Chronic Tissue Research Articles

Comparison of therapeutic effects of mesenchymal stem cells derived from superficial and deep subcutaneous adipose tissues

BackgroundFibrosis is a common histological feature in the process from chronic organ injury to organ failure. Chronic tissue injury causes inflammatory cell infiltration into the injured tissue. The persistence of this inflammatory cell infiltration leads to fibrosis and organ failure. Adipose-derived mesenchymal stem cells (ASCs) have received much attention as a regenerative therapeutic tool to prevent progression from organ injury to failure. Subcutaneous abdominal adipose tissue is divided into superficial and deep layers by a superficial fascia. Adipose tissue easily collected by liposuction is usually obtained from a deep layer, so ASCs derived from a deep layer are generally used for regenerative medicine. However, no research has been conducted to investigate differences in the therapeutic effects of ASCs from the superficial and deep layers (Sup-ASCs and Deep-ASCs, respectively). Therefore, we compared the therapeutic potencies of Sup-ASCs and Deep-ASCs.MethodsASCs were isolated from superficial and deep subcutaneous abdominal adipose tissues collected from patients who underwent breast reconstruction. We first compared cell characteristics, such as morphology, cell proliferation, cell surface markers, adipogenic and osteogenic differentiation, cell senescence markers, and expression of coagulation and anticoagulant factors between Sup-ASCs and Deep-ASCs. Furthermore, we compared their ability to promote polarization of M2 macrophages and to inhibit transforming growth factor (TGF)-β/Smad signaling using THP-1 cells and TGF-β1 stimulated HK-2 cells incubated with conditioned media from Sup-ASCs or Deep-ASCs. In in vivo experiments, after renal ischemia–reperfusion injury (IRI) procedure, Sup-ASCs or Deep-ASCs were injected through the abdominal aorta. At 21 days post-injection, the rats were sacrificed and their left kidneys were collected to evaluate fibrosis. Finally, we performed RNA-sequencing analysis of Sup-ASCs and Deep-ASCs.ResultsSup-ASCs had greater proliferation and adipogenic differentiation compared with Deep-ASCs, whereas both ASC types had similar morphology, cell surface markers, senescence markers, and expression of coagulation and anticoagulant factors. Conditioned media from Sup-ASCs and Deep-ASCs equally promoted polarization of M2 macrophages and suppressed TGF-β/Smad signaling. Moreover, administration of Sup-ASCs and Deep-ASCs equally ameliorated renal fibrosis induced by IRI in rats. RNA-sequencing analysis revealed no significant difference in the expression of genes involved in anti-inflammatory and anti-fibrotic effects between Sup-ASCs and Deep-ASCs.ConclusionsThese results indicate that both Sup-ASCs and Deep-ASCs can be used effectively and safely as an intravascular ASC therapy for organ injury.

Human iPSC-Derived Proinflammatory Macrophages cause Insulin Resistance in an Isogenic White Adipose Tissue Microphysiological System.

Chronic white adipose tissue (WAT) inflammation has been recognized as a critical early event in the pathogenesis of obesity-related disorders. This process is characterized by the increased residency of proinflammatory M1 macrophages in WAT. However, the lack of an isogenic human macrophage-adipocyte model has limited biological studies and drug discovery efforts, highlighting the need for human stem cell-based approaches. Here, human induced pluripotent stem cell (iPSC) derived macrophages (iMACs) and adipocytes (iADIPOs) are cocultured in a microphysiological system (MPS). iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity. Significantly more CLS-like morphologies formed in aged and palmitic acid-treated iMAC-iADIPO-MPS, showing the ability to mimic inflammatory severity. Importantly, M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs. Both RNAseq and cytokines analyses revealed a reciprocal proinflammatory loop in the interactions of M1 iMACs and iADIPOs. This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT, opening a door to study the dynamic inflammatory progression and identify clinically relevant therapies.

Chronic troponin elevation assessed by myocardial T1 mapping in patients with stable coronary artery disease.

