Acute Inflammatory Conditions Research Articles

DISULFIRAM EXERTS DOSE-DEPENDENT ACTIVATING AND INHIBITORY EFFECTS ON THE HUMAN INFLAMMASOME

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Gasdermin-D (GSDMD) is a pore-forming molecule that serves as the final effector of pyroptosis (a form of inflammatory cell death) following activation of the cellular inflammasome in monocytes. Disulfiram (DSM), a drug used in the treatment of alcohol abuse, has recently been shown to inhibit GSDMD via disruption of pore formation after its cleavage by the inflammatory caspases (1, 4, and 5). The aim of this study was to elucidate the inhibitory effects of DSM on GSDMD-mediated pyroptosis and explore its role as a potential therapeutic agent in sepsis. METHODS: A series of experiments was conducted using THP1 cells (a human monocytic cell line) or purified human monocytes from the blood of healthy donors. Samples were pretreated with DSM in various concentrations 30 minutes prior to inflammasome activation with bacterial lipopolysaccharide (LPS). Cells were then assessed under light microscopy for swelling and fluorescent microscopy for the formation of ASC specks (activated oligomers of the adaptor protein required for caspase activation). Cell death was assessed using a lactate dehydrogenase (LDH) cytotoxicity assay. Interleukin-1-beta (IL1s) release was measured by ELISA. GSDMD cleavage, pro-IL1s synthesis, and caspase-1 cleavage were assessed using immunoblots. RESULTS: Unexpectedly, low dose DSM accentuated inflammasome activation. Dramatic inflammasome induction was observed at a concentration of 10uM, a dose associated with near peak inhibition in the prior study. However, higher doses of 50 to 100 uM suppressed pyroptosis as evidenced by loss of cell swelling and ASC speck formation, as well as LDH and IL-1s release. The DSM effect occurred downstream of caspase-1 activation as evidenced by preserved intracellular pro-IL1s synthesis and caspase-1 cleavage in the presence of DSM. Contrary to the prior report, GSDMD cleavage appeared to be inhibited at these higher doses. CONCLUSIONS: DSM unexpectedly exhibits upstream activation of the inflammasome at low doses but downstream inhibition at high doses. CLINICAL IMPLICATIONS: Although DSM's inhibitory effects on inflammasome function make it a promising agent for the future treatment of acute inflammatory conditions such as sepsis and covid-19, our results indicate that further study is needed to better characterize its possible activating effects at lower concentrations. DISCLOSURES: Collaboration via BARDA grant funding relationship with Beckman Coulter, Inc. Please note: 9/19/2019-8/31/2014 Added 04/27/2021 by Elliott Crouser, source=Web Response, value=Grant/Research Support No relevant relationships by Gregory Eisinger, source=Web Response No relevant relationships by Mikhail Gavrilin, source=Web Response No relevant relationships by Wissam Osman, source=Web Response No relevant relationships by Evan Prather, source=Web Response No relevant relationships by Mark Wewers, source=Web Response

S2384 Recurrent GI Bleeding From Colo Pancreatic Fistula – A Rare Entity

Introduction: Acute pancreatitis is an acute inflammatory condition affecting the pancreas. Colonic complications rarely occur with acute and chronic pancreatitis. Localized ileus, obstruction, colonic ischemia, hemorrhage and fistula formation have been reported together with acute pancreatitis. Colo-pancreatic fistula occurs at a rate of 3% to 10% in patients with severe acute pancreatitis. Here, we discuss the case of a patient with recurrent GI bleeding from a colo-pancreatic fistula. Case Description/Methods: A 62-year-old White male with past medical history of COPD, CAD s/p PCI, history of paroxysmal atrial fibrillation on Eliquis, diabetes presented with complaints of bleeding per rectum. He denied any other complaints. MRI abdomen showed pancreatic pseudocyst with possible fistulization of the pancreatic pseudocyst to the proximal descending colon (Fig 1A). Patient underwent EGD and colonoscopy. Colonoscopy showed evidence of pancreatico enteric fistula distal to the splenic flexure, the remnants were cleared on lavage and patient was discharged once stable (Fig 1B). One month later patient presented with another episode of recurrent GI bleeding he required 2 units of PRBC given the prior findings on the colonoscopy, patient was referred to pancreatic surgeon for further intervention of the colo-pancreatic fistula. Discussion: CPF is a rare condition associated with high mortality in patients with acute pancreatitis. Abdominal CT with or without contrast is often used for diagnosis; however, colonoscopy is also used to detect CPF. Given the anatomical proximity of the left part of the colon to the pancreas, CPF is commonly seen on the left side. Patients present with symptoms such as nausea, abdominal pain, vomiting and gastrointestinal bleeding. In contrast to other pancreatic enteric fistulas, CPF is associated with a high risk of severe hemorrhage, perforation or infection. Unlike other pancreatic enteric fistulas CPF do not close spontaneously, surgery is often the recommended treatment; however, less invasive endoscopic interventions, such as those using conventional hemoclips or over the scope clip, have been reported to have successful outcomes.Figure 1.: Fig 1A: MRI Abdomen showing pancreatic pseudocyst (shown by two blue arrows). Fig 1B: Colonoscopy showing fistulous opening in the descending colon distal to splenic flexure (shown by black arrow).

