Higher Inflammatory Cell Infiltration Research Articles

A dual dynamically cross-linked hydrogel promotes rheumatoid arthritis repair through ROS initiative regulation and microenvironment modulation-independent triptolide release

High oxidative stress and inflammatory cell infiltration are major causes of the persistent bone erosion and difficult tissue regeneration in rheumatoid arthritis (RA). Triptolide (TPL) has become a highly anticipated anti-rheumatic drug due to its excellent immunomodulatory and anti-inflammatory effects. However, the sudden drug accumulation caused by the binding of “stimulus-response” and “drug release” in a general smart delivery system is difficult to meet the shortcoming of extreme toxicity and the demand for long-term administration of TPL. Herein, we developed a dual dynamically cross-linked hydrogel (SPT@TPL), which demonstrated sensitive RA microenvironment regulation and microenvironment modulation-independent TPL release for 30 days. The abundant borate ester/tea polyphenol units in SPT@TPL possessed the capability to respond and regulate high reactive oxygen species (ROS) levels on-demand. Meanwhile, based on its dense dual crosslinked structure as well as the spontaneous healing behavior of numerous intermolecular hydrogen bonds formed after the breakage of borate ester, TPL could remain stable and slowly release under high ROS environments of RA, which dramatically reduced the risk of TPL exerting toxicity while maximized its long-term efficacy. Through the dual effects of ROS regulation and TPL sustained-release, SPT@TPL alleviated oxidative stress and reprogrammed macrophages into M2 phenotype, showing marked inhibition of inflammation and optimal regeneration of articular cartilage in RA rat model. In conclusion, this hydrogel platform with both microenvironment initiative regulation and TPL long-term sustained release provides a potential scheme for rheumatoid arthritis.

Novel insight of N6-methyladenosine modified subtypes in abdominal aortic aneurysm.

Background: N6-methyladenosine (m6A) is the most prevalent non-cap reversible modification present in messenger RNAs and long non-coding RNAs, and its dysregulation has been linked to multiple cardiovascular diseases, including cardiac hypertrophy and atherosclerosis. Although limited studies have suggested that m6A modification contributes to abdominal aortic aneurysm (AAA) development, the full landscape of m6A regulators that mediate modification patterns has not been revealed. Methods: To distinguish the m6A methylation subtypes in AAA patients, an unsupervised clustering method was carried out, based on the mRNA levels of 17 m6A methylation regulators. Differentially expressed genes were identified by comparing clusters. An m6Ascore model was calculated using principal component analysis and structured to assess the m6A methylation patterns of single samples. Subsequently, the relationship between the m6Ascore and immune cells and the hallmark gene set was analyzed. Finally, pairs of circRNA-m6A regulators and m6A regulators-m6A related genes were used to establish a network. Results: We identified three m6A methylation subtypes in the AAA samples. The m6Acluster A and C were characterized as more immunologically activated because of the higher abundance of immune cells than that in m6Acluster B. The m6Acluster B was less enriched in inflammatory pathways and more prevalent in pathways related to extracellular matrix stability. Subsequently, we divided the individual samples into two groups according to the m6Ascore, which suggested that a high m6Ascore predicted more active inflammatory pathways and higher inflammatory cell infiltration. A network consisting of 9 m6A regulators and 37 circRNAs was constructed. Conclusion: This work highlighted that m6A methylation modification was highly correlated with immune infiltration of AAA, which may promote the progression of AAA. We constructed an individualized m6Ascore model to provide evidence for individualized treatments in the future.

Effect of Jinzhen Oral Liquid on cough after lipopolysaccharide-induced infection in rats and mechanism

