Systemic Inflammatory Events Research Articles

Periodontal Pathogens and Adverse Pregnancy Outcomes: A Narrative Review.

Periodontal disease is a multi-microbial infection of the teeth-supporting apparatus that manifests as clinical attachment loss and alveolar bone loss. The association between periodontal disease and systemic diseases has been proposed in the literature owing to the former's chronic state of inflammation, and adverse pregnancy outcomes are no exception. As a result of periodontal pathogen invasion, a series of systemic inflammatory and immunologic events affecting the safety of the fetoplacental unit may unfold. This may be further exaggerated by physiologic hormonal and metabolic fluctuations during pregnancy. This can not only negatively affect the gestation period and consequently cause preterm low weight but also complicate the pregnancy via preeclampsia and gestational diabetes. This narrative review article aims to provide a summary of relevant available evidence pertinent to the relationship between periodontal diseases, associated periodontal pathogens and virulence mechanisms mediated by pro-inflammatory cytokines and prostaglandins, and adverse pregnancy outcomes. Furthermore, this article highlights some of the literature addressing the impact of periodontal therapy interventions and pregnancy outcomes.

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility.

The type I IFN (IFN-I) system is essential to limit severe viral disease in humans. Thus, IFN-I deficiencies are associated with serious life-threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN-Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti-IFN-I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti-IFN-I autoAbs, such as reduced self-tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti-IFN-I autoAbs following "autoimmunization" with IFN-Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN-I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti-IFN-I autoAbs appear to have towards viral diseases such as severe COVID-19, influenza, or herpes (e.g., varicella-zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live-attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti-IFN-I autoAbs will be key to implementing effective prophylactic and therapeutic measures.

Alterations in the coagulation markers did not show differences with the severity of COVID-19 in Peruvian patients: A cross-sectional single-center study.

COVID-19 is a pandemic disease that can lead to altered lung function, systemic inflammatory events, and altered coagulation. During severe stages of the disease, changes in coagulation homeostasis increase, leading to thrombosis, and increased risk of death. In this cross-sectional study, we aimed to assess coagulation markers by COVID-19 severity in Peruvian adults. During the second wave of infections, we included 186 adults diagnosed with COVID-19 (mean age 53.3 ± 16.3 years). Patients were divided into mild, moderate, and severe stages of COVID-19, and coagulation markers included prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen, d-dimer, and platelet count. Of the total, 120 (64.5%) were males and 39 (21%) were in the intensive care unit. We determine 104 (55.9%), 43 (24.7%), and 36 (19.4%) patients in mild, moderate, and severe stages of COVID-19, respectively. In the severe stage of COVID-19, patients had an average concentration of PT, aPTT, fibrinogen, d-dimer, and platelets of 13.2 ± 0.9 s, 28.9 ± 4.3 s, 679.4 ± 185.1 mg/dL, 1.9 ± 3.1 µg/mL, and 272.8 ± 88.9 cel/10 mm,3respectively. We found no differences in the concentration of each marker according to severity (p < 0.05). Patients with severe COVID-19 had altered the aPTT, fibrinogen, d-dimer, and PT in 31 (57.4%), 48 (88.9%), 37 (68.5%), and 15 (27.8%) cases, respectively. Our results showed that although there is an alteration in coagulation markers, mainly fibrinogen and d-fiber, there are no differences in concentration according to the severity of COVID-19.

Associations between food-specific IgG antibodies and intestinal permeability biomarkers.