The Modulatory Activity of Tryptophan Displaying Nanodevices on Macrophage Activation for Preventing Acute Lung Injury.

Macrophages play an important role in the initiation, progression and resolution of inflammation in many human diseases. Effective regulation of their activation and immune responses could be a promising therapeutic strategy to manage various inflammatory conditions. Nanodevices that naturally target macrophages are ideal agents to regulate immune responses of macrophages. Here we described a special tryptophan (Trp)-containing hexapeptide-coated gold nanoparticle hybrid, PW, which had unique immunomodulatory activities on macrophages. The Trp residues enabled PW higher affinity to cell membranes, and contributed to inducing mild pro-inflammatory responses of NF-κB/AP-1 activation. However, in the presence of TLR stimuli, PW exhibited potent anti-inflammatory activities through inhibiting multiple TLR signaling pathways. Mechanistically, PW was internalized primarily through micropinocytosis pathway into macrophages and attenuated the endosomal acidification process, and hence preferentially affected the endosomal TLR signaling. Interestingly, PW could induce the expression of the TLR negative regulator IRAK-M, which may also contribute to the observed TLR inhibitory activities. In two acute lung injury (ALI) mouse models, PW could effectively ameliorate lung inflammation and protect lung from injuries. This work demonstrated that nanodevices with thoughtful design could serve as novel immunomodulatory agents to manage the dysregulated inflammatory responses for treating many chronic and acute inflammatory conditions, such as ALI.

Anti-inflammatory and analgesic activities of Vatavidhvamsana rasa, An Ayurvedic herbo-mineral formulation

Background: Inflammation is a complex process mainly comprises of three phases namely acute, sub-acute and chronic. In acute inflammatory conditions fluid and granulocytic cells accumulate at the site of injury because of the changes in small blood vessels. This response often activates systemic response such as leucocytosis, protein catabolism, fever and synthesis of C-reactive protein, an acute-phase protein In Ayurvedic texts, several herbo-mineral preparations to fight against inflammation have been found; among them, Vatavidhvamsana Rasa (VVR) is one, which is said to be remarkable in inflammation condition. Aim and Objectives: To assess the anti-inflammatory and analgesic effects of VVR in pharmacologically validated models. Materials and methods: Wistar strain albino rats weighing 200 ± 20 of either sex were used in the study. VVR was administered at a dose of 22.5 mg/kg for the rat. Results: Vatavidhvamsana Rasa (VVR) showed a significant decrease in the carrageenan-induced paw oedema after 1-hour interval in comparison to the control group (P<0.05) and at 3 hours and 5 hours intervals it showed a non-significant decrease in carrageenan-induced paw oedema in albino rats. In the analgesic activity, VVR treated group showed a significant increase in radiant heat response at 30 min. interval (P<0.05) and non-significant increase at 60 mins in comparison to initial and control group. Conclusion: The results concluded that Vatavidhvamsana Rasa has anti-inflammatory and analgesic activity. Accordingly, it can be used in the management of pain and inflammatory conditions.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

The anti-inflammatory activity of specific-sized hyaluronic acid oligosaccharides

