Chronic Inflammation Symptoms Research Articles

Retained Foreign Body Which Should be Suspected as a Cause of Retractable Chronic Hand Inflammation and Diagnostic Capacity of Ultrasonography

Background: Foreign bodies in the hand are common but easily and often missed in the initial evaluation of injury. Diagnosing retained foreign bodies is difficult due to radiolucent foreign bodies. Purpose of this study is to emphasize the need of consideration of foreign bodies in patients with chronic synovitis in hand. Methods: Twenty-five patients who had retained foreign body in soft tissue of hand with chronic inflammation symptoms were included. Ultrasonography was conducted in all of the patients. Patient age, sex, localization of foreign body, duration of symptom, history of injury, follow up period, complication, and biopsy results were recorded and reviewed. Also, patients' demographics and clinical results were retrospectively reviewed. Results: Nine of the 25 patients diagnosed with a foreign body in the hand did not remember the initial presentation of injury. The average symptom duration (from injury to hospitalization) was 10.5 months (range 1-96 months). The middle finger and the proximal interphalangeal joint were the most common site of a retained foreign body (10 patients). All patients were diagnosed via ultrasonography and underwent surgery. Biopsy results showed mainly chronic inflammation, fibrosis, granuloma, and foreign bodies. Conclusions: Patient with symptoms of cellulitis, osteomyelitis, and palpable mass in hand for over a month without a diagnosis should be suspected of retained FBs.

TNFR1 Blockade Rather then TNFR2 Blockade Reduces Chronic Inflammation in JAK2+/V617F Mice