This study aims to explore the effect of Jinzhen Oral Liquid(JOL) on cough after infection in rats and the mechanism. To be specific, a total of 60 male SD rats were classified into 6 groups: normal group(equivalent volume of distilled water, ig), model group(equivalent volume of distilled water, ig), Dextromethorphan Hydrobromide Oral Solution group(3.67 mL·kg~(-1), ig), high-, medium-, and low-dose JOL groups(11.34, 5.67, and 2.84 mL·kg~(-1), respectively, ig). Lipopolysaccharide(LPS, nasal drip), smoking, and capsaicin(nebulization) were employed to induce cough after infection in rats except the normal group. Administration began on the 19 th day and lasted 7 days. Capsaicin(nebulization) was used to stimulate cough 1 h after the last administration and the cough frequency and cough incubation period in rats were recorded. The pathological morphology of lung tissue was observed based on hematoxylin-eosin(HE) staining. Immunohistochemistry(IHC) was used to detect the specific expression of transient receptor potential vanilloid 1(Trpv1), nerve growth factor(NGF), tropomyosin receptor kinase A(TrkA), and phosphorylated-p38 mitogen-activated protein kinase(p-p38 MAPK) in lung tissue, Western blot the protein expression of Trpv1, NGF, TrkA, and p-p38 MAPK in lung tissue, and real-time fluorescent quantitative polymerase chain reaction(real-time PCR) the mRNA expression of Trpv1, NGF, and TrkA. The results showed that model group demonstrated significantly high cough frequency, obvious proliferation and inflammatory cell infiltration in lung tissue, significantly enhanced positive protein expression of Trpv1, NGF, TrkA, and p-p38 MAPK in lung tissue and significant increase in the mRNA expression of Trpv1, NGF, and TrkA compared with the normal group. Compared with the model group, JOL can significantly reduce the cough frequency, alleviate the pathological changes of lung tissue, and decrease the protein expression of Trpv1, NGF, TrkA, and p-p38 MAPK in lung tissue, and high-dose and medium-dose JOL can significantly lower the mRNA expression of Trpv1, NGF, and TrkA. This study revealed that JOL can effectively inhibit Trpv1 pathway-related proteins and improve cough after infection. The mechanism is that it reduces the expression of NGF, TrkA, and p-p38 MAPK in lung tissue, thereby decreasing the expression of Trpv1 and cough sensitivity.

Systematic Review: Targeted Molecular Imaging of Angiogenesis and Its Mediators in Rheumatoid Arthritis

Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.

Mast Cells Promote Nitrogen Mustard-Mediated Toxicity in the Lung Associated With Proinflammatory Cytokine and Bioactive Lipid Mediator Production.

Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells causing chronic respiratory inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, which was significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. Additionally, we utilized murine bone marrow-derived mast cells to assess NM-induced early and late activation. Although NM exposure did not result in mast cell degranulation, we observed an upregulation in PGD2 and IL-6 levels following exposure to NM. Results suggest that mast cells play a prominent role in lung injury induced by NM and may contribute to the acute and potentially long-term lung injury observed caused by SM.

Immunohistochemical assessment of the peri-implant soft tissue around different abutment materials: A human study.

Soft tissue reaction to dental implant abutments influences the sustainability of restoration. Several abutment materials, such as titanium and gold alloy, have been introduced for strength and esthetic solutions. Zirconia and titanium-base abutments have also become popular in recent years due to high esthetic demands. To investigate the immune cell infiltration into the soft tissue in response to different abutment materials. Twenty dental implants were placed in the posterior regions of 17 patients. Titanium, zirconia, gold alloy, and titanium-base were randomly selected for each patient on the day of surgery. After 8 weeks of healing, the abutments were removed along with 1 mm of peri-implant soft tissue. Immunohistochemical assessment was performed using labeled streptavidin-biotin to identify T cells, B cells, macrophages, plasma cells, and microvascular infiltration. Gold alloy demonstrated an overall higher inflammatory cell infiltration and highest number of CD3+ , CD20+ , and CD 68+ cells (P value <.05). The number of plasma cell and new microvascular infiltrations among abutment materials was not significantly different. Titanium, titanium-base, and zirconia abutments showed comparable infiltration profiles; gold alloy abutments showed the highest B-cell, T cell, and macrophage infiltration. None of the abutment materials caused clinical inflammation; hence, they can be effectively used.