Severe acute inflammatory conditions may cause tissue damage, sepsis, and death. As a critical component of the extracellular matrix, hyaluronic acid (HA) has been reported to possess pro- and anti-inflammatory properties via Toll-like receptors (TLRs). In this study, we prepared different sizes and structures of HA oligosaccharides and derivatives and investigated the effects on inflammation in vitro and in vivo. Our results showed that HA tetra-saccharide was the minimum fragment to enhance inflammation, whereas HA disaccharide competitively blocked TLR4-dependent inflammation. The enzymatic HA disaccharide (ΔHA2) inhibited lipopolysaccharide (LPS)-induced inflammation. Based on structure-activity relationship analysis, we observed that anti-inflammatory activity depended on HAs polymerization degree, acetyl group, and configuration. In addition, we demonstrated that ΔHA2 reduced LPS-induced pro-inflammatory cytokines production in vivo. ΔHA2, a native metabolite of HA polysaccharides, may have a potential role against LPS-mediated inflammatory diseases.

Patterns of brain c-Fos expression in response to feeding behavior in acute and chronic inflammatory pain condition.

Feeding behavior is known to have potential to alleviate pain. We recently demonstrated that both 24 h fasting and 2 h refeeding (food intake after 24 h fasting) induce analgesia in inflammatory pain conditions via different brain mechanisms. However, brain structures that distinctly involved fasting- and refeeding-induced analgesia is still unknown. Hence, this study is aimed to reveal brain structures mediating fasting- and refeeding-induced analgesia. Mice were given intraplantar (i.pl.) injection of formalin and complete Freund's adjuvant into the left hind paw to induce acute and chronic inflammatory pain, respectively. We examined changes in c-Fos expression with 24 h fasting and 2 h refeeding under acute and chronic inflammatory pain conditions in the contralateral brain. Under acute pain condition, c-Fos expression changed with fasting in the anterior cingulate cortex (ACC), central amygdala (CeA), lateral hypothalamus (LH) and nucleus accumbens core (NAcC). Refeeding changed c-Fos expression in the CeA, LH and lateral parabrachial nucleus (lPBN). On the other hand, under chronic inflammatory pain condition, c-Fos expression changed with fasting in the lPBN, medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcS) while refeeding changed c-Fos expression in the anterior insular cortex, lPBN, mPFC and NAcS. The present results show that brain regions that participated in the fasting- and refeeding-induced analgesia were completely different in acute and chronic inflammatory pain conditions. Also, refeeding recruits more brain regions under chronic inflammatory pain conditions compared to the acute inflammatory pain condition. Collectively, our findings provide novel insights into brain regions involved in fasting- and refeeding-induced analgesia, which can be potential neural circuit-based targets for the development of novel therapeutics.

Ameliorative Effect of Surface Proteins of Probiotic Lactobacilli in Colitis Mouse Models.

The increase in concern from viable cells of probiotics specifically in acute inflammatory conditions has led to the emergence of the concept of postbiotics as a safer alternative therapy in the field of health and wellness. The aim of the present study was to evaluate the efficacy of surface proteins from three probiotic strains in dextran sodium sulfate and trinitrobenzenesulphonic acid = induced colitis mouse models. The molecular weight of total surface proteins extracted from the three probiotic strains ranged from ∼25 to ∼250 kDa with the presence of negligible levels of endotoxins. Surface layer proteins (SLPs) (∼45 kDa) were found to be present only in the Lactobacillus acidophilus NCFM strain. In the in vivo study, significant differences were not observed in the weight loss and general appetite, however, the decrease in colon length was apparent in TNBS colitis control mice. Further, the administration of these surface proteins significantly reversed the histopathological damages induced by the colitogens and improved the overall histological score. The oral ingestion of these surface proteins also led to a decrease in myeloperoxidase activity and TNF-α expression while the IL-10 levels significantly increased for the strain NCFM followed by MTCC 5690 and MTCC 5689. Overall, the present study signifies the ameliorative role of probiotic surface proteins in colitis mice, thereby, offering a potential and safer alternative for the management of inflammatory bowel disorders.

The Endothelial Glycocalyx: Physiology and Pathology in Neonates, Infants and Children.