Cardiac troponin detected with sensitive assays can be chronically elevated, in the absence of unstable coronary syndromes. In patients with chronic coronary artery disease, clinically silent ischemic episodes may cause chronic troponin release. T1 mapping is a cardiovascular magnetic resonance technique useful in quantitative cardiac tissue characterization. We selected patients with anatomically and functionally normal hearts to investigate associations between chronic troponin release and myocardial tissue characteristics assessed by T1 mapping. We investigated the relationship between cardiac troponin I concentrations and cardiovascular magnetic resonance T1 mapping parameters in patients with stable coronary artery disease enrolled in MASS V study before elective revascularization. Participants had no previous myocardial infarction, negative late gadolinium enhancement, normal left ventricular function, chamber dimensions and wall thickness. A total of 56 patients were analyzed in troponin tertiles: nativeT1 and extracellular volume (ECV) values (expressed as means ± standard deviations) increased across tertiles: nativeT1 (1006 ± 27 ms vs 1016 ± 27 ms vs 1034 ± 37 ms, ptrend = 0.006) and ECV (22 ± 3% vs 23 ± 1.9% vs 25 ± 3%, ptrend = 0.007). Cardiac troponin I concentrations correlated with native T1(R = 0.33, P = .012) and ECV (R = 0.3, P = .025), and were independently associated with nativeT1 (P = .049) and ventricular mass index (P = .041) in multivariable analysis. In patients with chronic coronary artery disease and structurally normal hearts, troponin I concentrations correlated with T1 mapping parameters, suggesting that diffuse edema or fibrosis scattered in normal myocardium might be associated with chronic troponin release.

Systemic sclerosis: one year in review 2023.

Systemic sclerosis is a rare and chronic connective tissue disease resulting from an intricate pathogenesis and which is expressed in very heterogeneous clinical manifestations. Several studies try every year to unravel and shed a novel insight into the pathogenesis, organ involvement and treatment of this complex and severe disease. We herein provide an overview of the most relevant studies published in the literature in 2022.

Antagonizing FcαR1 (CD89) as treatment in IgA-mediated chronic inflammation and autoimmunity.

Immunoglobulin A (IgA) is mostly considered as a non-inflammatory regulator at mucosal areas. However, previous work of our group showed that IgA can also be involved in disease pathology, because it provides a potent stimulus to activate neutrophils after crosslinking of surface CD89 (FcaRI), resulting in chronic inflammation and tissue damage. IgA (auto)antibodies and neutrophils are key players in various diseases, including blistering skin diseases and rheumatoid arthritis. Therefore, we generated an array of anti-CD89 monoclonal antibodies (mAbs) for therapeutic targeting of CD89. The biological activity of newly developed anti-human CD89 mAbs and their potential therapeutic capacity were investigated. Human neutrophils were isolated from heparinized healthy donor blood. The ability of anti-CD89 mAbs to bind human neutrophils was investigated by flow cytometry. Furthermore, the capacity of these anti-CD89 mAbs to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and migration was studied. To this end, neutrophils were pre-incubated with/without anti-CD89 mAbs after which they were stimulated with IgA-coated beads. The amount of phagocytosed beads, NET release and migrated neutrophils were subsequently analysed. In parallel, chemoattractant leukotriene B4 and lactoferrin (as a measure for degranulation) release were determined. Finally, the therapeutic potential of our prototypic anti-CD89 mAb clone 10E7 was in vivo tested in anti-mouse collagen XVII human IgA-treated transgenic CD89 mice, a preclinical model for autoimmune linear IgA bullous disease (LABD). Our results show that all generated anti-CD89 mAbs bound surface CD89 on neutrophils. Although these anti-CD89 mAbs bind to different epitopes on EC1 of CD89, they all have the capacity to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and neutrophil migration. Moreover, IgA mediated leukotriene B4 and lactoferrin release are decreased in supernatant from anti-CD89 mAbs-treated neutrophils. Finally, anti-CD89 mAb clone 10E7, that was selected based on its selective binding profile on tissue micro arrays, reduced anti-mouse collagen XVII hIgA-induced neutrophil influx in an in vivo linear IgA bullous disease (LABD) mice model. This study clearly indicates that our newly developed anti-CD89 mAbs inhibited IgA-induced neutrophil activation and reduced anti-autoantigen IgA-induced neutrophil influx in vivo, supporting further clinical development for the treatment of LABD.