Infiltration of Lymphocytes and Mast Cells to Bladder Tissues in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome

Background: A different degree of severity of inflammation was detected in the bladder biopsy specimens; however, the cellular mechanisms of inflammation in interstitial cystitis/bladder pain syndrome (IC/BPS) and the processes leading to tissue damage and fibrosis are not yet completely clear. Objectives: The aim of this study was to determine the leukocyte and mast cell infiltration to the bladder tissue in various experimental models of IC/BPS. Methods: Various IC/BPS models have been generated using white New Zealand rabbits. Animals were divided into 4 groups depending on the type of the model: (1) The introduction of 0.5% HCl into the bladder; (2) The introduction of urine taken from the bladder into the wall of the bladder; (3) The introduction of 0.9% NaCl; (4) Intact animals. The number of cells in the tissues of the bladder was evaluated in points and histological analysis of the tissues of the bladder wall was performed. The analysis was carried out after 14 days of modeling. Results: Mast cells were determined only in groups 1 and 2 (P < 0.001). In the 2nd group, developing necrosis and mixed inflammatory infiltration, giant, necrotic, multinucleated histiocytes were noted. In group 3, tissue edema and single scattered lymphocytes were noted. Conclusions: The association of high inflammatory cell infiltration in the chemical version of the IC/BPS model and mast cell infiltration with impaired bladder integrity has been established.

Tumor-Infiltrating CD1a+ DCs and CD8+/FoxP3+ Ratios Served as Predictors for Clinical Outcomes in Tongue Squamous Cell Carcinoma Patients

Tumor-infiltrating immune cells engage in an extensive crosstalk with tumors and act as two-edged swords by inhibiting or promoting cancer growth. Therefore, identifying the density and prognostic values of tumor-infiltrating immune cells will provide valuable tips for cancer treatments. In this study, we identified the density of tumor inflammatory infiltrates and the number of tumor-infiltrating immune cells, including CD3+, CD4+, CD8+, FoxP3+ T cells and CD1a+ dendritic cells (DCs) in 153 tongue squamous cell carcinomas (TSCC). High inflammatory cell infiltration was associated with better overall survival (OS) and disease free survival (DFS). Moreover, the number of CD3+, CD4+, FoxP3+ and CD1a+ cells were associated with tumor differentiation (P<0.001) and the number of FoxP3+, CD1a+ cells and CD8+/FoxP3+ ratios were also associated with tumor stage (P<0.01, P<0.01, P<0.05). In addition, patients with higher CD1a+ DCs had better OS and increased CD8+/FoxP3+ ratios were associated with improved OS and DFS (P = 0.037; P = 0.047; P = 0.033). In conclusion, our results indicated that tumor-infiltrating CD1a+ DCs and CD8+/FoxP3+ ratios were associated with favorable clinical outcomes but not independent prognostic factors for TSCC patients.

An experimental model: intrauterine adhesion versus subendometrial fibrosis

Background: Intrauterine adhesions (IUA) remain a major cause of infertility. The prevalence of IUA varies geographically and keeps increasing over the last few decades due to increased hysteroscopic surgeries. Therefore, IUA management has received considerable attention. However, the management of IUAs still presents a big challenge: the recurrence rate could be up to 62.5% in severe IUAs. Intrauterine adhesion (IUA) occurs as a result of endometrial destruction by surgical interventions or infection causing obliteration of uterine cavity by the adhesions which interfere with embryonic implantation. Sub endometrial fibrosis may occurs, which causes narrowing of uterine cavity so no enough space for fetal growth. This leads to recurrent abortion. Aim: We aim in this experiment to apply a method for two models of IUA and or fibrosis by intrauterine injections of two different doses of trichloroacetic acid. Method: This experimental study was performed on 30 albino adult rats which were divided into three groups (n=10 rats/group) as follows, group 1: normal control rats, group 2: induced IUA and/or fibrosis that received low dose trichloroacetic acid, group 3: induced fibrosis that received high dose trichloroacetic acid, the extent of fibrosis, vascularization and inflammation were evaluated by; qRTPCR for IL-6, TNF, VEGF and TG-β immunohistochemistry examination for VEGF and TGF-β and histological assessment. Results: We found significant increase in IL-6, TNF and TGF in high dose group and significant decrease in VEGF in high dose group compared to normal group and low dose group (p<0.05). Discussion: The reproductive cells are the most sensitive to toxic environmental materials. In this study, we found that group II rats (IUAs), unlike control rats, had impaired endometrial epithelial cells, a lower number of endometrial glands, higher inflammatory cell infiltration, poor vascularity, and a severe narrowing of the uterine cavity with dense endometrial fibrosis as confirmed by H&E and Masson’s trichrome staining.