The endothelial glycocalyx (EG) as part of the endothelial surface layer (ESL) is an important regulator of vascular function and homeostasis, including permeability, vascular tone, leukocyte recruitment and coagulation. Located at the interface between the endothelium and the blood stream, this highly fragile structure is prone to many disruptive factors such as inflammation and oxidative stress. Shedding of the EG has been described in various acute and chronic diseases characterized by endothelial dysfunction and angiopathy, such as sepsis, trauma, diabetes and cardiovascular disease. Circulating EG components including syndecan-1, hyaluronan and heparan sulfate are being evaluated in animal and clinical studies as diagnostic and prognostic markers in several pathologies, and advances in microscopic techniques have enabled in vivo assessment of the EG. While research regarding the EG in adult physiology and pathology has greatly advanced throughout the last decades, our knowledge of the development of the glycocalyx and its involvement in pathological conditions in the pediatric population is limited. Current evidence suggests that the EG is present early during fetal development and plays a critical role in vessel formation and maturation. Like in adults, EG shedding has been demonstrated in acute inflammatory conditions in infants and children and chronic diseases with childhood-onset. However, the underlying mechanisms and their contribution to disease manifestation and progression still need to be established. In the future, the glycocalyx might serve as a marker to identify pediatric patients at risk for vascular sequelae and as a potential target for early interventions.

Preliminary Physico-Chemical Profile of Yashtimadhu Ghrita

Yashtimadhu ghrita is a single-herbal ghee formulation mentioned in the classical texts of Ayurveda and is indicated in sadya kshatavrana (an acute inflammatory condition or an acute wound associated with trauma). It also minimizes the pain related to the wound. The present study is intended to create a finger print profile of Yastimadhu ghrita through its pharmacognostical identification and the physico-chemical analysis. The genuineness of the dry specimen of Yashtimadhu (Glycyrrhiza glabra Linn.) was confirmed through organoleptic evaluation and cross-sectional microscopy. Yashtimadhu ghrita was prepared as per the Sneha paka (preparation of unctuous formulations using ghee, oil etc.) procedure mentioned in Sarngadhara Samhita Madhyama khanda and the standard operative procedures specified in Ayurvedic pharmacopoeia of India. The test result of the finished product shows Acid value 6.7, saponification value 213.4, and Refractive index value1.455 at room temperature, Iodine value 38.7, LOD 0.64. TLC and HPTLC were carried out for the characterization of the plant material in an appropriate solvent system. A total of nine spots were distinguished in 254 nm and five spots in 366 nm during the HPTLC scanning. The Rf value pertaining to the spots were identical in the methanolic extract which indicates the presence of definite constituents in Yashtimadhu ghrita.

Toll-interacting protein in the freshwater fish Labeo rohita exhibits conserved structural motifs of higher eukaryotes and is distinctly expressed in pathogen-associated molecular pattern stimulations and bacterial infections.

Toll-interacting protein (Tollip) is a critical regulator of TOLL- like receptor (TLR)-signaling pathway. It is predominantly associated with TLR2 and TLR4 during acute inflammatory conditions and inhibits the TLR-mediated nuclear factor-kappa activation by suppressing the autophosphorylation of interleukin-1 receptor-associated kinase and its kinase activity. This article describes the Tollip of Labeo rohita (LrTollip), a highly valuable freshwater fish from the Indian subcontinent. The full-length LrTollip complementary DNA (1412 nucleotides) encodes a 276-amino acid (aa) protein, depicting a highly conserved target of the Myb1 (Tom1)-binding domain (TBD; 1-53 aa), conserved core domain 2 (C2; 54-151 aa), and coupling of ubiquitin to endoplasmic reticulum degradation (CUE; 231-273 aa) domains of mouse and human counterparts. The key amino acids exerting the critical functions of Tollip, such as phospholipids recognition and ubiquitination, are present in the C2 and CUE domains of LrTollip, respectively. LrTollip is widely expressed in the kidneys, gills, spleen, liver, and blood, and among these tested tissues, the highest expression is observed in blood. In response to TLR ligands and NOD-like receptor (NLR) ligands stimulations and Aeromonas hydrophila, Edwardsiella tarda, and Bacillus subtilis infections, LrTollip gene expression is induced in various organs/tissues with remarkable difference in their kinetics. These data together suggest the important role of LrTollip in TLR- and NLR-signal transduction pathways and immune-related diseases in fish.

