Elevated Interleukin-6 Levels Research Articles

Impact of General Anesthesia and Antioxidants on Cognitive, Static and Locomotor Functions During Laparoscopic Cholecystectomy

Aim of the study: to reduce cognitive impairment during laparoscopic cholecystectomy by perioperative administration of drugs with antihypoxic and antioxidant effects under the control of stabilography. Materials and methods. We studied the effect of general anesthesia and antioxidants on cognitive, static and locomotor functions during laparoscopic cholecystectomy. We studied 90 patients with acute calculous cholecystitis randomized into three experimental groups (n=30, each group). The control group was composed of 24 healthy individuals. Group 1 patients received no antioxidants, group 2 patients received the combination antioxidant drug (sodium fumarate+sodium chloride+potassium chloride+magnesium chloride) in the post-operative period, and group 3 patients received methylethylpyridinol. The patient groups were comparable in sex, age and type of inflammatory and destructive process in the gallbladder. Surgical intervention was performed under endotracheal anesthesia. Premedication with atropine and promedol was given, and anesthesia induction was carried out with propofol, fentanyl and suxamethonium. Sevoflurane, fentanyl andcisatracurium were employed to maintain anesthesia, analgesia and myorelaxation, respectively. The patients were examined before surgery, 24 and 48 hours after surgery. In the groups of patients who received antioxidant therapy, blood sampling for hematological and biochemical examinations was performed 30 min after the administration of antioxidants. Stabilographic studies and MoCA test (Montreal Scale) were performed before antioxidant administration prior to surgery and after surgery, on days 2 and 3. Results. Neuropsychological testing revealed postoperative cognitive dysfunction on standard therapy which included impaired attention and concentration, executive function, memory, speech, visual constructional skills, abstract thinking, counting, and orientation (21 points on the MoCA scale versus 28–30 points for normal). We found that the pathogenetic factors of cognitive dysfunction included insufficient antioxidant protection, decreased TNF-α and elevated interleukin-18 levels along with an increased level of C-reactive protein in plasma, which manifested as activation of free-radical oxidation processes and reduced antioxidant system and performance of nonspecific resistance. Perioperative use of the combination antioxidant drug and methylethylpyridinol antioxidants reduced the frequency and severity of postoperative cognitive impairment in patients after laparoscopic cholecystectomy. Conclusion. The most important pathogenetic factors of cognitive dysfunction after laparoscopic cholecystectomy include activation of free-radical oxidation, reduction of antioxidant defense system performance and lack of nonspecific resistance factors. Adding the combination antioxidant drug or methylethylpyridinol to the standard therapy reduces the intensity of radical oxygen species generation, maintains the antioxidant potential, activates production and secretion of nonspecific resistance factors, preventing the development and reducing the severity of cognitive disorders in the perioperative period. Neuropsychological testing and stabilographic examination allow identifying the risk of cognitive disorders in patients after laparoscopic cholecystectomy and provide a rationale for the use of antioxidant therapy for their prevention.

Comorbidities and laboratory parameters associated with SARS-CoV-2 infection severity in patients from the southeast of Mexico: a cross-sectional study.

Background. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic. Among the risk factors associated with the severity of this disease is the presence of several metabolic disorders. For this reason, the aim of this research was to identify the comorbidities and laboratory parameters among COVID-19 patients admitted to the intensive care unit (ICU), comparing the patients who required invasive mechanical ventilation (IMV) with those who did not require IMV, in order to determine the clinical characteristics associated with the COVID-19 severity. Methods. We carried out a cross-sectional study among 152 patients who were admitted to the ICU from April 1 st to July 31 st, 2021, in whom the comorbidities and laboratory parameters associated with the SARS-CoV-2 infection severity were identified. The data of these patients was grouped into two main groups: "patients who required IMV" and "patients who did not require IMV". The nonparametric Mann-Whitney U test for continuous data and the χ2 test for categorical data were used to compare the variables between both groups. Results. Of the 152 COVID-19 patients who were admitted to the ICU, 66 required IMV and 86 did not require IMV. Regarding the comorbidities found in these patients, a higher prevalence of type 2 diabetes mellitus (T2DM), hypertension and obesity was observed among patients who required IMV vs. those who did not require IMV ( p<0.05). Concerning laboratory parameters, only glucose, Interleukin 6 (IL-6), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were significantly higher among patients who required IMV than in those who did not require IMV ( p<0.05). Conclusion. This study performed in a Mexican population indicates that comorbidities such as: T2DM, hypertension and obesity, as well as elevated levels of glucose, IL-6, LDH and CRP are associated with the COVID-19 severity.

