Presence Of Local Inflammation Research Articles

Intensive cholesterol-lowering treatment reduces synovial inflammation during early collagenase-induced osteoarthritis, but not pathology at end-stage disease in female dyslipidemic E3L.CETP mice

The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P=0.008, WTD: 95% CI: 1.4- 2.3; WTD+AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD+AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P=0.0005, 95% CI:-46.0 to-12.0; P=2.8×10-10, 95% CI:-398.3 to-152.1; P=2.1×10-9,-66.8 to-30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease. This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.

Granzyme B Expression in Visceral Adipose Tissue Associates With Local Inflammation and Glyco-Metabolic Alterations in Obesity.

Granzyme B (GrB) is a serine protease produced by immune and non-immune cells, able to promote multiple processes, like apoptosis, inflammation, extracellular matrix remodeling and fibrosis. GrB expression in visceral adipose tissue (VAT) was associated with tissue damage, local inflammation and insulin resistance in obesity murine model, but there is no data in humans. Aim of this study was to explore the expression of GrB in VAT from obese subjects in relation to adipose tissue injury, inflammation, metabolic alterations and GrB circulating levels. For this purpose, 85 obese individuals undergoing bariatric surgery and 35 healthy subjects (as control) were recruited at Sapienza University, Rome, Italy. Study participants underwent clinical work-up and routine biochemistry. mRNA expression of GrB in VAT and of a panel of VAT inflammatory markers was analyzed by real-time PCR. Serum GrB levels were measured by Elisa Affymetrix EBIO. We observed that 80% of obese patients expressed GrB mRNA in VAT, and GrB VAT expression was associated with the presence of local inflammation and glucose homeostasis alterations. Moreover, GrB serum levels, which were higher in obese subjects compared to non-obese healthy individuals, were associated with GrB expression in VAT and glyco-metabolic impairment. Our data show, for the first time in humans, that obese subjects with “sick” fat and altered glucose tolerance exhibit GrB expression in VAT, and suggest that GrB might contribute to obesity-related VAT inflammatory remodeling and glucose homeostasis dysregulation. Moreover, increased circulating GrB levels might represent a possible peripheral marker of VAT dysfunction in metabolic diseases.

Angiopoietin-Like Protein 4 Overexpression in Visceral Adipose Tissue from Obese Subjects with Impaired Glucose Metabolism and Relationship with Lipoprotein Lipase.

Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL); ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery; visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2–23; p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2–23; p < 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1α levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

Inflammation functions as a key mediator in the link between ACPA and erosion development: an association study in Clinically Suspect Arthralgia

BackgroundAnti-citrullinated protein antibodies (ACPA) are associated with more severe joint erosions in rheumatoid arthritis (RA), but the underlying mechanism is unclear. Recent in vitro and murine studies indicate that ACPAs can directly activate osteoclasts leading to bone erosions and pain. This study sought evidence for this hypothesis in humans and evaluated whether in patients with arthralgia who are at risk of RA, ACPA is associated with erosions (detected by magnetic resonance imaging (MRI)) independent of inflammation, and also independent of the presence of rheumatoid factor (RF).MethodsPatients with Clinically Suspect Arthralgia (n = 507) underwent determination of ACPA and RF and 1.5 T contrast-enhanced MRI of the metacarpophalangeal, wrist and metatarsophalangeal joints at baseline. MRIs were scored for presence of local inflammation and erosions. Comparisons of erosion scores were performed using the Kruskal-Wallis test. To evaluate if inflammation is, in statistical terms, intermediary in the causal path of ACPA and erosions, three-step mediation analysis was performed using linear regression.ResultsACPA-positive patients had higher erosion scores than ACPA-negative patients (p = 0.006). ACPA-positive patients without subclinical inflammation did not have higher erosion scores than ACPA-negative patients (p = 0.68), in contrast to ACPA-positive patients with local inflammation (p < 0.001). Mediation analyses suggested that local inflammation is in the causal path of ACPA leading to higher erosion scores. Compared to ACPA-negative/RF-negative patients, ACPA-positive/RF-negative patients did not differ (p = 0.30), but ACPA-positive/RF-positive patients had higher erosion scores (p = 0.006).ConclusionsThe effect of ACPA on erosions is mediated by inflammation and is not independent of RF.