5613426 LOW CHRONIC INFLAMMATION IN SCD

Introduction: Sickle Cell Disease (SCD) is a genetic disorder of hemoglobin affecting 30 million people worldwide in which the mutant HbS polymerize upon deoxygenation, causing the eritrocyte to assume a sickle morphology and reduce the fluidity of cell membrane, adhering to leucocyte immobilized to the endothelium, causing microvascular occlusion, vaso occlusive crisis and tissue ischemia (1). In additon to eritrocyte sickling, one of the hallmarks of SCD is the continuous presence of basal inflammatory process. SC patients report the following condition: higher baseline leucocyte count (2) Higher level of soluble CD62L (3) neutrofils express higher activation molecules, CD64 (4), CD11b/CD18 (5) monocytes demonstrate activated phenotypes and higer propensity to IL-1beta and TNF-alfa (6) platelets are chronically activated and express higher level of CD40L (7) patience exhibit increased intestinal permeability related to enterocyte injury (8) gut disbiosis that is associated with hospitalization and VOC (9) Ongoing inflammatory process not only render SCD patience to developing VOC, they also create vicious cicle of the pathology that represent a significant risk in the progression of the disease and in chronic damage tissue. Aims: While advance have been made to reduce the frequency of VOC in SCD, there have been very little change in the management of patience during symptom-free “steady state”. The results from various studies on treating VOC using monotherapy have so far been universally disappointing. This is not surprising in view of the complex nature of VOC. Successful treatment of VOC targeting of the downstream immunological pathways requires multipronged approaches using combination therapy, just like treatment of malignant diseases using combination chemotherapy. Methods: The reviwes of the scientific litterature is full of interesting articles in which is enlighted the interaction between the immune system and different stimuli in order to obtain a modulation of the immune reasponse toward a tolerogenic way. Results: In PubMed there are very interesting report that investigate the approach to the immune system in SCD in order to reduce the basal inflammation. There are many way to interact with the immune system to promote a tolerogenic way in SCD such as: supplement of Vitamin D to reduce resporatory illness (10) supplement of Omega-3 to reduce CRP (11) supplement of Glutamine to reduce hospitalization and pain crises (12) probiotic or enterosorbent can reduce gut disbiosis and ameliorate clinical outcome (13) moderate exercise improve cardiopulmonary function and quality life (14) (15) Conclusion: SCD is a genetic disorder caracterized by a continuous presence of low chronic inflammation and studies in human have found that in SCD patience, the more the immune system is activated, the more are likely to get involved in clinical complication such alloimmunization, hospitalization and pain crises (16). Recent evidence suggest that bioregulatory approach toward a tolerogenic way of the immune response could lead to an amelioration of clinical outcome and improvement of quality of life with cheap and feasible approaches.

LncRNA PSCK6-AS1-HIPK2 promotes Th1 differentiation via STAT1 phosphorylation to regulate colitis-related mucosal barrier damage.

This work aimed to investigate the role of long non-coding RNA (lncRNA) PCSK6-AS1 in inflammatory bowel disease (IBD). The levels of PCSK6-AS1 in human samples were detected, and its target protein HIPK2 was explored by protein mass spectrometry and ground select test (GST) method. Meanwhile, the HIPK2-STAT1 interaction relation was verified by pull-down assay. In the mouse model, Dextran Sulfate Sodium（DSS） was used to induce mouse colitis, then the effect of PCSK6-AS1 on mouse mucosal barrier was detected by immunohistochemical (IHC) staining, hematoxylin and eosin (H&E) staining, and the proportion of T-helper cells 1（Th1) cells was measured by flow cytometry (FCM). For in-vitro experiments, Th0 cells were used as the objects, and the effect of PCSK6-AS1 on Th1 differentiation was explored by FCM and enzyme-linked immunosorbent assay (ELISA). According to our results, the expression of PCSK6-AS1 in colitis tissues increased. PCSK6-AS1 interacted with HIPK2 to promote the expression of the latter, while HIPK2 promoted STAT1 phosphorylation to regulate Th1 differentiation. Th1 differentiation accelerated the mucosal barrier injury and aggravated the progression of colitis. In the Th0 model, PCSK6-AS1 promoted Th1 differentiation. In the animal model, PCSK6-AS1 enhanced Th1 differentiation in the tissues, decreased the tight junction (TJ) protein levels, and improved the mucosal barrier permeability. Suppressing PCSK6-AS1 and the HIPK2 inhibitor tBID decreased Th1 differentiation and tissue inflammation. According to our results, PCSK6-AS1 promotes Th1 cell differentiation via the HIPK2-STAT1 signaling, thus aggravating the chronic colitis-related mucosal barrier damage and tissue inflammation. PCSK6-AS1 has an important role in the occurrence and development of IBD.