Gabexate Mesylate-Poloxamer 407 Conjugate Alleviates Sodium Taurocholate-Induced Severe Acute Pancreatitis in an Optimized Rat Model.

We have previously shown that gabexate mesylate-poloxamer 407 conjugate (GMTI) alleviates traumatic pancreatitis in rats. In this study, we evaluated the therapeutic effect of GMTI on sodium taurocholate-induced severe acute pancreatitis (SAP) in an optimized rat model. An SAP rat model was established via microinjection of 3.5% sodium taurocholate and retention in the bile duct for 1min. SAP rats were administered GMTI via tail vein injection (i.v.) or tail vein injection + intraperitoneal injection (i.v. + i.p.). All rats were sacrificed at 12h after treatment. Biochemical approach and enzyme-linked immunosorbent assay were performed to measure the serum levels of amylase (AMY), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Hematoxylin and eosin staining and TUNEL assay were conducted to examine histopathology and acinar cell apoptosis in the rat pancreas. SAP was successfully induced in all model rats, as evidenced by progressively aggravating SAP symptoms and signs, pancreatic histopathological abnormalities, as well as elevated serum levels of TNF-α, IL-6, and AMY. The mortality rates at 1h, 6h, and 12h were 0%, 0%, and 25%, respectively. GMTI therapy via i.v. or i.v. + i.p. significantly reduced pancreatic wet weights, ascites amounts, pathological scores, and circulating levels of TNF-α and IL-6 while promoting acinar cell apoptosis in SAP rats. GMTI therapy via i.v. + i.p. outperformed i.v. in improving pancreatic histology and reducing TNF-α and IL-6 serum levels in SAP rats. Our optimized SAP rat model is reliable and reproducible. GMTI therapy is a promising approach against SAP.

Corticosterone potentiates ochratoxin A-induced microglial activation.

Microglial activation in the central nervous system (CNS) has been associated with brain damage and neurodegenerative disorders. Ochratoxin A (OTA) is a mycotoxin that occurs naturally in food and feed and has been associated with neurotoxicity, while corticosteroids are CNS' physiological function modulators. This study examined how OTA affected microglia activation and how corticosteroids influenced microglial neuroinflammation. Murine microglial cells (BV-2) were stimulated by OTA, and the potentiation effects on OTA-induced inflammation were determined by corticosterone pre-treatment. Expressions of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) were determined. Phosphorylation of mitogen-activated protein kinases (MAPKs) was analyzed by western blotting. OTA significantly increased the mRNA expression of IL-6, TNF-α, IL-1β, and iNOS and also elevated IL-6 and NO levels. Corticosterone pre-treatment enhanced the neuroinflammatory response to OTA in a mineralocorticoid receptor (MR)-dependent mechanism, which is associated with increases in extracellular signal-regulated kinase (ERK) and p38 MAPK activation. In response to OTA, microglial cells produced pro-inflammatory cytokines and NO, while corticosterone increased OTA-induced ERK and p38 MAPK phosphorylation via MR. Findings indicated the direct role of OTA in microglia activation and neuroinflammatory response and suggested that low corticosterone concentrations in the brain exacerbated neurodegeneration.