Echinodorus macrophyllus fraction with a high level of flavonoid inhibits peripheral and central mechanisms of nociception

Background and aim: Echinodorus macrophyllus (Kunth.) Micheli is popularly used for acute and chronic inflammatory conditions. The anti-inflammatory activity was previously demonstrated for its flavonoid-enriched fractions. The aim of this work assessed the antinociceptive properties of both aqueous extract and its fractions. Experimental procedure: The antinociceptive activity was determined by acetic acid-induced writhing, formalin test, tail immersion test, hot-plate test, xylene-induced ear edema methods, and the evaluation of its mechanism was performed in the writhing model. The aqueous extract of Echinodorus macrophyllus (AEEm) was fractionated, yielding Fr20, and Fr40. Fr40 composition was determined by HPLC-DAD-ESI-MS. Results and conclusion: Fr20 (all doses) and Fr40 (100 mg/kg) reduced the nociception in the tail-flick model. Both fractions increased the percentage of maximum possible effect with 25 mg/kg, in the hot-plate assay, at 60 min, while AEEm reduced pain only with 50 and 100 mg/kg. There was a reduction in xylene-edema index, with Fr40 (25 mg/kg), AEEm (50 mg/kg) and Fr20 (50 mg/kg). All doses of AEEm, Fr20, and Fr40 reduced both phases of the formalin model. In the abdominal contortion model, Fr40 presented the highest activity, reducing 96% of contortions and its antinociceptive mechanism was evaluated. The results indicated the involvement of NO and adrenergic activation pathways. The main components of Fr40 are swertisin, swertiajaponin, isoorientin 7,3′-dimethyl ether, swertisin-O-rhamnoside, isoorientin, isovitexin, isovitexin-Orhamnoside, and isovitexin-7-O-glucoside. The aqueous extract of E. macrophyllus leaves and its fractions exhibited significant analgesic effect, mediated through both peripheral and central mechanisms being considered a potentially antinociceptive drug.

Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment

Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease.

TIRAP in the Mechanism of Inflammation.

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

Exploration of the Underlying Nutritional, Inflammatory and Oxidative Stress Pathological Mechanisms in Preeclampsia using Principal Component Analysis

Normal pregnancy is characterized by a mild systemic inflammatory response and progressive increase in serum inflammatory cytokines that peak in the third trimester. During pregnancy pre-existing inflammatory conditions, acquired oxidative stress arising from the placenta malfunction and nutritional deficiencies can trigger intense systemic responses that lead to endothelial activation, dysfunction and preeclampsia. We investigated the principal nutritional, oxidative and inflammatory pathways that trigger the clinical manifestation of preeclampsia.
 This case-control study included 250 women with preeclampsia and 150 normotensive pregnant women. Urinary Iodine concentration (IUC) and serum levels of Ferritin, Thyroid-stimulating Hormone (TSH), selenium, Nitric Oxide (NO) gamma glutamyl transferase (GGT), Rheumatoid factor, and high sense C-reactive protein (hs-CRP) of cases and controls were compared using the student’s t and the Mann-Whitney U tests. Principal component analysis was carried out to delineate the patterns of association between nutritional, inflammatory and oxidative markers and preeclampsia.
 The main pathophysiological pathways identified were the interactions between selenium/iodine deficiency and elevated serum TSH (endothelial dysfunction); serum ferritin, GGT, CRP and low urinary iodine concentration (inflammatory oxidative stress); elevated serum hs-CRP and Rheumatoid factor subclinical inflammation and immune cell activation) and high T3/T4 ratio (acute TSH stimulation of thyroid with low thyroid iodine stores)
 Combined selenium and iodine deficiency resulting into elevated TSH, low NO and preferential T3 secretion; acute inflammatory conditions associated with elevated serum GGT, CRP, and Ferritin; and subclinical inflammatory conditions characterized by autoimmunity are some of the major oxidant and inflammatory pathways associated with increased risk of preeclampsia.