Moving orthopaedic procedures out of the operating theatre:Outpatient needle arthroscopy can reduce cost & waste, and increase inpatient capacity compared to conventional knee arthroscopy

BackgroundNeedle arthroscopy (NA) is an emerging technique that could streamline pathways, facilitate timely care, and reduce service burden. The primary aim was to assess the practical and economic viability of an outpatient NA service. Secondary aims were to assess the relative costs and benefits compared to a conventional arthroscopy (CA) service. MethodsThis service feasibility study was conducted between 2021–2022 in a high-volume national treatment centre. A NA pathway was established for patients with chronic soft tissue pathology or early degenerative knee disease. The pathway was evaluated in terms of: i) cost; ii) efficiency, and iii) waste production, and an assessment was conducted of the patient-related and service-related effects. ResultsThe cost of the NA pathway was £1555.20 per patient, compared to £2,351.53 for CA. Time to management was 45 days for NA versus 180 days for CA. The NA pathway involved two hospital attendances, whereas CA required a minimum of three. NA cases produced 1.4 kg of non-recyclable waste compared to 5.0 kg produced by CA. For every two cases managed by NA instead of CA, capacity for one additional obligate-inpatient procedure was created. ConclusionsThe NA pathway offers a technically and economically viable approach for the management of refractory knee symptoms in the context of chronic soft tissue or early degenerative disease. NA placed less demand on hospital resources, produced two-thirds less non-recyclable waste, and is amenable to a one-stop clinic approach. Clinical studies focused on objective and patient-reported outcome measures are required to assess clinical efficacy.

Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer.

Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients' sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3' untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment.

Endothelin-1 level in the tear fluid of children with primary congenital glaucoma

Purpose. To analyze the level of endothelin-1 (ET-1) in the tear fluid (TF) of children with primary congenital glaucoma (PCG) and to detect possible correlations between the clinical and the laboratory data. Material and methods. We examined 23 eyes of 15 children with PCG aged between 7 months and 15 years and 3 healthy fellow eyes of these children. 25 eyes of children of same age without glaucoma (somatically healthy with mild hyperopia and/or concomitant strabismus) served as control. A standard ophthalmological examination was supplemented by the flash visual evoked cortical potential, a total and a rhythmic electroretinogram, axial length (AL) echobiometry of the eye, optical coherence tomography of the optic nerve head, enzyme immunoassay (ELISA) of ET-1 level in TF were given. Results. In most children with PCG (95.6 %), the TF level of ET-1 (mean 9.69 ± 3.80 pg/ml) was higher than that in healthy children (4.65 ± 2,02 pg/ml) (p < 0.001). Increased levels of ET-1 (up to 8.90 pg/ml) were also detected in healthy fellow eyes of children with PCG. The mean level of ET-1 in children with PCG aged 3 to 15 years was significantly higher (p< 0.05) lower than in the initial stage. Our study revealed no correlations between the ET-1 level and the degree of retinal nerve fiber layer thinning, or the AL in children with PCG. Conclusion. For the first time, an increased level of ET-1 in the TF in children with PCG was revealed as compared to healthy children. A lower value of ET-1 in the far advanced PCG stage as compared to the initial stage can be explained by long-term chronic eye tissue hypoxia depleting the protective reserves of the eye. Since no obvious correlation between ET-1 level in the TF and clinical and functional data of children with PVG has been found, we cannot definitely view the ET-1 level in the TF as a measure of ischemia degree in PCG. Further studies are needed to obtain reliable correlations.

Brain BOLD and NIRS response to hyperoxic challenge in sickle cell disease and chronic anemias

PurposeCongenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects. MethodsA cohort of 38 sickle cell disease subjects (age 22 ± 8 years, female 39%), 25 non-sickle anemic subjects (age 25 ± 11 years, female 52%), and 31 healthy controls (age 25 ± 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups. ResultsRegional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure. ConclusionThese results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction.