Increasing translational evidence suggests that intestinal permeability may be a contributing factor to systemic inflammatory events and numerous pathologies. While associations between IgE-mediated food allergies and increased intestinal permeability have been well-characterized, the relationship between IgG-mediated food sensitivities and intestinal permeability is not well-described in the literature. Thus, we tested for associations between intestinal permeability biomarkers and food-specific IgG antibodies in 111 adults, with and without gastrointestinal symptoms. All biomarkers and food-specific IgG antibodies were measured via ELISA. The intestinal permeability biomarkers anti-lipopolysaccharide (LPS) and anti-occludin IgG and IgA antibodies, but not anti-vinculin or anti-CdtB IgG antibodies, were significantly and positively associated with IgG-mediated food sensitivities. These significant relationships were attenuated by adjusting for the severity of wheat, dairy, and egg reactions. The results of this study support strong associations between titers of food-specific IgG antibodies and intestinal permeability biomarkers in adults, to the extent that the presence of multiple IgG antibodies to food, and increasing IgG food titers, can be considered indicative of increased antibodies to LPS and occludin. Notably, neither IgG titers to wheat, eggs, and dairy, nor permeability biomarkers, were increased in symptomatic participants compared to those without symptoms.

VetVirtopsy by CT and MRI–Complementing conventional necropsy

• Imaging detects the cause of death in a majority of deceased dogs and cats. • Conventional necropsies are not competed; however, they can be simplified and supplemented. • In cases of space-occupying lesions and trauma, imaging finds the causes of death most reliably. • In cases with systemic inflammatory disease, it is most difficult for imaging to arrive at a correct diagnosis. Post mortem (PM) examination of euthanized or deceased individual animals or a herd is important to clarify forensic cases, confirm or correct clinical diagnosis, and improve future therapeutic approaches. The aim of this descriptive study is to evaluate PM imaging by CT and MRI (VetVirtopsy) and to compare the results to conventional necropsy. Hundred deceased or euthanized dogs and cats (47 dogs, 53 cats) of different age, breed, and body weight from the Small Animal Clinic of the University of Zurich underwent VetVirtopsy followed by a conventional necropsy and histologic examination with investigators unblinded to VetVirtopsy. All animals were examined by PM whole body CT (PMCT), 31 of them also by MRI (PMMRI) in selected regions. The findings of VetVirtopsy were compared with the pathology report as the gold standard. In a majority of cases of 81% VetVirtopsy detected the cause of death. The agreement was high in cases with trauma and space occupying lesions and low in systemic inflammatory diseases. VetVirtopsy produced 336 (Median: 3, Min: 1, Max: 11) additional findings in multiple organs. The strengths of VetVirtopsy in supporting conventional necropsy lie in the detection of trauma and space-occupying lesions. Advantageous is the detailed overview, whereby the relevance of the findings must remain in focus. VetVirtopsy could be very helpful in cases without owner consent for dissection. In systemic inflammatory events, disease with discrete, morphologic changes, or in contagious, at most zoonotic cases, it would need imaging-guided specimen sampling.

Experimental Bothropsatrox Envenomation: Blood Plasma Proteome Effects after Local Tissue Damage and Perspectives on Thromboinflammation.

The clinical manifestations of Bothrops atrox envenoming involve local and systemic changes, among which edema requires substantial attention due to its ability to progress to compartmental syndromes and sometimes cause tissue loss and amputations. However, the impact of edema on the poisoned body’s system has not been explored. Thus, the present study aimed to explore the systemic pathological and inflammatory events that are altered by intraplantar injection of B. atrox venom in a mouse model through hematologic, lipidic, and shotgun proteomics analysis. Plasma samples collected showed a greater abundance of proteins related to complement, coagulation, lipid system, platelet and neutrophil degranulation, and pathways related to cell death and ischemic tolerance. Interestingly, some proteins, in particular, Prdx2 (peroxiredoxin 2), Hba (hemoglobin subunit alpha), and F9 (Factor IX), increased according to the amount of venom injected. Our findings support that B. atrox venom activates multiple blood systems that are involved in thromboinflammation, an observation that may have implications for the pathophysiological progression of envenomations. Furthermore, we report for the first time a potential role of Prdx2, Hba, and F9 as potential markers of the severity of edema/inflammation in mice caused by B. atrox.

Beneficial effect of polyphenols in COVID-19 and the ectopic F1 FO -ATP synthase: Is there a link?