Comorbidities and laboratory parameters associated with SARS-CoV-2 infection severity in patients from the southeast of Mexico: a cross-sectional study

Background . Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic. Among the risk factors associated with the severity of this disease is the presence of several metabolic disorders. For this reason, the aim of this research was to identify the comorbidities and laboratory parameters among COVID-19 patients admitted to the intensive care unit (ICU), comparing the patients who required invasive mechanical ventilation (IMV) with those who did not require IMV, in order to determine the clinical characteristics associated with the COVID-19 severity. Methods. We carried out a cross-sectional study among 152 patients who were admitted to the ICU from April 1 st to July 31 st, 2021, in whom the comorbidities and laboratory parameters associated with the SARS-CoV-2 infection severity were identified. The data of these patients was grouped into two main groups: “patients who required IMV” and “patients who did not require IMV”. The nonparametric Mann–Whitney U test for continuous data and the χ 2 test for categorical data were used to compare the variables between both groups. Results. Of the 152 COVID-19 patients who were admitted to the ICU, 66 required IMV and 86 did not require IMV. Regarding the comorbidities found in these patients, a higher prevalence of type 2 diabetes mellitus (T2DM), hypertension and obesity was observed among patients who required IMV vs. those who did not require IMV ( p<0.05). Concerning laboratory parameters, only glucose, Interleukin 6 (IL-6), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were significantly higher among patients who required IMV than in those who did not require IMV ( p<0.05). Conclusion. This study performed in a Mexican population indicates that comorbidities such as: T2DM, hypertension and obesity, as well as elevated levels of glucose, IL-6, LDH and CRP are associated with the COVID-19 severity.

The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)-5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL-5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL-5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti-IL-5, anti-immunoglobulin-E, and anti-IL-4/13) may provide further evidence of how eosinophils and IL-5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL-5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL-5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL-5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP.

Inflammatory Blood Biomarker Kynurenine Is Linked With Elevated Neuroinflammation and Neurodegeneration in Older Adults: Evidence From Two 1H-MRS Post-Processing Analysis Methods.

Rationale and ObjectivesPro-inflammatory processes have been argued to play a role in conditions associated with cognitive decline and neurodegeneration, like aging and obesity. Only a limited number of studies have tried to measure both peripheral and central biomarkers of inflammation and examined their interrelationship. The primary aim of this study was to examine the hypothesis that chronic peripheral inflammation would be associated with neurometabolic changes that indicate neuroinflammation (the combined elevation of myoinositol and choline), brain gray matter volume decrease, and lower cognitive functioning in older adults.Materials and MethodsSeventy-four older adults underwent bio-impedance body composition analysis, cognitive testing with the Montreal Cognitive Assessment (MoCA), blood serum analysis of inflammatory markers interleukin-6 (IL-6) and kynurenine, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Neurometabolic findings from both Tarquin and LCModel 1H-MRS post-processing software packages were compared. The regions of interest for MRI and 1H-MRS measurements were dorsal posterior cingulate cortex (DPCC), left hippocampal cortex (HPC), left medial temporal cortex (MTC), left primary sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (DLPFC).ResultsElevated serum kynurenine levels were associated with signs of neuroinflammation, specifically in the DPCC, left SM1 and right DLPFC, and signs of neurodegeneration, specifically in the left HPC, left MTC and left SM1, after adjusting for age, sex and fat percentage (fat%). Elevated serum IL-6 levels were associated with increased Glx levels in left HPC, left MTC, and right DLPFC, after processing the 1H-MRS data with Tarquin. Overall, the agreement between Tarquin and LCModel results was moderate-to-strong for tNAA, tCho, mIns, and tCr, but weak to very weak for Glx. Peripheral inflammatory markers (IL-6 and kynurenine) were not associated with older age, higher fat%, decreased brain gray matter volume loss or decreased cognitive functioning within a cohort of older adults.ConclusionOur results suggest that serum kynurenine may be used as a peripheral inflammatory marker that is associated with neuroinflammation and neurodegeneration, although not linked to cognition. Future studies should consider longitudinal analysis to assess the causal inferences between chronic peripheral and neuroinflammation, brain structural and neurometabolic changes, and cognitive decline in aging.

Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations.