Introduction: Chronic myeloproliferative neoplasms (CMN) are characterized by expansion of myeloid cells, splenomegaly and thrombosis. Recent studies have demonstrated that chronic inflammation promotes the disease development as mutated hematopoietic cells are stimulated by pro-inflammatory cytokines. The most common driver mutation in BCR-ABL negative CMN is the activating point mutation JAK2-V617F. The constitutively activated JAK2 signaling leads to strongly elevated TNF levels in polycythemia vera, essential thrombocythemia and primary myelofibrosis (Fleischman et al, Blood, 2011). Recently, it has been reported that defective negative regulation of Toll-like receptor signals leads to excessive TNF in monocytes from CMN. Interestingly, this is not directly driven by JAK2-V617F in a cell-intrinsic manner (Lai et al., Blood, 2019). Thus, blockade of TNF signaling may represent a valuable anti-inflammatory pharmacological target in CMN. Therefore, in the Vav1-Cre x JAK2+/V617F (JAK2VF+) mouse model, we investigated the effects of TNFR1 or TNFR2 blockade using neutralizing antibodies (Ab) and we applied genetic disruption of the TNFRs. Methods: To study the genetic disruption of TNFR1 or TNFR2, TNFR1-/- or TNFR2-/- mice were crossed with the JAK2VF+ mouse model. For αTNFR1 Ab study, JAK2VF+ were crossed with a mouse (huTNFR1) expressing a chimeric TNFR1 consisting of the human extracellular domain and the murine transmembrane and intracellular domains, allowing treatment with an anti-human TNFR1 Ab. Over 3 weeks, JAK2VF+ mice received i.p. 3 x per week αTNFR1 (H398; 20 mg/kg) or 2 x per week αTNFR2 (TR75-54.7; 5 mg/kg) Abs or specific IgG controls. Blood was collected weekly for blood count measurements. After treatment, cell composition of blood, bone marrow and spleen was analyzed by flow cytometry. Serum cytokines were measured using a bead-based assay. HSCs and progenitor cells (MPP) were isolated from untreated huTNFR1 x JAK2VF+ mice and plated in MethoCult ± αTNFR1 or αTNFR2 (10µg/l). Colonies were analyzed after 7 days. Results: Blood count and spleen size of TNFR1-/- or TNFR2-/- x JAK2VF+ mice showed no differences as compared to TNFRWT x JAK2VF+ mice. In addition, the immune cell composition was similar to TNFRWT x JAK2VF+ mice. These results indicate that the disruption of a single cytokine pathway has no influence in this model, as other cytokines likely will compensate the signal during initiation of the disease.In contrary, αTNFR1 Ab treatment (n = 6) reduced the mean HCT after 3 weeks from 72.5 to 60.0%, which was not observed in the control group (n = 5). This was partly a result of a reduced MCV in αTNFR1 treated mice (34.9 versus 30.9 fl) as there was no reduction of the RBC. WBC number increased upon αTNFR1 treatment from 14.3 to 17.9 x 109 cells/l. Remarkably, αTNFR1 Ab treatment resulted in a major decrease of total cytokines as TNF, IL-1β, IL-10 and others when compared to the control group. Thus, αTNFR1 treatment is able to reduce chronic inflammation in the JAK2VF+ mouse but has minor impact on the HCT and WBC. Similar experiments were performed using αTNFR2 Ab (n = 4). This treatment showed only a minimal change on the complete blood counts of αTNFR2 treated mice in comparison to the IgG treated mice (n = 4). Thus, the HCT of αTNFR2 treated mice declined from 79.3 to 71.3 %, MCV and RBC remained stable during treatment phase. Of note, αTNFR2 treatment had no major impact on serum cytokine levels. Further, no differences in spleen size or immune cell composition were detected. In total, αTNFR2 therapy failed to reduce inflammation in the JAK2VF+model. To test whether αTNFR1/2 Ab treatment would impact on the stem cell compartment, a clonogenic assay was performed employing HSCs and MPPs ± αTNFR1 or αTNFR2. Almost no (αTNFR1) or minor (αTNFR2) reduction in colony number was measured; indicating that blockade of TNFRs has minor impact on the stem cell compartment in the JAK2VF+ mouse. Conclusions: Our study employing the JAK2VF+ mouse model revealed an involvement of TNF-TNFR1 in induction of chronic inflammation rather than TNF-TNFR2. αTNFR1 treatment strongly reduces cytokine levels but only slightly reduces HCT. Therefore targeting TNFR1 in CMN may have beneficial effects on chronic inflammation. In our view, a clinical trial investigating combination therapy with JAK1/2 inhibitors such as Ruxolitinib in patients with persisting symptoms of chronic inflammation is warranted. Disclosures Richter: Baliopharm GmbH: Other: F.R. is named inventor on patent applications covering Fc heterodimerization modules and monovalent inhibitors of TNFR1 interaction.. Pfizenmaier:Baliopharm GmbH: Other: K.P. is named inventor on patent applications covering Fc heterodimerization modules and monovalent inhibitors of TNFR1 interaction..

Anti- trachea inflammatory effects of diosgenin from Dioscorea nipponica through interactions with glucocorticoid receptor α.

Asthma is a heterogeneous disease characterized by symptoms of chronic inflammation and airway structural and functional changes. It affects about 300 million people worldwide and causes 250 000 deaths annually, but its symptoms can be greatly relieved by regular use of inhaled glucocorticoids (GCs). GCs exert their function through interacting with glucocorticoid receptors (GRs). Diosgenin is a naturally occurring steroidal saponin abundantly present in many medicinal plants, including Dioscorea nipponica, which shares a similar steroidal structure with GC. In this study, ovalbumin (OVA)-induced asthmatic mice and primary tracheal epithelial cells (TECs) were used as research models. ELISAs were applied to measure the secretion of TNF-α, IL-1β, and IL-6, while quantitative PCR and western blotting were applied to evaluate expression of GRs SLPI, TTP, GILZ, MKP-1, and NF-κB. Our data demonstrated that diosgenin suppressed the secretion of TNF-α, IL-1β, and IL-6 by enhancing the expression of GRs, SLPI, GILZ, and MKP-1, and inhibiting the expression of HSP70. These data provide some evidence on the molecular mechanism of diosgenin, which might facilitate its clinical applications.