COVID‐19 has been proposed to be an endothelial disease, as endothelial damage and oxidative stress contribute to its systemic inflammatory and thrombotic events. Polyphenols, natural antioxidant compounds appear as promising agents to prevent and treat COVID‐19. Polyphenols bind and inhibit the F1Fo‐ATP synthase rotary catalysis. An early target of polyphenols may be the ectopic F1Fo‐ATP synthase expressed on the endothelial plasma membrane. Among the pleiotropic beneficial action of polyphenols in COVID‐19, modulation of the ecto‐F1Fo‐ATP synthase, lowering the oxidative stress produced by the electron transfer chain coupled to it, would not be negligible.

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer.

Simple SummaryImmunotherapy has transformed breast cancer treatment. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. In our current communication, using breast tumor models, we demonstrated that a low salt diet could reduce irAE development following ICI therapy. Importantly, a low salt diet did not change the anti-tumor efficiency. Our current study provides a basis for future clinical trials to verify the role of a low salt diet in long-term immunotherapeutic efficiency in breast cancer patients.Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy.

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC.

The application of hepatitis B virus (HBV)–T‐cell receptor (TCR) T‐cell immunotherapy in patients with HBV‐related hepatocellular carcinoma (HBV‐HCC) has been apathetic, as the expression of HBV antigens by both normal HBV‐infected hepatocytes and HCC cells with HBV‐DNA integration increases the risk of on‐target off‐tumor severe liver inflammatory events. To increase the safety of this immunotherapeutic approach, we developed messenger RNA (mRNA) HBV‐TCR‐redirected T cells that—due to the transient nature of mRNA—are functionally short lived and can be infused in escalating doses. The safety of this approach and its clinical potential against primary HBV‐HCC have never been analyzed in human trials; thus, we studied the clinical and immunological parameters of 8 patients with chronic HBV infection and diffuse nonoperable HBV‐HCC treated at weekly intervals with escalating doses (1 × 104, 1 × 105, 1 × 106, and 5 × 106 TCR+ T cells/kg body weight) of T cells modified with HBV‐TCR encoding mRNA. The treatment was well tolerated with no severe systemic inflammatory events, cytokine storm, or neurotoxicity observed in any of these patients throughout treatment. Instead, we observed a destruction of the tumor lesion or a prolonged stable disease in 3 of 8 patients. Importantly, the patients without clinically relevant reductions of HCC did not display any detectable peripheral blood immunological alterations. In contrast, signs of transient localized liver inflammation, activation of the T‐cell compartment, and/or elevations of serum chemokine (C‐X‐C motif) ligand (CXCL) 9 and CXCL10 levels were detected in patients with long‐term clinical benefit. Conclusion: We show that despite the reduced in vivo half‐life (3‐4 days), adoptive transfer of mRNA HBV‐TCR T cells into patients with HBV‐HCC show long‐term clinical benefit that was associated with transient immunological alterations.

Neuropeptide W Attenuates Oxidative Multi-Organ Injury in Rats Induced with Intra-Abdominal Sepsis.

Sepsis leads to systemic hypotension, disturbed perfusion, inflammation, and tissue toxicity in vital organs. Neuropeptide W (NPW) has modulatory effects in the control of blood pressure and inflammatory processes, implicating a potential beneficial effect against sepsis-induced oxidative damage. Under anesthesia, male Sprague Dawley rats underwent cecal ligation and puncture. Immediately after surgery, either saline or TNF-alpha inhibitor (etanercept; 1 mg/kg) antibiotic (ceftriaxon; 10 mg/kg) combination or NPW (0.1, 1, or 3 μg/kg) was given subcutaneously, and injections were repeated on the 12thand 24thh. The sham-operated control group was treated with saline at the same time points. All rats were euthanized on the 25thh of surgery. Sepsis resulted in oxidative damage of the brain, heart, lung, liver, and kidney. Elevations in blood urea nitrogen and alkaline phosphatase, showing renal and hepatic dysfunction, were not evident when septic rats were treated with NPW. NPW reduced serum levels of C-reactive protein, corticosterone, and interleukin-6, while histopathologically verified tissue damage in all the studied tissues was ameliorated. NPW treatment suppressed lipid peroxidation in the heart, lung, and brain, and the depleted antioxidant GSH levels of the brain and heart were replenished by NPW. Moreover, sepsis-related neutrophil recruitment to the liver and lung was also suppressed by NPW. Although the survival rate of the rats was not significantly prolonged by NPW, most of these improvements in systemic and local inflammatory events were comparable with those reached by the etanercept and antibiotic combination, suggesting the therapeutic impact of NPW during the acute period of sepsis.