Interleukin 6 (IL-6) is a cytokine with various biological functions in immune regulation, hematopoiesis, and inflammation. Elevated IL-6 levels have been identified in several severe disorders such as sepsis, acute respiratory distress syndrome (ARDS), and most recently, COVID-19. The biological activity of IL-6 relies on interactions with its specific receptor, IL-6Rα, including the membrane-bound IL-6 receptor (mIL-6R) and the soluble IL-6 receptor (sIL-6R). Thus, inhibition of the interaction between these two proteins would be a potential treatment for IL-6 related diseases. To date, no orally available small-molecule drug has been approved. This study focuses on finding potential small molecules that can inhibit protein-protein interactions between IL-6 and its receptor IL-6Rα using its crystal structure (PDB ID: 5FUC). First, two pharmacophore models were constructed based on the interactions between key residues of IL-6 (Phe74, Phe78, Leu178, Arg179, Arg182) and IL-6Rα (Phe229, Tyr230, Glu277, Glu278, Phe279). A database of approximately 22 million compounds was screened using 3D-pharmacophore models, molecular docking models, and ADMET properties. By analyzing the interactive capability of successfully docked compounds with important amino acids, 12 potential ligands were selected for further analysis via molecular dynamics simulations. Based on the stability of the complexes, the high interactions rate of each ligand with the key residues of IL-6/IL-6Rα, and the low binding free energy calculation, two compounds ZINC83804241 and ZINC02997430, were identified as the most potential IL-6 inhibitor candidates. These results will pave the way for the design and optimization of more specific compounds to combat cytokine storm in severe coronavirus patients.

Immune Response to LinB13, a Lutzomyia Intermedia Salivary Protein Correlates With Disease Severity in Tegumentary Leishmaniasis.

We have previously shown that seropositivity to rLinB-13, a salivary protein from Lutzomyia intermedia, predicted sand fly exposure and was associated with increased risk of developing cutaneous leishmaniasis (CL). Here, we investigated the cellular immune response to saliva from Lu. intermedia, using rLinB-13 as a surrogate antigen in naturally exposed individuals presenting positive serology to LinB-13. We also investigated the response to rLinB-13 in leishmaniasis patients, displaying active ulcers and positive PCR for Leishmania braziliensis. Peripheral blood mononuclear cells (PBMCs) stimulated in vitro with rLinB-13 secreted elevated levels of interleukin-10 (IL-10), IL-4, IL-1β, IL-1α, IL-6, and chemokines (CCL3, CCL4, CCL5, and CXCL5). CL and disseminated leishmaniasis (DL) patients displayed a significantly higher immunoglobulin G (IgG) response to rLinB-13 compared with healthy subjects, and anti-rLinB-13 IgG was positively correlated with the number of lesions in DL patients. Positive serology to rLinB-13 was also associated with chemotherapy failure. PBMCs from DL patients stimulated with rLINB-13 secreted significantly higher levels of IL-10 and IL-1β compared with CL individuals. In this study, we observed an association between humoral and cellular immune response to the sand fly salivary protein rLinB-13 and disease severity in tegumentary leishmaniasis. This study brings evidence that immunity to rLinB-13 influences disease outcome in L. braziliensis infection and results indicate that positive serology to rLinB-13 IgG can be used as a marker of DL, an emerging and severe form of disease caused by L. braziliensis.

Impact of inflammatory factors, hemoglobin A1c, and platelet parameters in gestational diabetes mellitus.

The aim of this study was to evaluate the relationship among inflammatory cytokines including hypersensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), glycated hemoglobin A1c (HbA1c), and platelet distribution width (PDW) in women with gestational diabetes mellitus (GDM). Data on 191 pregnant women (96 women with GDM; 95 healthy controls) were extracted from routine prenatal examination records in Nanjing, China. Fasting concentrations of hs-CRP, IL-6, HbA1c, blood cell indices, and glucose at 24-28th gestational weeks were determined. The levels of hs-CRP, IL-6, FPG, PG1h, PG2h, HbA1c, RBC, and PDW significantly were increased (P < 0.05) in GDM group. hs-CRP had a positive correlation with HbA1c and PLT (P < 0.05). The odds ratios of HbA1c and PDW were 7.817 (95% CI 1.921-31.816, P = 0.004) and 1.523 (95% CI 1.158-2.002, P = 0.003), respectively. Furthermore, AUC of the combined diagnosis of GDM including HbA1c, FPG, and PDW reached 0.754, with specificity of 80.0% and sensitivity of 60.4%. Our findings support that elevated levels of hs-CRP, IL-6, HbA1c, and PDW at 24-28th gestational weeks even within the conventional normal range, may be implicated in the pathogenesis of GDM and their evaluation should be part of prenatal care routine.