Available, Bed-sided, Comprehensive (ABC) score to a diagnosis of Methicillin-resistant Staphylococcus aureus infection: a derivation and validation study

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) infections continue to be a leading problem in health care facilities worldwide.MethodsThis single-center retrospective cohort study consisted of a derivation phase and a validation phase. The derivation phase included all patients admitted to Osaka University Hospital between May 2010 and April 2011. We proposed a provisional available, bed-sided, comprehensive (ABC) score, and evaluated its accuracy using the clinical diagnosis as a reference. We subsequently revised ABC scores based on k coefficient scores of each variable; this revision was validated by applying it to another patient population.ResultsA total of 172 patients and 154 cases were enrolled in the derivation and validation studies, respectively. The revised ABC score consisted of four simple variables: type of clinical specimen (1 to 3 points), Gram-staining result (1 point), presence of local inflammation (2 points), and a systemic inflammatory response (2 points). A revised score of ≥5 points was sensitive (93.8%) and specific (90.6%), and the area under the receiver-operating curve was 0.969 (95% CI; 0.957–1).ConclusionsWe developed a simple and comprehensive scoring system for diagnosis of nosocomial MRSA infections; this system is applicable in a wide variety of situations.

Local Inflammation Alters MMP-2 and MMP-9 Gelatinase Expression Associated with the Severity of Nifedipine-Induced Gingival Overgrowth: a Rat Model Study

Nifedipine-induced gingival overgrowth (NIGO) is characterized by cell proliferation and extracellular matrix (ECM) component accumulation in gingival connective tissues, with varying degrees of inflammation and fibrosis. Impaired collagen and ECM homeostasis may be among the underlying molecular mechanisms that lead to the fibrotic changes that occur in drug-induced gingival overgrowth (DIGO). Because matrix metalloproteinases (MMPs) play vital roles in regulating collagen and ECM metabolism, many studies have been performed to reveal the relationship between MMPs and DIGO. It is thought that the gelatinases MMP-2 and MMP-9, both type IV collagenases, are involved in the development of tissue inflammation and organ fibrosis. However, the few studies regarding gelatinase expression in DIGO are controversial. Recent studies have demonstrated the inhibitory effect of cyclosporine A (CsA) on gelatinase expression and/or activity; however, similar changes have yet to be detected in Nif-treated gingival tissues. In this study, we verified that Nif treatment could lead to gingival overgrowth in rats and that gingival inflammation played a pro-proliferative role in NIGO development. Additionally, we examined the temporal expression of gelatinases on days 0, 7, 14, 21, 30, and 40 during NIGO development. The aim was to investigate whether MMP-2 and MMP-9 played significant roles in regulating NIGO development and progression. MMP-2 gene expression was not altered by Nif treatment alone but was significantly inhibited by Nif treatment for 30days in the presence of local inflammation. However, no significant alterations in MMP-2 protein expression were detected in the Nif-treated gingival tissue, regardless of the presence or absence of local inflammation. Moreover, Nif treatment could lead to transient and significant increases in MMP-9 gene and protein expression levels in the presence of local inflammation. In particular, active MMP-9 expression increased significantly in the gingival tissue that received the combined effect of Nif and ligation treatment; besides, a temporal, but not significant, change was also observed in the gingival tissue that received Nif treatment alone. Taken together, these results provided evidence that temporal changes in MMP-2 and MMP-9 expression occurred during NIGO development. Nif treatment accompanied by local inflammation regulated MMP-2 and MMP-9 expression, primarily MMP-9, which was most likely associated with NIGO severity. Thus, MMP-9 is a potential contributing factor in the process of NIGO development.

Local anaesthetics: 10 essentials.