JAK1 As a Convergent Regulator of Hematopoietic Stem Cell Function and Stress Hematopoiesis

Cytokine-mediated signal transduction is critical to hematopoiesis, immune responses, and other physiological processes. Aberrant production and secretion of pro-inflammatory cytokines disturbs homeostasis and proper immune function and if persistent results in symptoms of chronic inflammation. Previous studies have illustrated the importance of JAK1 as an effector of cytokine signaling, including in immunological and neoplastic diseases such that selective JAK1 inhibition is currently being investigated in clinical trials. However, the role of Jak1 in hematopoietic stem cell (HSC) function has not been delineated. This has led us to investigate the impact of loss of Jak1 signaling on HSC function by developing a novel conditional Jak1 knockout allele (Fig. 1a). Mice with conditional deletion of Jak1 in the hematopoietic system (hereafter referred to as Jak1 KO) are characterized by leukocytosis (Jak1 KO avg. 6.34K/ul, Jak1 WT avg. 10.76K/ul, P<0.01), and reduced spleen (Jak1 KO avg. 73.76mg, Jak1 WT avg. 98.86mg, P<0.01) and thymus weights (Jak1 KO avg. 49.31mg, Jak1 WT avg. 80.82mg, P<0.01). High dimensional single cell analysis of the hematopoietic compartment of these mice using mass cytometry showed that conditional Jak1 loss in hematopoietic cells attenuates B cell and NK cell differentiation in vivo, and results in differentiation towards the myeloid lineage at the expense of lymphoid fate commitment. Further, we observed a significant reduction of lineage-Sca1+cKit+ (LSK) cells in the bone marrow of Jak1 KO mice, including a decrease in CD34-Flk2- long-term HSCs (LT-HSCs) and in CD34+Flk2- short-term HSCs (ST-HSCs) (Fig.1b). Jak1-deficient cells formed fewer colonies in colony formation unit assays, which was also seen when clonogenic assays were performed in the presence of JAK1 inhibitor GLPG0634. Most importantly, Jak1-deficient stem cells exhibited decreased competitiveness in bone marrow transplantation assays. Flow analysis at 4 weeks post transplantation showed a 3-fold reduced blood chimerism in recipients transplanted with Jak1 KO bone marrow cells and at 16 weeks, Jak1KO cells were largely outcompeted by CD45.1-positive WT cells (Fig. 1c). Jak1-deficient stem cells were also unable to rescue hematopoiesis in the setting of myelosuppressive insults leading to a worse survival of Jak1 KO mice when serially injected with 5-fluorouracil (5-FU) (Fig. 1d).Consistent with the stem cell phenotype observed in JAK1 KO mice, we found that a significant larger proportion of Jak1-deficient stem cells lacks expression of the proliferation marker Ki67 and that Jak1-deficient stem cells fail to enter the cell cycle in response to hematopoietic stress. To begin to determine the mechanism by which Jak1 regulates normal stem cell function in vivo, we assessed the impact of loss of Jak1 on transcriptional output. Gene expression profiling of LT-HSCs from Jak1 KO and WT mice identified 259 significant genes, many of which were known to be Jak1 downstream targets. Gene set enrichment analysis (GSEA) revealed that the majority of genes that were altered following deletion of Jak1 corresponded to interferon signaling and inflammatory response pathways. Consistent with these findings, our functional in vitro and in vivo assays demonstrated that Jak1-deficient cells were insensitive to type I interferons as shown by lack of Stat1 and Stat5 activation (Fig. 1e), retained Sca1 surface expression, and an unchanged cell cycle status upon IFN stimulation. Moreover, the HSC defect observed in the setting of Jak1 loss was not fully rescued by expression of a constitutively active Jak2 allele, suggesting there is non-redundant signaling in HSCs within the JAK kinase family. Together, our data suggests that Jak1 functions as a central node for interferon signaling in HSCs and reveals an essential and nonredundant role of Jak1 in HSC homeostasis and stress response. [Display omitted] DisclosuresKoppikar:Amgen: Employment. Nolan:Fluidigm: Consultancy. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees.

Clinical manifestation of self-limiting acute retinal necrosis.