Attenuated Superoxide Dismutase 2 Activity Induces Atherosclerotic Plaque Instability During Aging in Hyperlipidemic Mice.

BackgroundAtherosclerosis progression during aging culminates in the development of vulnerable plaques, which may increase the risk of cardiovascular events. Increased generation and/or decreased scavenging of reactive oxygen species in the vascular wall are major contributors to atherogenesis. We previously showed that superoxide dismutase 2 deficiency increased vascular oxidative stress and reduced aortic compliance in aged wild‐type mice and that young Apoe −/−/Sod2 +/− had increased mitochondrial DNA damage and atherosclerosis versus young Apoe −/− mice. Here we investigated the effects of superoxide dismutase 2 deficiency on atherosclerosis progression and plaque morphology in middle‐aged Apoe −/− mice.Methods and ResultsCompared with Apoe −/−, middle‐aged Apoe −/−/Sod2 +/− mice had increased vascular wall reactive oxygen species (P<0.05) and higher atherosclerotic lesion area (P<0.001). The atherosclerotic plaques in middle‐aged Apoe −/−/Sod2 +/− mice had an increased necrotic core with higher inflammatory cell infiltration, a thinned fibrous cap with depleted smooth muscle content, and intraplaque hemorrhage. In addition, the plaque shoulder area had higher levels of calpain‐2, caspase‐3, and matrix metalloproteinase‐2 in intimal smooth muscle cells and depleted fibrous cap collagen. Targeting mitochondrial reactive oxygen species with MitoTEMPO attenuated features of atherosclerotic plaque vulnerability in middle‐aged Apoe −/−/Sod2 +/− mice by lowering expression of calpain‐2, caspase‐3, and matrix metalloproteinase‐2 and decreasing smooth muscle cell apoptosis and matrix degradation.ConclusionsEnhanced mitochondrial oxidative stress under hyperlipidemic conditions in aging induces plaque instability, in part by increasing smooth muscle cell apoptosis, necrotic core expansion, and matrix degradation. Targeting mitochondrial reactive oxygen species or its effectors may be a viable therapeutic strategy to prevent aging‐associated and oxidative stress–related atherosclerosis complications.

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100% O2.

Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100 % O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.

4D-PET/CT with [11C]-PK11195 and [11C]-d-deprenyl Does not Identify the Chronic Inflammation in Asymptomatic Abdominal Aortic Aneurysms

The aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [(11)C]-PK11195 which targets the translocator protein (18kDa) expressed on macrophages and [(11)C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation. Prospective clinical study. Five patients were examined with [(11)C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [(11)C]-d-deprenyl-PET/CT. Nine large AAAs (54-66mm) scheduled for repair and six small AAA (35-44mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on. No aortic uptake was recorded on the visual inspection, neither with [(11)C]-PK11195 nor with [(11)C]-d-deprenyl. For [(11)C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8-1.0) and for [(11)C]-d-deprenyl, 0.7 (range 0.4-1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages. The chronic inflammation observed in the vessel wall was not detectable with [(11)C]-PK11195 and [(11)C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.

Inflammation in the walls of asymptomatic abdominal aortic aneurysms is not associated with increased metabolic activity detectable by 18-fluorodeoxglucose positron-emission tomography

We hypothesized that the general inflammation observed in the wall of large, asymptomatic abdominal aortic aneurysms (AAAs) could be detected in vivo by 18-fluorodeoxglucose (FDG) positron-emission tomography (PET) and, if so, that this method could be used to study if active inflammation is an early pathogenetic finding in small AAAs detected by screening. In this prospective clinical study, 12 men were examined with FDG-PET computed tomography. Seven had large asymptomatic AAAs (range, 52-66 mm) that required surgery, and five had small AAAs (range, 34-40 mm) under surveillance. In the surgery group, biopsy specimens were taken from the aneurysm wall for histologic examinations. Compared with normal segments of the aorta, liver, and blood and compared with healthy controls matched for age and sex, no increased FDG uptake, measured as standardized uptake value, was detected in any of the large or small AAAs. The SUV(mean) difference between infrarenal aorta and blood was -0.3 for cases and -0.1 for controls (P = .06). The corresponding differences between the infrarenal aorta and liver was -0.8 and -0.8 (P = .91) and between infrarenal aorta and suprarenal aorta was -0.2 and -0.1 for cases and controls, respectively (P = .20). The histologic examination of the aneurysm walls showed high inflammatory cell infiltration with T lymphocytes, B lymphocytes, and macrophages. The chronic inflammation observed in the wall of asymptomatic AAAs was not sufficiently metabolically active to result in an increased glucose metabolism detectable by FDG-PET by means of this standard protocol. To study the importance of inflammation in the pathogenesis of AAAs in vivo, PET tracers other than FDG need to be developed.