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

BackgroundMetabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. MethodA total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. ResultsOf the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. ConclusionWe have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry.

The Fetal Inflammatory Response Syndrome (Clinical lecture)

The article highlights the problem of fetal inflammatory response syndrome (FIRS) in modern conditions. This term has been introduced into the clinical practice to describe the systemic activation of the innate or acquired immune system of the fetus. FIRS can occur in response to infection or inflammation and is divided into two types depending on the type of immune response. FIRS I and II types are different clinical syndromes and correspond to acute and chronic inflammatory processes.The main pathophysiological mechanisms and clinical features of different variants of FIRS are described. Fetuses with this syndrome have signs of multiorgan damage. The consequences of FIRS are a high rate of complications in newborns: sepsis, congenital pneumonia, intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, neurosensory deafness, necrotic enterocolitis and others. The detailed description of fetal organs and systems damage by FIRS is presented. In further life, such children are at risk of long-term complications. This syndrome can also be the cause of unexplained antenatal fetal death.Laboratory diagnostic criteria for FIRS type I include elevated levels of interleukin-6 and acute phase reagents. Histologically there are the signs of funiculitis or chorionic vasculitis.The marker of FIRS type II is the chemotactic chemokine CXCL10, which simulates maternal antifetal rejection.The article presents the basic mechanisms of the immune response in FIRS. In this type of pathology there are chronic inflammatory lesions of the placenta which are determined by histological study (chronic chorioamnionitis, vilitis of unknown etiology, chronic deciduitis).

Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes

BackgroundPrevious research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement.MethodsWe induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy.ResultsUC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen.ConclusionsOur results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future.

Elevated Levels of Interleukins, Leukocyte Protein and Cathelicidin Antimicrobial Peptide are Strongly Associated with Early to Mid-Stage of Pythium insidiosum Infection in Rabbit Corneas

PurposeCorneal infection in humans caused by Pythium insidiosum can lead to blindness and the host ocular immune response to it is less studied. Herein, we investigate the expression of mediators of innate and adaptive immune responses in a rabbit model.MethodsP. insidiosum zoospores were injected intracorneally in right eye of the nine New Zealand White rabbits while left eye was injected with 1XPBS. RT-qPCR and multiplex ELISA (mELISA) were used to study the expression of antimicrobial peptides (AMPs) and immune mediators in infected cornea on 3rd, 7th and 9th day of post-infection(PI). STRING-11.0 analysis was used to predict the interactions of immune mediators. mRNA expressions of pathogen recognition receptors (PRRs) were determined in human corneal epithelial cells (HCECs) stimulated with P. insidiosum zoospores. Data was analyzed using one-way ANOVA with Post-Hoc Tukey HSD test and p-value <0.05 was considered significant.ResultsmRNA expression assay for IL-1β, IL-6, IL-8 and Cathelicidin antimicrobial peptide (CAP)-18 showed significant upregulation (p-value < 0.05) on 7th day post-infection (PI) compared to 3rd and 9th day while Leukocyte protein (LeukoP) was elevated significantly on 3rd day followed by 7th and 9th day PI . Only IL-17A among other adaptive immune cytokines showed significant upregulation on 7th day compared to 9th day PI. Expressed in pg/mL, mELISA showed significant higher levels (p-value < 0.05) of IL-1β, IL-8 in infected tissue in each of the time points compared to control. STRING analysis revealed co-expression of IL-1β, IL-8 and IL-6. Among PRRs, Dectin 1 and TLR4 showed significant upregulation in HCECs at 12 hrs compared to 6 hrs.ConclusionIn the rabbit P. insidiosum keratitis model, innate immune mediators: IL-1β, IL-8, IL-6, AMPs: LeukoP and CAP-18 are strongly associated in early to mid-stage of corneal infection. Dectin 1 and TLR4 were observed to be associated with recognition of P. insidiosum.