BackgroundThe purpose of this paper was to present a case series of self-limiting, peripheral acute retinal necrosis and to demonstrate efficacy of treatment with valacyclovir in patients resistant to acyclovir. The diagnosis was made on ophthalmoscopic examination and positive serum tests for herpes viruses.Material/MethodsTen patients (6F and 4M) aged 19–55 years were diagnosed and treated for self-limiting acute retinal necrosis (ARN). The following endpoints were reported: visual outcomes, clinical features, disease progression, treatment, and complications. Patients received only symptomatic treatment because they did not consent to vitreous puncture.ResultsPeripheral, mild retinitis was diagnosed in all eyes at baseline. Initially, all patients were treated with systemic acyclovir (800 mg, 5 times a day), prednisone (typically 40–60 mg/day), and aspirin in an outpatient setting. In 6 patients, treatment was discontinued at 6 months due to complete resolution of the inflammatory process. Four patients with immune deficiency showed signs and symptoms of chronic inflammation. Two patients did not respond to acyclovir (2 non-responders); however, those patients were successfully treated with valacyclovir. Complete resolution of inflammatory lesions was observed in 8 patients. In 2 patients, the disease progressed despite treatment – 1 female patient after kidney transplant who stopped the prescribed medications, and 1 male patient with SLE and antiphospholipid syndrome who experienced breakthrough symptoms on-treatment. He died due to cerebral venous sinus thrombosis. Neurological complications (encephalitis and meningitis) were observed in 2 female patients. Prophylactic laser photocoagulation was performed in 1 subject.ConclusionsA series of cases of self-limiting acute retinal necrosis (ARN) is presented. This clinical form of ARN can resemble toxoplasmic retinitis in some cases. Oral antiviral medications provide an effective alternative to intravenous formulations in patients with self-limiting ARN. Retinitis is associated with the risk of encephalitis.

Protein biomarkers in cystic fibrosis research: where next?

Cystic fibrosis is one of the most common life-limiting inherited disorders. Its clinical impact manifests chiefly in the lung, pancreas, gastrointestinal tract and sweat glands, with lung disease typically being most detrimental to health. The median age for survival has increased dramatically over the past decades, largely thanks to advances in understanding of the mechanisms and consequences of disease, leading to the development of better therapies and treatment regimes. The discovery of dysregulated protein biomarkers linked to cystic fibrosis has contributed considerably to this end. This article outlines clinical trials targeting known protein biomarkers, and the current and future contributions of proteomic techniques to cystic fibrosis research. The treatments described range from those designed to provide functional copies of the mutant protein responsible for cystic fibrosis, to others addressing the associated symptoms of chronic inflammation. Preclinical research has employed proteomics to help elucidate pathways and processes implicated in disease that might present opportunities for therapy or prognosis. Global analyses of cystic fibrosis have detected the differential expression of proteins involved in inflammation, proteolytic activity and oxidative stress, which are recognized symptoms of the cystic fibrosis phenotype. The dysregulation of other processes, such as the complement and mitochondrial systems, has also been implicated. A number of studies have focused specifically on proteins that interact with the cystic fibrosis protein, with the goal of restoring its normal proteostasis. Consequently, proteins involved in synthesis, folding, degradation, translocation and localization of the protein have been identified as potential therapeutic targets. Cystic fibrosis patients are prone to lung infections that are thought to contribute to chronic inflammation, and thus proteomic studies have also searched for microbiological biomarkers to use in early infection diagnosis or as indicators of virulence. The review concludes by proposing a future role for proteomics in the high-throughput validation of protein biomarkers under consideration as outcome measures for use in clinical trials and routine disease monitoring.