Environmental organophosphate co‐exposure in pre‐existing systemic inflammation can Increase susceptibility to SARS‐COV‐2 infection in human lung epithelial cells

Environmental exposures from pollutants in air, water and food cause systemic inflammatory events to persist. Studies have shown that environmental co exposures alter the microbiome profile and cause long lasting systemic inflammation. This is common in the general population as well as a certain subsection of veterans having Gulf War Illness who were co exposed to organophosphates decades ago. With COVID19 pandemic claiming more than 335,000 deaths in USA alone, we aimed to study the susceptibility of SARS‐COV‐2 virus entry and its potential inflammatory mechanisms in the lung epithelial cells following co‐exposure to IL6 and pesticide chlorpyrifos. Notably, a recent report confirms more than 160,000 positive SARS‐COV‐2 cases of veterans with mortality rate of more than 4%. Recent studies from our laboratory and others suggested that pesticide exposure during war theater and increased IL‐6 in blood serum played pivotal role in physiological complications which include neurological and gastrointestinal disturbances. In the present report, we aim to identify whether pesticides and IL‐6 co‐exposure increases the risk of SARS‐COV‐2 infection by invitro studies with human lung airway epithelial cells. Cells were exposed to organophosphate Chlorpyriphos (20 µg/ml) or human recombinant IL‐6 (20 pg/ml) or with both for 6 h and treated with recombinant SARS‐COV‐2 spike protein (50 ng/ml) and observed for Angiotensin Converting Enzyme 2 expression (ACE2) on the apical or basolateral surface of airway epithelial cells. ACE‐2 has been identified as putative receptor for SARS‐COV‐2 entry where it's spike protein pivotal to the entry of viral particle in cells. With reports showing abundant expression of ACE2 receptor protein to apical surface of polarized epithelial cells might support viral entry and replication in host cells, we performed Immunofluorescence microscopy to study ACE 2 protein expression in Apical cell surface (FoxJ1) or in basolateral cell surface (Sodium‐Potassium ATPase 2). Results showed organophosphate and IL 6 exposure significantly increased ACE2 protein expression on the apical cell surface compared to when cells were unexposed or exposed with organophosphate alone. Furthermore, results showed that co exposure of IL 6 and organophosphate were instrumental in increased apoptosis of lung airway epithelial cells in presence of SARS‐COV‐2 spike protein compared to untreated cells. The following results though preliminary may pave the way for more mechanistic studies in rodent models to identify mechanisms of susceptibility of severe COVID19 outcomes in the general population and veterans who were co exposed to environmental agents in early life.

Immunological Window of Myocardial Infarction

Acute myocardial infarction (MI) describes as an irreversible death of heart muscle which is initiated by a shortage of myocardium oxygen supply and accompanies by a complex of pro- and anti-inflammatory events. During the last decades, innate and adaptive immune responses are considered more serious for controlling myocardial infarction. As, it was confirmed that deregulated immune system which triggers excessive local and systemic inflammatory events is responsible for serious adverse effects associated with acute MI. Bone marrow activation, spleen monocytopoiesis, a remarkable increase of circulating cytokines and adhesion molecules, in addition to elevated levels of active peripheral leukocytes and platelets are playing significant roles in determining the clinical outcome of patients with MI. The previous experience demonstrated the failure of traditional harsh anti-inflammatory strategies. High mortality rate and poor quality of life observed for survivors of MI despite current progress in the field highlight the urgent need for such interdisciplinary studies in the context of molecular cardiology. Hence, unraveling the cellular and molecular events which are involved in the management of inflammatory responses post-MI is of special focus. The concept of immune regulation after myocardial infarction is not new, but our perception for dealing with the challenge has been changed during the last decades with gaining more in-depth molecular/immunological knowledge. It seems that fine-tuning the interplay between innate and adaptive immune responses and regulating their cross-talk should be in special focus to establish effective therapeutic strategies.

Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus

BackgroundInfants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood.MethodsPrenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC.ResultsPostnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS.ConclusionPrenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.

The impact of dextran sodium sulphate and probiotic pre-treatment in a murine model of Parkinson\u2019s disease

BackgroundRecent work has established that Parkinson’s disease (PD) patients have an altered gut microbiome, along with signs of intestinal inflammation. This could help explain the high degree of gastric disturbances in PD patients, as well as potentially be linked to the migration of peripheral inflammatory factors into the brain. To our knowledge, this is the first study to examine microbiome alteration prior to the induction of a PD murine model.MethodsWe presently assessed whether pre-treatment with the probiotic, VSL #3, or the inflammatory inducer, dextran sodium sulphate (DSS), would influence the PD-like pathology provoked by a dual hit toxin model using lipopolysaccharide (LPS) and paraquat exposure.ResultsWhile VSL #3 has been reported to have anti-inflammatory effects, DSS is often used as a model of colitis because of the gut inflammation and the breach of the intestinal barrier that it induces. We found that VSL#3 did not have any significant effects (beyond a blunting of LPS paraquat-induced weight loss). However, the DSS treatment caused marked changes in the gut microbiome and was also associated with augmented behavioral and inflammatory outcomes. In fact, DSS markedly increased taxa belonging to the Bacteroidaceae and Porphyromonadaceae families but reduced those from Rikencellaceae and S24-7, as well as provoking colonic pro-inflammatory cytokine expression, consistent with an inflamed gut. The DSS also increased the impact of LPS plus paraquat upon microglial morphology, along with circulating lipocalin-2 (neutrophil marker) and IL-6. Yet, neither DSS nor VSL#3 influenced the loss of substantia nigra dopamine neurons or the astrocytic and cytoskeleton remodeling protein changes that were provoked by the LPS followed by paraquat treatment.ConclusionsThese data suggest that disruption of the intestinal integrity and the associated microbiome can interact with systemic inflammatory events to promote widespread brain-gut changes that could be relevant for PD and at the very least, suggestive of novel neuro-immune communication.

Endometrial inflammasome activation accompanies menstruation and may have implications for systemic inflammatory events of the menstrual cycle.

Endometrial inflammasome activation accompanies menstruation and may have implications for systemic inflammatory events of the menstrual cycle.

Systemic Immune Response to Traumatic CNS Injuries-Are Extracellular Vesicles the Missing Link?

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.

Study protocol: ASCRIBED: the impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in dementia: a study in acute hip fracture patients

BackgroundHip fracture represents a substantial acute inflammatory trauma, which may constitute a significant insult to the degenerating brain. Research suggests that an injury of this kind can affect memory and thinking in the future but it is unclear whether, and how, inflammatory trauma injures the brain. The impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in Dementia: a study in acute hip fracture patients (ASCRIBED) explores this relationship, to understand the effect of inflammation on the progression of dementia.MethodsThis protocol describes a multi-centre sample collection observational study. The study utilises the unique opportunity provided by hip fracture operations undertaken via spinal anaesthesia to collect cerebrospinal fluid (CSF) and blood, to investigate the impact of acute brain inflammation caused by hip fracture on the exacerbation of dementia. We will recruit 200 hip fracture patients with a diagnosis or evidence of dementia; and 200 hip fracture patients without dementia. We will also recruit ‘Suitable informants’, individuals in regular contact with the patient, to provide further proxy evidence of a patient’s potential cognitive decline. We will compare these 400 samples with existing CSF and blood samples from a cohort of dementia patients who had not experienced a systemic inflammatory response due to injury. This will provide a comparison between patients with and without dementia who are suffering a systemic inflammatory response; with stable patients living with dementia.DiscussionWe will test the hypothesis that hip fracture patients living with dementia show elevated markers of brain inflammation, as well as neuronal injury and Alzheimer-related plaque pathology, in comparison to (1) stable patients living with dementia and (2) hip fracture patients without dementia, as measured by biomarkers in CSF and blood. The findings will address the hypothesis that systemic inflammatory events can exacerbate underlying dementia and inform the search for new treatments targeting inflammation in dementia.Trial registrationISRCTN43803769. Registered 11 May 2017.