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP + mono- and multineacleated cells was seen in patients with bone exposure < 2 cm 2. High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase +/calcitonin receptor − mono- and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

Distinct synovial immunopathologic characteristics of juvenile‐onset spondylarthritis and other forms of juvenile idiopathic arthritis

To characterize the synovial immunopathologic features of juvenile-onset spondylarthritis (SpA) in relation to adult SpA and other forms of juvenile idiopathic arthritis (JIA). Synovial biopsy samples were obtained from 10 patients with juvenile-onset SpA, 23 with adult SpA, 19 with rheumatoid arthritis (RA), 8 with juvenile polyarthritis, and 12 with juvenile oligoarthritis. Synovial immunopathologic features were studied by extensive histologic and immunohistochemical analyses. Synovitis in juvenile SpA was characterized by marked lining layer hyperplasia, clear hypervascularity, and pronounced inflammatory cell infiltration with lymphocytes and macrophages, independent of disease duration or time of sampling. The immunopathologic features of juvenile SpA resembled those of adult SpA in terms of hypervascularity and absence of RA-specific intracellular citrullinated proteins and HLA-DR4/human cartilage glycoprotein 39(263-275) complexes, but differed markedly by a stronger lining layer hyperplasia and lower numbers of CD163+ macrophages. Accordingly, class prediction analysis failed to classify juvenile SpA synovitis in the SpA group. Comparison of juvenile SpA with other JIA subtypes showed a broad overlap, with the exception of slightly lower vascularity in juvenile polyarthritis and higher inflammatory cell infiltration in juvenile oligoarthritis. Unsupervised clustering analysis identified a subgroup of samples characterized by high plasma cell infiltration, which corresponded with active, longstanding JIA, mostly of the oligoarthritis subtype. Despite some similarities with adult SpA, the findings with regard to lining layer hyperplasia and CD163+ macrophage infiltration are indicative of important differences in the synovial immunopathologic features of juvenile-onset SpA. The partial overlap with other JIA subtypes emphasizes the need for further biologic characterization of JIA in order to define pathophysiologic, rather than phenotypic, subgroups.

Comparative Analysis of Genetically Engineered Immunodeficient Mouse Strains as Recipients for Human Myoblast Transplantation

The development of an optimized animal model for the in vivo analysis of human muscle cells remains an important goal in the search of therapy for muscular dystrophy. Here we examined the efficiency of human myoblast xenografts in three distinct immunodeficient mouse models. We found that different conditioning regimes used to provoke host muscle regeneration (i.e., cardiotoxin versus cryodamage) had a marked impact on xenograft success. Tibialis anterior muscle of Rag2-, Rag-/gammac-, and Rag-/gammac-/C5- mice was treated by cardiotoxin or cryodamage, submitted to enzymatic digestion, and analyzed by cytofluorometry to quantitate inflammatory cells. Human myoblasts were injected into pretreated muscles from immunodeficient recipients and the cell engraftment evaluated by immunocytochemistry, 4-8 weeks after transplantation. Donor cell differentiation and dispersion within the host muscles was also investigated. Host regeneration in cardiotoxin-treated mice was accompanied by a higher inflammatory cell infiltration when compared to that induced by cryodamage. Accordingly, when compared to the cardiotoxin group, more human myogenic cells were found after cryodamage. When the distinct immunodeficient mice were compared, we found that the alymphoid strain lacking the complement component C5 (Rag-/gammac-/C5- mice) was the most efficient host for human muscle xenografts, when compared with C5(+)Rag-/gammac- mice or Rag- mice. Our results demonstrate that cryolesion-conditioned muscles of Rag-/gammac-/C5- mice provide the best environment for long-term in vivo human myoblast differentiation, opening the way for a novel approach to study the pathophysiology of human muscle disorders.