Effect of Lipopolysaccharide-Induced Inflammatory Challenge on β-Glucuronidase Activity and the Concentration of Quercetin and Its Metabolites in the Choroid Plexus, Blood Plasma and Cerebrospinal Fluid

Quercetin-3-glucuronide (Q3GA), the main phase II metabolite of quercetin (Q) in human plasma, is considered to be a more stable form of Q for transport with the bloodstream to tissues, where it can be potentially deconjugated by β-glucuronidase (β-Gluc) to Q aglycone, which easily enters the brain. This study evaluates the effect of lipopolysaccharide (LPS)-induced acute inflammation on β-Gluc gene expression in the choroid plexus (ChP) and its activity in blood plasma, ChP and cerebrospinal fluid (CSF), and the concentration of Q and its phase II metabolites in blood plasma and CSF. Studies were performed on saline- and LPS-treated adult ewes (n = 40) receiving Q3GA intravenously (n = 16) and on primary rat ChP epithelial cells and human ChP epithelial papilloma cells. We observed that acute inflammation stimulated β-Gluc activity in the ChP and blood plasma, but not in ChP epithelial cells and CSF, and did not affect Q and its phase II metabolite concentrations in plasma and CSF, except Q3GA, for which the plasma concentration was higher 30 min after administration (p < 0.05) in LPS- compared to saline-treated ewes. The lack of Q3GA deconjugation in the ChP observed under physiological and acute inflammatory conditions, however, does not exclude its possible role in the course of neurodegenerative diseases.

Dermal Discoloration Secondary to Triamcinolone Acetonide Injection Observed in Patients with Autoimmune Disorders.

Triamcinolone acetonide is a synthetic glucocorticoid used to treat numerous acute and chronic inflammatory conditions. The various side effects of this drug from parenteral administration are well documented in the literature. In this study, three patients present with a rare side effect of violaceous dermal pigmentation. To the best of the authors' knowledge, this finding is rarely presented in the current literature. The purpose of this study is to provide awareness of a less-documented, delayed side effect from triamcinolone acetonide administration. Although all patients presenting in this study had a known history of autoimmune disease (eg, lupus, psoriatic arthritis) further research is needed to suggest a possible association between dermal violaceous change and the use of triamcinolone.

Higher Rates of Anticoagulation Among Patients with Portal Vein Thrombosis Are Not Associated with Better Outcomes

Introduction : Portal vein thrombosis (PVT) is an unusual-site thrombosis mainly encountered in patients with malignancies, cirrhosis, myeloproliferative disorders (MPN) and acute abdominal inflammatory conditions (AIC). Given the associated comorbidities that can increase bleeding risks in this heterogeneous population, management is challenging. Current recommendations suggest that anticoagulation improves recanalization rates but there is limited information on venous thromboembolism (VTE) recurrence rates and whether the varied etiologies of PVT fare similarly with anticoagulation.Aim: To compare the anticoagulation rates of patients with PVT in patients with cirrhosis, malignancy and AIC and to determine its effect on clinical outcomes of cavernous transformation, recanalization, PVT progression, PVT recanalization, VTE recurrence and mortality.Methods: Approval was obtained from Montefiore Institutional Review Board to review records of patients from 2005 to 2015. Institutional data mining software was used to identify patients diagnosed with PVT and their etiologies by ICD9 and the index exam results were reviewed manually to ensure accuracy. Results regarding cavernous transformation, PVT recanalization and progression were acquired directly from follow-up imaging studies; data regarding VTE recurrence, mortality and anticoagulation were obtained from chart review. For the purposes of this study, patients with imaging confirmation, imaging follow-up and a diagnosis of cirrhosis, malignancy or AIC were selected. AIC was defined as abdominal infections, acute intra-abdominal surgical procedures or bacteremia occurring within 60 days preceding PVT diagnosis.Results: 698 patients were diagnosed with PVT. Among them, 198 (28.4%) had cirrhosis, 151 (21.6%) had malignancy and 35 (5%) had AIC. Of these, 141 patients had follow-up and were included in the analysis; 78 patients with cirrhosis, 35 with malignancy and 28 with AIC. The mean age was 58.1 ± 12.8 years, 38.8% were Hispanic and 29.6% were African-American and the AIC cohort was the youngest at 52.3yrs. The median follow-up was 35 months.Only 32.6% of patients received anticoagulation. Patients with malignancy were anticoagulated more frequently compared to those with cirrhosis (37.1% vs 10.3%, p<0.001) but patients with AIC were placed on anticoagulation most often (89.3%, p<0.001). Cirrhotic patients that were anticoagulated had higher PVT progression rates than those not anticoagulated (25% vs 2.9%, p<0.05) and we did not detect a significant benefit of anticoagulation in PVT recanalization, decreased recurrence or lower mortality rates for patients within cohorts of either the cirrhosis or the malignancy groups. AIC patients did have a lower rate of VTE recurrence with AC (0/25 as compared to 1/3) but the numbers were small. Comparing patients that did not receive anticoagulation across cohorts, recanalization rates were higher and progression rates were lower for patients with cirrhosis versus malignancy (62.8% vs 14.3%, p<0.001 for recanalization; 2.9% vs 22.7% for progression, p=0.002). PVT recanalization rate was also higher when compared to patients with AIC, no matter the therapy (32.1% vs 60.2%, p<0.001).However, there was a trend towards increased rates of cavernous transformation in PVT patients with cirrhosis compared to patients with AIC or cancer (40.9% for cirrhosis vs 22.7% for malignancy and 28.6% for AIC, p=0.1).Conclusion: Despite lower rates of anticoagulation, patients with cirrhosis were more likely to achieve recanalization and did not have an increased risk of recurrence, progression or mortality compared to other groups. Patients with AIC were younger than those with cirrhosis and malignancy and were more likely to get anticoagulation; however, this did not correlate with higher PVT recanalization or lower progression, recurrence or mortality rates. PVT is associated with multiple pathologies; one therapy for all causes of PVT may not be beneficial. [Display omitted] DisclosuresBillett:Janssen Pharmaceutical: Research Funding.