This review seeks to address 10 essential questions regarding the clinical use of local anaesthetics. Each local anaesthetic has distinctive physicochemical properties but with the same mode of action; they block voltage-gated sodium channels in the axon. Sodium channel block is brought about by a conformational change and the creation of a positive charge in the channel pore. Different local anaesthetics can reach the local anaesthetic binding site in the axon from the cytoplasmic compartment (classic hydrophilic pathway), or directly via its lipid membrane (hydrophobic pathway), or can enter via large-pore channels (alternative hydrophilic pathway). Beyond the nervous system, local anaesthetics exert beneficial effects on pain and can affect the inflammatory response and the haemostatic system. There are problems with the efficacy of local anaesthetics in the presence of local inflammation, and with significant intravascular toxicity, which can be fatal. But when preventive measures are taken, the incidence of cardiac arrest is low. Intralipid has been proposed to treat systemic local anaesthetic overdose and has been enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood. Intralipid is an aid to the management of local anaesthetic toxicity rather than an antidote and meticulous conduct of regional anaesthesia remains paramount. All local anaesthetics are toxic, in a dose- and time-dependent manner, on virtually all tissues, including nerves and muscles. The question of whether local anaesthetics protect against perioperative tumour progression cannot be answered at this moment, and results from clinical (retrospective) studies are equivocal. Future areas of interest will be the design of new subtype-specific sodium channel blockers, but as we look forward, older local anaesthetics such as 2-chloroprocaine are being reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques for some indications.

Effects of low-intensity laser therapy over mini-implants success rate in pigs

The success rate of miniscrews when used as temporary orthodontic anchorage is relatively high, but some factors could affect its clinical success such as inflammation around the miniscrew. Low-intensity laser therapy has been widely used for biostimulation of tissue and wound healing specially for its anti-inflammatory effects. The purpose of this study was to evaluate the effect of low-intensity laser therapy over the miniscrew success rate. Five Landrace's pigs received 50 miniscrews on the buccal side of the mandible and on the palate of the maxilla. All the miniscrews were immediately loaded with 250 gf. The laser group were irradiated with a 780-nm diode laser with 70 mWs for 1 min (dose = 34 J/cm(2)); the contralateral side was used as the control group. The miniscrews were photographed and analyzed clinically every week to determine their stability and presence of local inflammation. After 3 weeks, histological analysis and fluorescent microscopy were performed to compare the laser and the control side. Clinical results showed a success rate of 60% for the control group and 80% for the laser-treated group. The histological analysis and fluorescent microscopy demonstrated that the laser group had less inflammatory cells than the control group and the bone neoformation around the miniscrew was more intense. Low-intensity laser therapy increased the success rate of orthodontic miniscrews, probably due to anti-inflammatory effect and bone stimulation.

Fungal sinusitis in immunocompromised hosts

The term “immunocompromised host” is generally applied to a variety of patients with various immune defects. Invasive rhinosinusitis is defined by the presence of local inflammation, with vascular and osseous necrosis with extensive soft tissue extension, and occurs almost exclusively in immunocompromised patients. Fungi have been increasingly recognized as important pathogens in severe acute and chronic sinusitis in immunosuppressed hosts. Earlier recognition of the disease, medical attention specific to the patient’s needs are required. After medical remission, significant complications of invasive fungal infection may be seen. Patients should be followed in the long-term, until remucosalization of the sinuses. Key word: Fungal sinusitis, immunocompromised hosts, rhinosinusitis, immune defects.

Infections rhinocérébrales chez l’immunodéprimé en hématologie

Invasive rhinosinusitis, occurring almost exclusively in immunosuppressed patients, is defined by the presence of local inflammation with vascular and osseous necrosis with extensive soft tissue extension. Imaging and bacteriological and even histological (mycelial filaments) criteria have been established. Because it can evolve to death in patients with hematological disorders, accurate diagnosis is important but difficult to achieve due to the non-specific nature of signs and symptoms. Imaging plays an important role with CT of the paranasal sinuses and MR imaging of the brain for early diagnosis and treatment in order to improve prognosis. We will present the imaging features of three cases of rhinocerebral infections, with two cases of fungal infection and one case of invasive bacterial sinus infection.