Keel bone damage affects behavioral and physiological responses related to stress and fear in two strains of laying hens.

Keel bone damage (KBD) is more prevalent in alternative laying hen housing systems than in conventional cages, and its incidence differs from strain to strain. However, the information of KBD in Lindian chickens, a native Chinese strain, is limited. To investigate the effect of KBD on fearfulness and physiological indicators of stress in Lindian chickens and commercial laying hens, a total of two hundred 25-wk-old chickens (100 Hy-line Brown and 100 Lindian chickens) were studied for 7wk. The birds were housed in furnished cages with 10 birds per cage for each strain. At 32-wk of age, the birds in each strain were divided into normal (NK), deviated (DK), and fractured (FK) hens according to the keel bone status. Ten birds in each keel bone status per strain were subsequently selected to collect blood for the determination of stress and fear-related indicators, including corticosterone, serotonin, interleukin-1β, and interleukin-6, and measure fear responses, including novel object test (NOT), human approach test (HAT), and tonic immobility (TI) test. The results showed that egg production was lower and the incidence of keel bone fractures was higher in Lindian chickens than in Hy-line Brown hens (P < 0.05). Lindian chickens showed a significantly increased whole blood serotonin content, NOT-latency, HAT-score, and TI induction times (P < 0.05) and decreased serum interleukin-6 content and TI-duration (P < 0.05) compared with Hy-line Brown hens. Additionally, FK hens had significantly elevated whole blood corticosterone, serum interleukin-1β and interleukin-6 levels, TI-duration, and NOT-latency (P < 0.05), and a reduced whole blood serotonin content (P < 0.05) compared with NK and DK hens. Our results indicated that KBD affected stress and fear responses, and this impact was mainly reflected by FK hens compared with NK and DK hens. We suggest that keel bone fractures are the main factor impairing hen welfare. Besides, the incidence of keel bone fractures and stress and fear responses of Lindian chickens are more severe than Hy-line Brown laying hens, indicating that the strain type can affect the health and welfare of laying hens.

Does Cetuximab Reduce the Risk of Anemia in Patients Undergoing Radiation Therapy for Head and Neck Cancers?

<h3>Purpose/Objective(s)</h3> Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels promote RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, resulted in significantly lower rates of RT induced anemia for locally advanced head and neck squamous cell carcinoma (HNSCC) patients receiving definitive RT vs RT-alone according to Bonner et al; and other studies compared to concomitant chemotherapy. However, little is known for cases receiving cetuximab with RT in the adjuvant setting. <h3>Materials/Methods</h3> We queried our institutional HNSCC database for surgically staged non-metastatic cases that received adjuvant RT with or without concomitant cetuximab between 2006-2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. All included patients need to have at least one complete blood count pre- and post-RT end. We compared RT-cetuximab vs RT-alone for prevalence of baseline and post-RT anemia, defined as Hb below 12g/dL in females and 13g/dL in males, and mean hemoglobin (Hb) levels. We also assessed the improvement in Hb level post-RT (resolution of baseline anemia or Hb increase of at least 1g/dL above baseline), in addition to overall survival (OS) in relation to anemia/Hb dynamics. <h3>Results</h3> We were able to identify 66 patients who fit our inclusion criteria, of which 27 (41%) received RT-cetuximab, with the remaining receiving RT-alone (n=39, 59%). Median age was 62.5 years (range, 34-88 years), males 80%, black 29%, and 85% had a smoking history. The majority of cases (73%) were locally advanced. Oral cavity and oropharynx were the most common subsites (37.5% each), with HPV+ve cases representing 52% of the later. The study groups were well-balanced, except for higher rates of positive final surgical margins, and extracapsular space invasion and median RT dose (<i>p<0.05</i>). Baseline anemia was diagnosed in 70.4% in RT-cetuximab vs 76.9% in the RT-alone, p=0.76; with similar mean Hb level (11.7g/dL in both). Meanwhile, baseline iron, vitamin-B12 and folate deficiencies, and chronic kidney disease were non-different. After completion of RT, mean Hb was significantly higher in the RT-alone (12.9±1.4 g/dL) compared to RT-Cetuximab (11.9±2.1 g/dL), <i>p=0.02</i>. Nevertheless, higher anemia levels (70% vs 51%) and lower improvement of Hb post-RT (81.5% vs 92.3%) were both non-significant for RT-cetuximab vs RT-alone respectively, p>0.05 for both. On multivariate analysis, baseline anemia was associated with worse OS (p=0.0052), unlike improvement of Hb post-RT (p=0.14) with a corresponding better improvement of Hb (56.4% vs. 25.9%, p=0.014), albeit lower anemia levels (70% vs. 51%), was non significant (p=0.195). On multivariate analysis, lack of baseline anemia was associated with better OS (p=0.0052), whereas improvement of Hb post-RT was only marginal (p=0.068). <h3>Conclusion</h3> In a homogenous cohort of HNSCC patients treated postoperatively, concomitant cetuximab was not associated with lower RT-induced anemia, in contrast to previous studies.