Systemic inflammatory event induces persistent dysregulation of memory and gene expression

A systemic inflammatory event occurring during illness or surgery may result in memory deficits that last for years after recovery. To understand how transient inflammatory signaling induces persistent alterations in memory, we used subchronic systemic immune challenge and examined long-lasting changes in memory, gene expression, and epigenetic modifications. Since males and females differ in immune responses and susceptibility to persistent memory deficits, we compared both sexes. Our paradigm used intermittent systemic injections of either lipopolysaccharide (LPS: 250 μg/kg) or polyI:C (6 mg/kg). Persistent changes in hippocampal-dependent memory were assessed eight weeks after the last injection using contextual fear conditioning and novel-object recognition. We observed sex-specific dysregulation of hippocampal-dependent memory that depended on type of immune challenge. Males showed impairments in contextual fear conditioning after polyI:C treatment and impairments in object recognition after both types of immune challenges while females showed increased fear-associated memory but impairments in object recognition after LPS treatment. Sex-specific, enduring changes in gene expression in the hippocampus were detected using RNA-sequencing, with differential expression of growth factor signaling, activity-dependent transcription factors, and immune related pathways in males and monoaminergic-associated signaling in females. Histone acetylation marks associated with changes in gene expression were of particular interest. Collectively, these data demonstrate that a systemic immune challenge induces sustained dysregulation of hippocampal-dependent memory and enduring differences in gene expression that may underlie the changes in memory.

Radiation-induced inflammatory cascade and its reverberating crosstalks as potential cause of post-radiotherapy second malignancies.

The disease-free survival following radiotherapy is often limited by the development of second/secondary cancers. This significant impediment to effective cancer treatment implicated even in the modern-day radiotherapy needs to be countered effectively. Critical analysis reveals that besides achieving effective tumor control, radiotherapy elicits certain cellular and systemic inflammatory events in tumor infiltrate, which remain relatively stable and tend to facilitate "in-field" or "out of field" oncogenesis in due course of time. Acute pro-inflammatory cytokines generated as a result of radiation-induced oxidative insult and DNA damage induce genetic instability that contributes to tumor heterogeneity and plasticity. The reverberating crosstalks between radiation-targeted tumor and its microenvironment in turn initiate inflammatory loops that feedback the immune system to manifest as systemic consequences. An "inflammatory switchover" within the tumor microenvironment is thus induced by cumulative radiation exposure, initiating pro-tumor events that can severely limit the outcome of radiotherapy. Various pro-survival tumorigenic pathways activated as a result regulate radiation-induced hypoxia, ECM remodeling, angiogenesis/vasculogenesis, and immune suppression/evasion within the tumor microenvironment. NF-κB, HIF and STAT are identified as central regulating mediators among others that orchestrate inflammatory switchover from apoptosis-mediated tumor surveillance to radiation-induced carcinogenesis. Radiation-induced interleukins stimulate recruited macrophages and endothelial cells to promote intravasation, which is further aided by release of chemokines favoring extravasation and secondary site lesions. We hence propose that delineating the inflammatory signaling network emanating from irradiation of complex tumor tissue is critical for devising suitable therapeutic strategies to prevent post-radiotherapy second cancers or metastasis. Graphical Abstract ᅟ.

Is there a correlation between the periodontitis-related systemic inflammatory burden and future cardiovascular events’ risk? A preliminary report

Is there a correlation between the periodontitis-related systemic inflammatory burden and future cardiovascular events’ risk? A preliminary report