Association between levels of serotonin, melatonin, cortisol and the clinical condition of patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic connective tissue disease of autoimmune basis. It is characterized by inflammation of joints and systemic complications. The etiopathogenesis is still unknown. Predisposing factors for the disease include genetic, immunological and environmental. Chronic disease and the stress experienced by patients disrupt the body’s homeostatic state and weaken the human immune system. Reduced immunity and endocrine disruption may influence the development of autoimmune diseases and exacerbate their course. The aim of the study was to investigate whether there is a relationship between the blood levels of hormones such as cortisol, serotonin, melatonin and the clinical status of RA patients as determined by the DAS28 index and CRP protein. A total of 165 people participated in the study of these 84 subjects had RA and the rest were the control group. All participants completed a questionnaire and had their blood drawn to determine hormones. Patients with RA had higher plasma cortisol (324.6 ng/ml vs. 292.9 ng/ml) and serotonin concentrations (67.9 ng/ml vs. 22.1 ng/ml) and lower plasma melatonin (116.8 pg/ml vs. 330.2 pg/ml) compared to controls. Patients whose CRP concentration were above normal also had elevated plasma cortisol concentration. No significant association was observed in RA patients between plasma melatonin, serotonin and DAS28 values. However, it can be concluded that those with high disease activity had lower melatonin levels as compared to patients with low and moderate DAS28 values. Significant differences were found between RA patients not using steroids and plasma cortisol (p = 0.035). In RA patients, it was observed that as plasma cortisol concentration increased, the chance of having an elevated DAS28 score, indicating high disease activity, increased.

Probabilistic cellular automata modelling of intercellular interactions in airways: complex pattern formation in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease characterized by chronic inflammation and tissue remodeling possibly induced by unusual interactions between fibrocytes and CD8+ T lymphocytes in the peribronchial area. To investigate this phenomenon, we developed a probabilistic cellular automata type model where the two types of cells follow simple local interaction rules taking into account cell death, proliferation, migration and infiltration. We conducted a rigorous mathematical analysis using multiscale experimental data obtained in control and disease conditions to estimate the model’s parameters accurately. The simulation of the model is straightforward to implement, and two distinct patterns emerged that we can analyse quantitatively. In particular, we show that the change in fibrocyte density in the COPD condition is mainly the consequence of their infiltration into the lung during exacerbations, suggesting possible explanations for experimental observations in normal and COPD tissue. Our integrated approach that combines a probabilistic cellular automata model and experimental findings will provide further insights into COPD in future studies.

Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods.

The present study aims to determine how various dosages of chronic roflumilast affect testicular tissue and testosterone levels in healthy rats. Biochemical tests, along with histopathological, immunohistochemical, and immunofluorescence studies, were carried out. Loss of tissue in the seminiferous epithelium, degeneration in the interstitial area, a separation between cells, desquamation, interstitial edema, and degenerative alterations in testicular tissue were observed in roflumilast groups when compared with the other groups. While apoptosis and autophagy were statistically negligible in the control and sham groups, the roflumilast groups had significantly higher apoptotic and autophagic alterations, as well as immunopositivity. Serum testosterone levels in the 1 mg/kg roflumilast group were lower than those in the control, sham, and 0.5 mg/kg roflumilast groups. Analyses of the research findings revealed that continuous usage of the broad-spectrum active component roflumilast exerted unfavorable effects on the testicular tissue and testosterone levels of rats.

Bovine meat and milk factor protein expression in tumor-free mucosa of colorectal cancer patients coincides with macrophages and might interfere with patient survival.

Bovine milk and meat factors (BMMFs) are plasmid-like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co-markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor-adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n= 246)], low-/high-grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co-immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor-adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD-adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC-specific death were increased for higher Rep expression (TMA), with high tumor-adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF-specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.

Changes in Tophus Composition During Urate-Lowering Therapy: A Dual-Energy Computed Tomography Study.

The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.

Bioengineered Water-Responsive Carboxymethyl Cellulose/Poly(vinyl alcohol) Hydrogel Hybrids for Wound Dressing and Skin Tissue Engineering Applications.