Studies on analysis of gastric mucosal blood flow by electronic endoscopic image. Especially on atrophic gastritis

The electronic endoscopic image of gastric mucosa was converted by image processing unit SP-1000 (A/D changed) into the one, which was treated with the color conversion method to measure the gastric mucosal hemoglobin index (Hb-index: HI). At the same time, biopsy specimens of gastric mucosa were removed from such 4 different sites as antrum lesser curvature, lower body lesser curvature, lower body anterior wall and upper body posterior wall. On pathohistological examination, the author observed the inflammatory cell infiltration, mucin production, the number and diameter of blood vessels, the degree of atrophic changes in gastric mucosa. HI values were compared with histological findings and with the degree of endoscopic appearance of blood vessel in the lower body lesser curvature. The following results were obtained. HI values were lower in the group with higher inflammatory cell infiltration and less mucin production, while the values were higher in the group with more numerous vessels and larger size ones in diameter. In the group with higher degrees of the pathohistological atrophic change and the endoscopic appearance of blood vessel, HI showed lower values.

Mechanism for the recruitment of macrophages to cancer site. In vivo concentration gradient of monocyte chemotactic activity.

Tumor stroma is characterized by the development of new blood vessels, an inflammatory cell infiltration, and a fibrotic reaction. The inflammatory component of tumor stroma plays an important role in the modulation of tumor expansion. In this respect, macrophages constitute a major part of the inflammatory cell infiltration and can exert cytotoxic activity against tumor cells. The accumulation of macrophages in the vicinity of the tumor suggests their recruitment from circulating blood monocytes through the local release of chemotactic factors for monocytes. To detect the existence of a concentration gradient of monocyte chemotactic activity (MCA) between the tumor vicinity and blood vessels, malignant pleural effusions defined by the local presence of cancer cells were evaluated for quantification of MCA. Unlike nonmalignant pleural effusions, malignant pleural effusions were characterized by the presence of increased levels of MCA, and in lung adenocarcinoma (a cancer with high inflammatory cell infiltration), pleural levels of MCA were significantly greater than in small cell lung carcinoma (a cancer with low inflammatory cell reaction). An MCA concentration gradient between pleural fluid and plasma was present in malignant effusions because pleural MCA levels in all cancer types were significantly greater than MCA levels in the plasma of the same patients. Thus, an increased local level of MCA is a feature of cancers with high inflammatory cell infiltration, and the presence of an in vivo concentration gradient of MCA suggests the direct role of this biologic activity in recruiting blood monocytes to the cancer site.

Electrical/magnetic materials

We hypothesized that the general inflammation observed in the wall of large, asymptomatic abdominal aortic aneurysms (AAAs) could be detected in vivo by 18-fluorodeoxglucose (FDG) positron-emission tomography (PET) and, if so, that this method could be used to study if active inflammation is an early pathogenetic finding in small AAAs detected by screening.In this prospective clinical study, 12 men were examined with FDG-PET computed tomography. Seven had large asymptomatic AAAs (range, 52-66 mm) that required surgery, and five had small AAAs (range, 34-40 mm) under surveillance. In the surgery group, biopsy specimens were taken from the aneurysm wall for histologic examinations.Compared with normal segments of the aorta, liver, and blood and compared with healthy controls matched for age and sex, no increased FDG uptake, measured as standardized uptake value, was detected in any of the large or small AAAs. The SUVmean difference between infrarenal aorta and blood was −0.3 for cases and −0.1 for controls (P = .06). The corresponding differences between the infrarenal aorta and liver was −0.8 and −0.8 (P = .91) and between infrarenal aorta and suprarenal aorta was −0.2 and −0.1 for cases and controls, respectively (P = .20). The histologic examination of the aneurysm walls showed high inflammatory cell infiltration with T lymphocytes, B lymphocytes, and macrophages.The chronic inflammation observed in the wall of asymptomatic AAAs was not sufficiently metabolically active to result in an increased glucose metabolism detectable by FDG-PET by means of this standard protocol. To study the importance of inflammation in the pathogenesis of AAAs in vivo, PET tracers other than FDG need to be developed.