Autoimmune thyroid diseases in patients with primary pulmonary hypertension

Abnormal metabolism due to thyroid disorders could cause the additional significant right ventricular (RV) overload in patients with primary pulmonary hypertension (PPH). The purpose of this study was the prospective determination of autoimmune thyroid status in PPH patients. 45 patients (33 women and 12 men, mean age 38 years+/-13) with moderate and severe PPH (mean pulmonary artery pressure 61 mmHg+/-18 mmHg). PPH was diagnosed when other reason of pulmonary hypertension had been excluded especially thromboembolic, venous and hypoxemic. Titer of antibodies to thyroglobulin and thyroid peroxidase were measured. Thyroid gland dysfunction was determined by biochemical measurements of thyrotropin and free thyroxine; thyroid ultrasonographic examination was also performed. The prevalence of thyroid autoantibodies is estimated at 13% in general population. RESULTS. In 14 patients (31%) increased titer of thyroid antibodies was found in our group. Hyperthyroidism was recognized in 2 patients and in 3 cases we diagnosed hypothyroidism with high antibodies level requiring treatment. Ultrasonographic abnormalities were revealed in 21 patients (nodular changes--11 patients, fibrosis--3 patients, chronic inflammation symptoms--7). Ultrasonographic abnormalities were present in all patients with detectable antithyroid antibodies. We haven't confirmed more frequent prevalence of hormonal disorders in patient treated with prostacyclin's analogues. The prevalence of autoimmune thyroid diseases is about 3 times higher in PPH patients than in general population. The treatment of patients with clinically evident hyper- or hypothyroidism is necessary. The monitoring of clinically silent disorders seems to be recommended especially prior to lung transplantation qualification.

260. Effects of diet-induced obesity on ovarian function and female fertility

Obesity and its related complications (metabolic syndrome, Type II diabetes and polycystic ovary syndrome) are increasingly associated with female infertility. Our research is focused on understanding how diet-induced obesity, which triggers insulin resistance and symptoms of chronic inflammation, directly impacts ovarian function and female fertility. Female mice were maintained on a “Western style” diet (22% fat, 0.15% cholesterol) or a matched control diet. Body weights were monitored weekly and after 16 weeks fasting insulin levels and glucose tolerance were assessed. Mice were then paired with males and tissues collected on day 1 on pregnancy. Blood samples were taken to determine levels of progesterone, metabolites (glucose, HDL/LDL) and inflammatory cytokines. Tissue weights (fat pads, liver, kidney, spleen, pancreas, ovary and uterus) were recorded and the reproductive tissues were fixed for analysis of histology and gene expression. Zygotes were isolated from the oviduct, cultured in vitro and scored for on-time development and differentially stained to assess blastocyst quality. Indices of ovarian function, including ovulation rate, steroid production and oocyte quality/blastocyst development will then be correlated with degrees of insulin resistance, dyslipidemia and inflammation. Five strains of mice were tested (CBA, Balb/c, C57, SV129 and Swiss) and showed significant differences in susceptibility to diet-induced obesity and insulin resistance. In CBA mice, the first group to be completed, the high fat diet significantly increased body weight, but did not result in overtly impaired glucose tolerance. The number of days to mating was slightly extended compared to mice on the control diet. Interestingly, the high fat diet did not affect ovulation rate but resulted in dramatically impaired blastocyst development. The results of this study will reveal how ovarian folliculogenesis, oocyte competence and ovulation are affected by obesity-induced metabolic changes, which are increasingly affecting women of reproductive age.

The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes.

Acquired cold urticaria syndromes represent one of the more common forms of physical urticaria. The syndromes are heterogenous, and a diagnostic classification is presented to facilitate collation for future studies. Acquired cold urticaria represents an excellent reproducible in vivo model to investigate the mechanisms of urticaria. The discussion includes clinical manifestations, laboratory features, pathogenesis, and management of these disorders. A description of familial types, particularly familial cold auto-inflammatory syndrome (FCAS) that is manifested by cold-evoked signs and symptoms of chronic inflammation, is included. FCAS historically has been included with acquired cold urticaria, even though the exanthem of FCAS is maculopapular caused by leukocytic infiltration. FCAS has become an important investigative syndrome, as it represents a reproducible in vivo model of chronic inflammation.

Endoscopic management of a chronic ethmoid and sphenoid sinus foreign body

Whereas foreign bodies of the nose are relatively common, foreign bodies of the paranasal sinuses occur infrequently. They may present in a delayed fashion, frequently with symptoms of chronic inflammation, and necessitate careful removal because of their relationship to vital structures. 1 We present a case of chronic sinusitis caused by a sphenoid and ethmoid sinus foreign body of 16 years’ duration and its endoscopic removal.