Peripheral Muscle Alterations in Non-COPD Smokers

Although tobacco smoke is the main cause of COPD, relatively little attention has been paid to its potential damage to skeletal muscle. This article addresses the effect of smoking on skeletal muscle. The vastus lateralis muscle was studied in 14 non-COPD smokers (FEV(1)/FVC, 78 +/- 5%) and 20 healthy control subjects (FEV(1)/FVC, 80 +/- 3%). Muscular structure, enzyme activity, constitutive and inducible nitric oxide (NO) synthases (endothelial NO oxide synthase [eNOS], neuronal NO synthase [nNOS] and inducible NO synthase [iNOS]), nitrites, nitrates, nitrotyrosine, and the presence of macrophages were analyzed. In smokers, type I muscle fibers cross-sectional area was decreased, and a similar trend was found in type IIa fibers. Lactate dehydrogenase levels and the percentage of fibers with low oxidative and high glycolytic capacity were increased in smokers. nNOS (96.9 +/- 11.7 vs 125.4 +/- 31.9 ng/mg protein; p < 0.01) and eNOS (38.9 +/- 11.0 vs 45.2 +/- 7.7 ng/mg protein [+/- SD]; p < 0.05) were lower in smokers, while fiber type distribution, capillarity measures, beta-hydroxy-acyl-CoA-dehydrogenase levels, iNOS, nitrite, nitrate, and nitrotyrosine levels, and macrophage number in the muscle tissue were similar to the nonsmoker subjects. Smokers presented some alterations of skeletal muscle such as oxidative fiber atrophy, increased glycolytic capacity, and reduced expression of the constitutive NO synthases (eNOS and nNOS). The findings support some muscular structural and metabolic damage but not the presence of local inflammation in the smokers. In addition, they suggest a possible effect of tobacco smoke impairing the normal process of NO generation.

Epidermal hyperplasia of the tympanic membrane and deep external ear canal: novel histo‐pathological features, embryological and clinical correlates

Objectives. To study the histology and developmental biology of epidermis of tympanic membrane and deep ear canal and to correlate the histo‐pathological features with clinical conditions.Method. Histo‐pathological and electron microscopic examination was performed of deep meatal skin, keratosis, keratosis obturans, external canal cholesteatoma, retraction pockets, acquired cholesteatoma and tympanic membrane perforations.Results. In some mature ears, a marked change in the normal flat thin epidermis to one resembling that of the fetus is seen in the presence of local inflammation. This hyperplastic epidermis is present in varying lengths on the tympanic membrane and deep ear canal and displayed as hyperplastic bands growing down into sub‐epidermal tissue and sometimes penetrated the collagen layer of the tympanic membrane to enter the middle ear. Keratosis was frequent on the surfaces of the tympanic membrane and deep ear canal, which may also be found in the invading bands, where they produced small keratin cysts.Conclusions. Severe chronic otitis media, with inflammatory exudates, glandular metaplasia or tympanosclerosis, may be associated with hyperplasia. This type of epidermal hyperplasia appeared to be pathogenic and was observed in several structurally distinct entities such as keratosis, keratosis obturans, retraction pockets, and cholesteatoma of the deep external canal. Invading epidermis in the middle ear, in some cases, is indistinguishable from acquired cholesteatoma. This reverse differentiation highlights a primordial property of auditory epithelium, which was not previously recognised. Furthermore, hyperplastic epidermis appears to be pathogenic and may be the cause of some specific conditions or their complications.References 1 Johnson A., Hawke M., Berger G. (1984) Hodge memorial Award‐surface wrinkles, cell ridges, and desquamation in the external auditory canal. J Otolaryngol.13, 345–3542 Johnson A., Hawke M. (1985) Cell shape in the migratory epidermis of the external auditory canal. J Otolaryngol.14, 273–281

Chlorine in Breath Condensate – A Measure of Airway Affection in Pollinosis?

