotherapy initiation in patients with autoimmune comorbidities were mostly assessed as precaution for use and not formal contraindication. A multidisciplinary and case by case approach can be helpful and complementary of general guidelines in the management of immunological toxicities. Clinical Registration Number: The study was registered with the French National Data Protection Commission (Commission Nationale de l’Informatique et des Libertes; reference: 2098694v0). Funding Statement: Gustave Roussy and the Gustave Roussy Immunotherapy Programme. Ethical Approval Statement: All the patients gave their verbal, informed consent to the publication of their anonymized data, and the study was approved by the institutional review board at Gustave Roussy (Villejuif, France).

GLCCI1 and STIP1 variants are associated with asthma susceptibility and inhaled corticosteroid response in a Tunisian population

Objective: Pharmacogenetic studies have recognized specific genes that highly correlate with response to inhaled corticosteroids (ICS) treatment in asthma patients. Among the genes identified, we selected glucocorticoid-induced transcript 1 (GLCCI1) and stress-induced phosphoprotein 1 (STIP1) to evaluate the impact of these gene polymorphisms on ICS treatment response in Tunisian asthmatics.Methods: We analyzed four single nucleotide polymorphisms (SNPs): two in GLCCI1 (rs37972 and rs37973), and two in STIP1 (rs2236647 and rs2236648), which are genes associated with susceptibility to asthma and response to ICS in a Tunisian cohort. The SNPs were genotyped using reverse transcriptase polymerase chain reaction (RT-PCR) techniques.Results: This case–control study consisted of 230 adult asthmatic patients and 236 healthy subjects. Seventy-five asthmatics were selected and followed through 12 weeks of routine treatment. The T allele rs2236648 in STIP1 was associated with allergic asthma (OR = 0.38, 95%CI = 0.20–0.69, p = 0.001). The rs37972 and rs37973 of GLCCI1 were associated with a higher risk of asthma (p < 0.001). The T allele rs37972 and G allele rs37973 were correlated with a strong risk for developing severe asthma (p < 0.001). Asthma patients carrying the rs37973 GG genotype had less improvement in the forced expiratory volume in one second (FEV1) than those with the AA or AG genotypes after 12 weeks of treatment (p < 0.001). Also, the G allele of rs37973 was associated with worse response to ICS after 12 weeks of treatment (p < 0.001).Conclusion: The rs37972 and rs37973 polymorphisms can serve as potential asthma risk biomarkers in a Tunisian population.

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.

Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P<0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q=0.03) in all cohorts and lower IL12B expression (ρ=0.34, P=0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q=0.04) in all cohorts and higher CORT expression (ρ=0.20, P=0.045) in CAMP. Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.

Neutrophils as a Protagonist and Target in Chronic Rhinosinusitis.

Neutrophils have traditionally been acknowledged as the first immune cells that are recruited to inflamed tissues during acute inflammation. By contrast, their importance in the context of chronic inflammation has been studied in less depth. Neutrophils can be recruited and are largely present in the nasal mucosa of patients with chronic rhinosinusitis (CRS) both in Asians and in Caucasians. Increased infiltration of neutrophils in patients with CRS has been linked to poor corticosteroid response and disease prognosis. Meanwhile, tissue neutrophils may possess specific phenotypic features distinguishing them from resting blood counterparts and are endowed with particular functions, such as cytokines and chemokines production, thus may contribute to the pathogenesis of CRS. This review aims to summarize our current understanding of the pathophysiologic mechanisms of CRS, with a focus on the roles of neutrophils. We discuss recruitment, function, and regulation of neutrophils in CRS and outline the potential therapeutic strategies targeting neutrophils.

Different endotypes and phenotypes drive the heterogeneity in severe asthma.

The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type-2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type-2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non-type-2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.

Discovery of potential urine-accessible metabolite biomarkers associated with muscle disease and corticosteroid response in the mdx mouse model for Duchenne.