Elevated levels of interleukin-18 are associated with several indices of general and visceral adiposity and insulin resistance in women with polycystic ovary syndrome.

Our aim was to analyze levels of proinflammatory biomarker interleukin-18 (IL-18) in healthy controls and patients with polycystic ovary syndrome (PCOS) focusing on its association with obesity, clinical, hormonal, and metabolic characteristics. Fifty-eight patients with PCOS were enrolled in the study fulfilling the Rotterdam criteria and were matched for age, body mass index (BMI), and ethnicity with 30 healthy controls. Detailed anthropometric measurements, clinical investigations, hormonal and biochemical tests were obtained between the 3rd and 5th day of a menstrual cycle. A subanalysis of the PCOS group was performed separating patients into several groups according to a waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum IL-18 levels were measured using the ELISA method. Levels of IL-18 were similar between PCOS patients and controls. IL-18 was higher in overweight/obese women compared to normal-weight women when analyzing all participants together and separately PCOS or controls group (p < 0.001, p < 0.001, p = 0.01, respectively). Additionally, IL-18 levels were higher in high-WHtR and IR subgroups compared to low-WHtR (p < 0.001) and non-IR PCOS women (p < 0.001). PCOS women with high FAI had greater serum IL-18 levels than normal-FAI patients (p = 0.002). Levels of IL-18 correlated positively with most of the anthropometric and metabolic parameters. In multiple linear regression, age, waist circumference, and fasting insulin were independently related factors with IL-18. Elevated levels of IL-18 were related to several indices of general and visceral adiposity and insulin resistance in PCOS.

Analysis of Gut Microbiota in Patients with Exacerbated Symptoms of Schizophrenia following Therapy with Amisulpride: A Pilot Study.

Evidence is mounting that the gut microbiome is related to the underlying pathogenesis of schizophrenia. However, effects of amisulpride on gut microbiota are poorly defined. This study was aimed at analyzing cytokines and fecal microbiota in patients with exacerbated symptoms of schizophrenia treated with amisulpride during four weeks of their hospital stay. In the present study, feces collected from patients with schizophrenia were analyzed using 16S rRNA pyrosequencing and bioinformatic analyses to ascertain gut microbiome composition and fasting peripheral blood cytokines. We found that patients undergoing treatment of schizophrenia with amisulpride had distinct changes in gut microbial composition at the genus level, increased levels of short-chain fatty acid-producing bacteria (Dorea and Butyricicoccus), and reduced levels of pathogenic bacteria (Actinomyces and Porphyromonas), but the level of Desulfovibrio was still high. We also found a significant downregulation of butanoate metabolism based on functional analysis of the microbiome. After treatment, elevated levels of interleukin- (IL-) 4 and decreased levels of IL-6 were found. Our findings extend prior work and suggest a possible pharmacological mechanism of amisulpride treatment for schizophrenia, which acts via mediation of the gut microbiome.

