Osteomielitis por Klebsiella pneumoniae BLEE. Reporte de un caso y revisión de la literatura. / OSTEOMYELITIS DUE TO KLEBSIELLA PNEUMONIAE ESBL. REPORT OF A CASE AND LITERATURE REVIEW

Las betalactamasas de espectro extendido (BLEE) son enzimas producidas por bacilos gram negativos capaces de hidrolizar las cefalosporinas de amplio espectro y los monobactámicos. La mayoría pertenece a la familia de Enterobacteriae, tales como Klebsiella pneumoniae y Escherichia coli: Sin embargo, se asocian también con otras bacterias como Proteus, Serratia, Salmonella, Pseudomonas aeruginosa y Acinetobacter. Las enterobacterias productoras de carbapenemasas no sólo han sido aisladas en el ambiente hospitalario, sino que también provienen de la comunidad. Se presenta una paciente de sexo femenino con antecedentes de sida y osteomielitis secundaria a artritis séptica producida por una Klebsiella pneumoniae BLEE de la comunidad. Un tratamiento oportuno y eficaz puede evitar la opción quirúrgica, disminuyendo la morbimortalidad asociada con esta afección

Extended-spectrum beta-lactamases (ESBL) are enzymes produced by gram-negative rods capable of hydrolyzing broad-spectrum cephalosporins and monobactams. Most belong to the Enterobacteriae family, such as Klebsiella pneumoniae and Escherichia coli. However, they are also associated with other bacteria such as Proteus, Serratia, Salmonella, Pseudomonas aeruginosa and Acinetobacter. Carbapenemase-producing Enterobacteriaceae have not only been isolated from the hospital environment, but also from the community. We present a female patient with a history of AIDS and secondary osteomyelitis to septic arthritis caused by a community Klebsiella pneumoniae ESBL. It is concluded that a timely and effective treatment can avoids the surgical option, reducing the morbidity and mortality of this condition.

An Engineered Pseudo-Macrophage for Rapid Treatment of Bacteria-Infected Osteomyelitis via Microwave-Excited Anti-Infection and Immunoregulation.

Preventing deep bacterial infection and simultaneously enhancing osteogenic differentiation are in great demand for osteomyelitis. Microwave (MW) dynamic therapy is attracting attention due to its excellent penetration ability, but the mechanism of MW-induced reactive oxygen species (ROS) is still unknown. Herein, MW-responsive engineered pseudo-macrophages (M-Fe3 O4 /Au nanoparticles (NPs)) are fabricated to clear Staphylococcus aureus infections and induce M2 polarization of macrophages to improve osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs) under MW irradiation. Fe3 O4 /Au NPs can generate ·O2 - and heat under MW irradiation in a saline solution, and the mechanism is put forward via finite element modeling and density functional theory calculations. Due to the gap plasmon, electromagnetic hotspots are produced at Fe3 O4 -Au interface at 2.45 GHz. Because of these induced electromagnetic hotspots, the sodium species is field-ionized and subsequently reacts with oxygen to produce ·O2 - . Meanwhile, the Fe3 O4 /Au NPs have a stronger ability than Fe3 O4 NPs to fix oxygen, favoring the production of ROS. Additionally, MW-treated macrophages diminish to secrete inflammatory cytokines, resulting in the decrease of ROS production in MSCs and thus enhancing their osteogenic differentiation. These engineered pseudo-macrophages will be promising for effectively treating bacterial infections and promoting osteoblast differentiation simultaneously in deep tissues under MW irradiation.

Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis.

Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)-scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination.

Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome-positive acute lymphoblastic leukaemia-case report.

BACKGROUND: Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered. CASE PRESENTATION: Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel. CONCLUSIONS: In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.

Ureaplasma septic polyarthritis in a young woman with neuromyelitis optica receiving rituximab.

We report a case of septic polyarthritis caused by Ureaplasma urealyticum in a woman with neuromyelitis optica who was receiving rituximab. Her case exemplifies some of the unique characteristics of invasive Ureaplasma infections that can lead to delayed diagnosis as well as treatment challenges including recurrence following antibiotic discontinuation.

Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis.

OBJECTIVE: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS: A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1ß secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/ß, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION: We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

Psoriasis Associated With Tumor Necrosis Factor Inhibitors in Children With Inflammatory Diseases.

OBJECTIVE: To estimate the incidence rate (IR) of psoriasis in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic noninfectious osteomyelitis (CNO) with tumor necrosis factor inhibitor (TNFi) exposure as compared to children without TNFi exposure and to the general pediatric population. METHODS: This was a single-center retrospective cohort study of children with IBD, JIA, or CNO from 2008 to 2018. TNFi exposure was defined as a prescription for adalimumab, etanercept, infliximab, certolizumab, or golimumab, and the primary outcome was incident psoriasis. IRs and standardized incidence ratios (SIRs) were calculated. Cox proportional hazards models were used to assess the association of psoriasis with TNFi exposure and other risk factors. RESULTS: Of the 4,111 children who met inclusion criteria, 1,614 (39%) had TNFi exposure and 2,497 (61%) did not, with 4,705 and 6,604 person-years of follow-up, respectively. There were 58 cases (IR 12.3 per 1,000 person-years) and 25 cases (IR 3.8 per 1,000 person-years) of psoriasis in children with and without TNFi exposure, respectively. The SIR was 18 (95% confidence interval [95% CI] 15-22) overall, 30 (95% CI 23-39) for children with TNFi exposure, and 9.3 (95% CI 6.3-14) for children without TNFi exposure. The hazard ratio of psoriasis comparing TNFi exposure to no TNFi exposure was 3.84 (95% CI 2.28-6.47; P < 0.001). CONCLUSION: Children with IBD, JIA, and CNO had an increased rate of psoriasis compared to the general pediatric population, with the highest rate in those with TNFi exposure.