Urine is increasingly being considered as a source of biomarker development in Duchenne Muscular Dystrophy (DMD), a severe, life-limiting disorder that affects approximately 1 in 4500 boys. In this study, we considered the mdx mice—a murine model of DMD—to discover biomarkers of disease, as well as pharmacodynamic biomarkers responsive to prednisolone, a corticosteroid commonly used to treat DMD. Longitudinal urine samples were analyzed from male age-matched mdx and wild-type mice randomized to prednisolone or vehicle control via liquid chromatography tandem mass spectrometry. A large number of metabolites (869 out of 6,334) were found to be significantly different between mdx and wild-type mice at baseline (Bonferroni-adjusted p-value < 0.05), thus being associated with disease status. These included a metabolite with m/z = 357 and creatine, which were also reported in a previous human study looking at serum. Novel observations in this study included peaks identified as biliverdin and hypusine. These four metabolites were significantly higher at baseline in the urine of mdx mice compared to wild-type, and significantly changed their levels over time after baseline. Creatine and biliverdin levels were also different between treated and control groups, but for creatine this may have been driven by an imbalance at baseline. In conclusion, our study reports a number of biomarkers, both known and novel, which may be related to either the mechanisms of muscle injury in DMD or prednisolone treatment.

Value of Extracellular High Mobility Group Box 1 (HMGB1) in the Clinical Context of Immune Thrombocytopenia

Introduction: High mobility group box 1 protein (HMGB1) is a non-histone chromosomal protein with dual activity. First within the nucleus, binds to DNA and acts as a regulator and second, outside the cell, interacts with receptors for inflammation as a signal molecule. We aimed to investigate and contribute to the value of extracellular HMGB1 in clinical context of ITP and to flourish future clinical directions to this biomarker. Methods: 50 newly diagnosed and treatment naive patients with ITP and 30 healthy controls were enrolled in our study. Results: Age or gender were not related with HMGB1 levels in patients and controls. Platelet levels were significantly related with HMGB1. Especially in patients with platelet counts below 30.000/mm3 highest levels of HMGB1 were observed. Regarding clinical presentation, bleeding was related with low platelet counts and high HMGB1 levels. Response to corticosteroids was observed to be better in patients with high HMGB1 levels. Conclusion: As a sample of autoinflammatory disorders, we observed a relation with extracellular HMGB1 levels and platelet levels in ITP patients. Corticosteroid response and HMGB1 relation supports the assumption of the value of HMGB1 as a potential surrogate of inflammation. This view should be evaluated with larger scale studies.

Long-lasting behavioral and neuroendocrine changes provoked in rabbits by cancelling a single nursing bout in early lactation.

To restore estrus in lactating doe rabbits, nursing was prevented on lactation day 10 and allowed again from day 12 onward. This "biostimulation" procedure, used to accelerate reproduction, allows kit survival despite a 48hr fast. Yet, the consequences of "biostimulation" on their psychobiological and neuroendocrine development are largely unknown. Therefore, we determined, in adult males and females, tested in the morning or afternoon: corticosteroid secretion (baseline and reactive), sexual behavior, and responses in six tests measuring stress/anxiety. The latter were not affected by maternal deprivation or time of testing in either sex. The lordosis quotient was reduced in deprived does (relative to controls), an effect eliminated when only non-kins (of both groups) were compared. Deprived males showed altered sexual behavior, evidenced by a large number of mounts not culminating in ejaculation. Corticosterone and cortisol secretion increased (relative to baseline) following i.m. saline in all groups, but the magnitude of the response was affected by maternal deprivation, time of day, and sex. Results indicate that particular behaviors and reactivity to stress have different thresholds regarding the effects of mother-litter separation in early lactation.

Neutrophil-to-lymphocyte ratio: An effective predictor of corticosteroid response in IgA nephropathy

BackgroundThe neutrophil-to-lymphocyte ratio (NLR) has been shown to have a strong predictive ability for the prognosis of various diseases. However, the role of the NLR in IgA nephropathy is currently unknown. In this study, we attempted to evaluate how useful the NLR is for predicting corticosteroid response in IgA nephropathy. MethodsFor retrospective cohort with IgA nephropathy, the patients who received corticosteroid therapy were recruited. To identify independent factors for corticosteroid response, the NLR and other parameters were analyzed using the multivariate regression model. The predictive usefulness was determined by the area under the receiver operating characteristics curve (AUROC). Survival analysis was conducted to compare the corticosteroid response between different groups according to the cut-off of NLR. ResultsMultivariate analyses showed that NLR, serum creatinine, uric acid, and estimated glomerular filtration rate (eGFR) were independent factors for corticosteroid response. The AUROC of NLR (0.748) was higher than those of other factors. Patients with NLRs <2.43 had a higher remission rate than those with NLR ≥2.43 (P < 0.001). ConclusionNLR is an effective predictor of corticosteroid response in IgA nephropathy.