Background: Infiltration of inflammatory cells in bronchial mucosa and glandular hypersecretion are hallmarks of asthma. It has been postulated that exhaled breath condensate (EBC) mirrors events in epithelial lining fluid of airways, such as presence of local inflammation as well as glandular hypersecretion. It is also well known that eosinophil cationic protein (ECP) and cysteinyl-leukotrienes (cys-LT) are released by circulating inflammatory cells when triggered by antigen stimulation in asthma patients. Objectives: The aim of this study was to evaluate whether chlorine and/or cys-LT in EBC would reflect changes of exposure of airborne pollen in patients with asthma. Methods: EBC and serum were collected from 23 patients with allergic asthma during a pollen season and repeated 5 months later during a period with no aeroallergens. Chlorine was measured by means of a sensitive coulometric technique and cys-LT by an EIA technique. Serum ECP was measured and lung function tests were performed and symptoms noted during both occasions. Results: Significantly higher concentrations of chlorine in EBC (p = 0.007) and ECP in serum (p = 0.003) were found during the pollen season compared to post-season. Chlorine levels tended to be higher in patients who reported of chest symptoms compared to those who denied symptoms during the pollen season (p = 0.06). Areas under the receiver-operated characteristic curves (AUC_ROC) were compared and similar discriminative power to identify exacerbations of asthma was recorded by chlorine in EBC (range 0.67–0.78) and ECP in serum (range 0.64–0.78). Conclusion: It is concluded that chlorine in EBC and ECP in serum decreased significantly post-season, and this is suggested to mirror the decrement in airborne antigen. It is furthermore proposed that chlorine in EBC and ECP in serum tend to have a similar capacity to identify seasonal variations in airborne pollen in patients with asthma.

Minireview Interleukin-1 and osteoarthritis

Il-1, a multifunctional monokine, can stimulate both synoviocytes and articular chondrocytes to release neutral proteases and prostaglandin E 2. It is also capable of promoting bone resorption. Therefore, this molecule (or family of molecules) is likely to play an important role in the mechanism of articular cartilage destruction that occurs in degenerative arthropathies. The synovial tissue itself can produce Il-1 (Catabolin) in some conditions, such as a slight traumatism, so that the presence of local inflammation is not necessary for “Il-1-cartilage” interaction to occur. Fundamental macromolecules of cartilage (collagens, proteoglycans) exert a stimulatory effect on Il-1 production, either as such or in the form of immune complexes. Some activated complement fractions (C3a and C5a) may also be actively involved. Studies on the mechanisms which regulate Il-1 synthesis and release, as well as investigations on the response of target cells to Il-1, are presently fascinating goals that could lead to new strategies in therapeutic research.

The complications of intravenous cannulae incorporating a valved injection side port

In a series of 519 intravenous cannulae with valved injection side-ports the incidence of cannula-related local inflammation was 25.2% and bacteraemia 0.2%. Severe local inflammation was associated with a longer mean duration of cannulation, 59.4 v. 81.4 h (P = less than 0.05). There was no significant association between the presence of local inflammation and microbial colonization of either the intravascular segment of the cannula, the adjacent skin, or the side-port. The data suggest that colonization of the cannulae was usually secondary to prior skin colonization. Side-port colonization did not predispose to cannula colonization. Organisms colonizing the side-port were biologically different and were possibly derived from the skin of medical attendants. In the final 157 patients, randomized to receive either isopropyl alcohol or 0.5% chlorhexidine in 70% spirit skin preparation, there was no difference in the incidence of either local inflammation or microbial colonization.

Infections caused by arterial catheters used for hemodynamic monitoring

Utilizing a semiquantitative technique for culturing vascular catheters, we prospectively studied the risk and profile of infection caused by arterial catheters used for hemodynamic monitoring in 95 patients with a high risk of nosocomial infection. Of 130 catheters, 23 (18 per cent) produced local infection (≥15 colonies on semiquantitative culture) and five septicemia (4 per cent). Sixteen of the 23 local infections and all septicemias occurred with catheter placements exceeding four days (p < 0.001). Other factors associated with an increased risk of infection included insertion by surgical cut-down rather than percutaneously (ninefold increased rate of bacteremia, p = 0.008) and the presence of local inflammation (12-fold increase, p = 0.009). Systemic antimicrobial therapy (given to 80 per cent of the entire group and to four of the five with septicemia) did not protect against catheter-related infection but may account for the predominance of enterococci, Candida and gram-negative bacilli in these infections. Twelve per cent of all nosocomial bacteremias occurring in this critical care unit population originated from an arterial catheter. Indwelling arterial catheters pose a significant risk of bacteremic infection to critically ill patients. The percutaneous mode of placement is preferred; when prolonged arterial cannulation is required, the site should be rotated every four days. Local pain or inflammation, or clinical signs of sepsis without an obvious source should prompt removal and culture of the catheter.