Laboratory parameters associated with prolonged hospital length of stay in COVID-19 patients in Johannesburg, South Africa

Background. Coronavirus disease (COVID-19) has imposed unprecedented stressors on South Africa (SA)’s healthcare system. Superimposed on the country’s quadruple burden of disease, pandemic-related care further exposes existing inequities. Some of these inequities are specific to hospital-based inpatient services, such as the geographical maldistribution of hospital beds, lack of oxygen supplies and assisted ventilation, and scarcity of trained healthcare workers. Certain high-risk groups, such as individuals with cardiometabolic comorbidity, are likely to develop severe COVID-19 disease requiring hospitalisation with potential for a prolonged length of stay (LoS). It may be helpful for health authorities to identify those at risk for prolonged LoS to facilitate appropriate health systems planning. Objectives. To identify hospital admission laboratory parameters associated with a hospital stay &gt;14 days in patients with COVID-19 pneumonia. Methods. A retrospective observational study design was used. Laboratory data were obtained from an SA private laboratory for 642 inpatients with suspected or confirmed COVID-19 pneumonia, comprising 7 months of admission laboratory data from six private hospitals in Johannesburg, Gauteng Province. Results. Of 642 hospital admissions for pneumonia, 497 were confirmed to have COVID-19 infection (reverse transcription-polymerase chain reaction test positive). In the COVID-19-positive group, hospital LoS was prolonged in 35.4% of admissions. Univariate analysis demonstrated an association with the following risk factors for prolonged LoS: older age; male sex; high serum creatinine, sodium (Na), chloride, potassium and urea levels and low estimated glomerular filtration rate; raised white blood cell count, lymphopenia, neutrophilia and an elevated neutrophil-to-lymphocyte ratio (NLR); and elevated levels of D-dimers, interleukin-6 (IL-6), and procalcitonin (PCT). The strongest univariate associations (relative risk (RR) ≥2.0) with a hospital stay &gt;14 days were high Na levels, NRL &gt;18, high PCT levels and IL-6 &gt;40 pg/mL. On multivariable analysis, the following factors remained significantly associated with prolonged LoS: older age (RR 1.015 per year of age; 95% confidence interval (CI) 1.005 - 1.024); hypernatraemia (RR 1.80; 95% CI 1.25 - 2.60); hyperkalaemia (RR 1.61; 95% CI 1.18 - 2.20); and neutrophilia (RR 1.47; 95% CI 1.15 - 1.88). Conclusions. COVID-19 pandemic preparedness requires hospital-based inpatient care to be prioritised in resource-limited settings, and availability of beds and prompt admissions are essential to ensure good clinical outcomes. In this study of COVID-19 patients admitted with pneumonia, multivariable analysis showed older age, hypernatraemia, hyperkalaemia and neutrophilia to be associated with LoS &gt;14 days. This may assist with healthcare systems planning.

Interleukin-6 is upregulated and may be associated with myocardial injury in some patients who have recovered from COVID-19.

Coronavirus disease (COVID-19) causes myocardial injury by inducing a cytokine storm in severe cases. Studies have reported that myocardial injury persists for a prolonged period during COVID-19 recovery, and cardiac troponin is a useful indicator of myocardial injury. The interleukin-6 (IL-6) level is known to be associated with the morbidity and mortality of COVID-19, but this association has not been studied during recovery. The current study examined the association between IL-6 levels and myocardial damage during COVID-19 recovery. Four of 209 patients (1.9%) who recovered from COVID-19 had elevated IL-6 levels. All 4 patients tested positive for high-sensitivity troponin T, and 3 patients had subclinical left ventricular (LV) dysfunction according to echocardiography. Positivity for IL-6 during COVID-19 recovery suggests ongoing myocardial damage due to inflammation.