The burden of chronic wounds is growing due to the increasing incidence of trauma, aging, and diabetes, resulting in therapeutic problems and increased medical costs. Thus, this study reports the synthesis and comprehensive characterization of water-responsive hybrid hydrogels based on carboxymethyl cellulose (CMC) and poly(vinyl alcohol) (PVA) using citric acid (CA) as the chemical crosslinking agent, with tunable physicochemical properties suitable to be applied as a wound dressing for soft tissue engineering applications. They were produced through an eco-friendly process under mild conditions. The hydrogels were designed and produced with flexible swelling degree properties through the selection of CMC molecular mass (Mw = 250 and 700 kDa) and degree of functionalization (DS = 0.81), degree of hydrolysis of PVA (DH > 99%, Mw = 84-150 kDa) associated with synthesis parameters, CMC/PVA ratio and extension of chemical crosslinking (CA/CMC:PVA ratio), for building engineered hybrid networks. The results demonstrated that highly absorbent hydrogels were produced with swelling degrees ranging from 100% to 5000%, and gel fraction from 40% to 80%, which significantly depended on the concentration of CA crosslinker and the presence of PVA as the CMC-based network modifier. The characterizations indicated that the crosslinking mechanism was mostly associated with the chemical reaction of CA carboxylic groups with hydroxyl groups of CMC and PVA polymers forming ester bonds, rendering a hybrid polymeric network. These hybrid hydrogels also presented hydrophilicity, permeability, and structural features dependent on the degree of crosslinking and composition. The hydrogels were cytocompatible with in vitro cell viability responses of over 90% towards model cell lines. Hence, it is envisioned that this research provides a simple strategy for producing biocompatible hydrogels with tailored properties as wound dressings for assisting chronic wound healing and skin tissue engineering applications.

Understanding Neutrophil Dynamics during COVID-19 Infection

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in varied clinical outcomes, with virus-induced chronic inflammation and tissue injury being associated with enhanced disease pathogenesis. To determine the role of tissue damage on immune populations recruitment and function, a mathematical model of innate immunity following SARS-CoV-2 infection has been proposed. The model was fitted to published longitudinal immune marker data from patients with mild and severe COVID-19 disease and key parameters were estimated for each clinical outcome. Analytical, bifurcation, and numerical investigations were conducted to determine the effect of parameters and initial conditions on long-term dynamics. The results were used to suggest changes needed to achieve immune resolution.

Morphea: The 2023 update.

Morphea, also known as localized scleroderma, is a chronic inflammatory connective tissue disorder with variable clinical presentations, that affects both adults and children. It is characterized by inflammation and fibrosis of the skin and underlying soft tissue, in certain cases even of the surrounding structures such as fascia, muscle, bone and central nervous system. While the etiology is still unknown, many factors may contribute to disease development, including genetic predisposition, vascular dysregulation, TH1/TH2 imbalance with chemokines and cytokines associated with interferon-γ and profibrotic pathways as well as certain environmental factors. Since the disease may progress to permanent cosmetic and functional sequelae, it is crucial to properly assess the disease activity and to initiate promptly the adequate treatment, thus preventing subsequent damage. The mainstay of treatment is based on corticosteroids and methotrexate. These, however, are limited by their toxicity, especially if applied long-term. Furthermore, corticosteroids and methotrexate often do not sufficiently control the disease and/or the frequent relapses of morphea. This review presents the current understanding of morphea by discussing its epidemiology, diagnosis, management and prognosis. In addition, it will describe recent pathogenetic findings, thus proposing potential novel targets for therapeutic development in morphea.

Chronic anemia complicated by cardiac failure, pulmonary hypertension, and pericardial effusion: a case report

BackgroundWorldwide, iron deficiency anaemia (IDA) is the most common cause of anaemia. Iron deficiency alone has an association with heart failure and pulmonary hypertension. Chronic iron deficiency anemia triggers various physiologic adjustments, leading to hyperdynamic circulation and enhanced hypoxic pulmonary vasoconstriction. Those mechanisms may result in the development of high output cardiac failure and pulmonary hypertension; however, pericardial effusion remains a rare association.Case presentationA 44-year-old Nepalese man presented with fatigability and swollen ankles. Except for a hemorrhoidectomy 4 years ago, he had no comorbidities. Labs confirmed severe iron deficiency anemia (hemoglobin 1.8 grams per deciliter) likely secondary to hemorrhoids. An echocardiogram revealed high output cardiac failure, pericardial effusion, and severe pulmonary hypertension. He responded well to the correction of anemia and diuretics with the resolution of vascular complications.ConclusionWe report a unique presentation of chronic severe iron deficiency anemia complicated by heart failure, pulmonary hypertension, and pericardial effusion. We believe it to be the first-ever such case reported in the literature. These cardiovascular complications seem to result from internal homeostatic mechanisms against the chronic tissue hypoxemia observed in severe anemia. Furthermore, iron deficiency alone has an association with heart failure and pulmonary hypertension. After excluding other potential causes, we confirmed iron deficiency anaemia as the cause of those complications. The correction of anemia led to an excellent recovery without any sequelae. Our case report highlights the fact that management of such a case should be focused on underlying etiology rather than the complications.