Unexpected Salt/Cocrystal Polymorphism of the Ketoprofen–Lysine System: Discovery of a New Ketoprofen–l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties

Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a different sensorial kinetics compared to the cocrystal, suggesting that different coating/flavoring processes should be envisioned for the new compound. Thus, the new KLS polymorphic form with its different physicochemical and pharmacokinetic characteristics can open the way to the development of a new KET–LYS polymorph drug that can emphasize the properties of commercial KLS for the treatment of acute inflammatory and painful conditions.

50 Years Ago in TheJournalofPediatrics: Inflammation and Vasculitis: Changing Paradigms

Chamberlain JL, Perry LW. Infantile periarteritis nodosa with coronary and brachial aneurysms: a case diagnosed during life. J Pediatr 1971;78:1039-42. Prior to the recognition of Kawasaki disease, or mucocutaneous lymph node syndrome, as it was originally called, an entity entitled periarteritis nodosa existed, to capture infants and others presenting with rash and vasculitis, including infants with coronary aneurysms and no other known etiology. Chamberlain and Perry described a case of this rare, and often undiagnosed ante-mortem condition, based on a combination of clinical history, physical examination (including palpation of brachial aneurysms), and angiography of the coronary arteries and arterial tree, a daunting task in a 20-week old infant in 1971. The child survived after weeks of chronic inflammatory symptoms. I had a similar patient, treated in an era when gamma globulin was not available to dramatically shorten the clinical course, who suffered for weeks with inflammation, lost a digit to vaso-occlusion, and required a coronary artery bypass. Periarteritis nodosa still exists, but is much rarer and more circumscribed, as the etiology of overlapping conditions has been identified, or syndromic identification has replaced use of that term. Unfortunately, our perplexity regarding the etiology of acute pediatric inflammatory conditions associated with vasculitis. remains as well. The patient in this report, as was mine, would now be diagnosed with Kawasaki disease; the description of that cluster of clinical findings was a clinical revelation, as have been related diagnostic and therapeutic innovations over the last 40 years. Nonetheless, the cause remains unknown. And now, in the last year, comes another revelation, multisystem inflammatory syndrome in children, re-energizing conversations on the etiology, mechanism, and treatment of childhood inflammatory vascular injury.1Rowley A.H. Multisystem inflammatory syndrome in children and Kawasaki disease: two different illnesses with overlapping clinical features.J Pediatr. 2020; 224: 129-132Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The extraordinary effort undertaken by Chamberlain and Perry, with the tools at their disposal, to provide knowledge about a perplexing condition, was repeated by the early investigators of Kawasaki disease, with results benefitting many children. Nature has thrown us another curve, and we have newer anti-inflammatories and cardio-respiratory support to improve outcomes. Maybe we will find some causes too.