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles.

Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.

Lack of Humoral Immunity Against Glucosaminidase Is Associated with Postoperative Complications in Staphylococcus aureus Osteomyelitis.

BACKGROUND: Glucosaminidase (Gmd) is known to be a protective antigen in animal models of Staphylococcus aureus osteomyelitis. We compared the endogenous anti-Gmd antibody levels in sera of patients with culture-confirmed S. aureus bone infections to their sera at 1 year after operative treatment of the infection. METHODS: A novel global biospecimen registry of 297 patients with deep-wound culture-confirmed S. aureus osteomyelitis was analyzed to assess relationships between baseline anti-Gmd serum titers (via custom Luminex assay), known host risk factors for infection, and 1-year postoperative clinical outcomes (e.g., infection control, inconclusive, refracture, persistent infection, septic nonunion, amputation, and septic death). RESULTS: All patients had measurable humoral immunity against some S. aureus antigens, but only 20 patients (6.7%; p < 0.0001) had high levels of anti-Gmd antibodies (>10 ng/mL) in serum at baseline. A subset of 194 patients (65.3%) who completed 1 year of follow-up was divided into groups based on anti-Gmd level: low (<1 ng/mL, 54 patients; 27.8%), intermediate (<10 ng/mL, 122 patients; 62.9%), and high (>10 ng/mL, 18 patients; 9.3%), and infection control rates were 40.7%, 50.0%, and 66.7%, respectively. The incidence of adverse outcomes in these groups was 33.3%, 16.4%, and 11.1%, respectively. Assessing anti-Gmd level as a continuous variable showed a 60% reduction in adverse-event odds (p = 0.04) for every tenfold increase in concentration. No differences in patient demographics, body mass index of >40 kg/m, diabetes status, age of ≥70 years, male sex, Charlson Comorbidity Index of >1, or Cierny-Mader host type were observed between groups, and these risk factors were not associated with adverse events. Patients with low anti-Gmd titer demonstrated a significant 2.68-fold increased odds of adverse outcomes (p = 0.008). CONCLUSIONS: Deficiency in circulating anti-Gmd antibodies was associated serious adverse outcomes following operative treatment of S. aureus osteomyelitis. At 1 year, high levels of anti-Gmd antibodies were associated with a nearly 3-fold increase in infection-control odds. Additional prospective studies clarifying Gmd immunization for osteomyelitis are needed. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Dysregulated NADPH Oxidase Promotes Bone Damage in Murine Model of Autoinflammatory Osteomyelitis.

Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1ß by neutrophil granulocytes. In this study, we show that in addition to IL-1ß, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1ß levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.

MRI and clinical features of acute fungal discitis/osteomyelitis.

OBJECTIVES: To compare imaging and clinical features of fungal and Staphylococcus aureus discitis-osteomyelitis (DO) for patients presenting for CT-guided biopsies. METHODS: Our study was IRB-approved and HIPAA-compliant. A group of 11 fungal DO (FG) with MRI within 7 days of the biopsy and a control group (CG) of 19 Staphylococcus aureus DO were evaluated. Imaging findings (focal vs diffuse paravertebral soft tissue abnormality, partial vs complete involvement of the disc/endplate), biopsy location, pathology, duration of back pain, immune status, history of intravenous drug, history of prior infection, current antibiotic treatment, and history of invasive intervention. Differences were assessed using the Fisher exact test and Kruskal-Wallis test. Naïve Bayes predictive modeling was performed. RESULTS: The most common fungal organisms were Candida species (9/11, 82%). The FG was more likely to have focal soft tissue abnormality (p = 0.040) and partial disc/endplate involvement (p = 0.053). The clinical predictors for fungal DO, in order of importance, back pain for 10 or more weeks, current antibiotic use for 1 week or more, and current intravenous drug use. History of invasive instrumentation within 1 year was more predictive of Staphylococcus aureus DO. CONCLUSION: MRI features (focal partial soft tissue abnormality and partial involvement of the disc/endplate) in combination with clinical features may help to predict fungal species as a causative organism for DO. KEY POINTS: • MRI features of discitis-osteomyelitis (focal partial soft tissue abnormality and partial involvement of the disc/endplate) in combination with clinical features may help to predict fungal species as a causative organism for DO.

Staphylococcus Aureus Osteomyelitis as an Inducer of Tolerance to Escherichia Coli Pyelonephritis: an Experimental Study.

The high incidence of osteomyelitis in vulnerable populations like those with multiple injuries or elderly undergoing joint arthroplasties generates the question what may be their responses to subsequent infection by high virulent isolates. Rabbits were subject to two operations at three week intervals; sham osteomyelitis and sham pyelonephritis (group S); sham osteomyelitis and Escherichia coli pyelonephritis (group P); and Staphylococcus aureus osteomyelitis and E. coli pyelonephritis (group OP). Survival was recorded; cytokine stimulation of circulating mononuclear cells (PBMCs) and tissue myeloperoxidase (MPO) activity and bacterial growth were monitored. In some experiments, dalbavancin treatment was given before pyelonephritis. Healthy PBMCs were pre-treated with bone homogenate, S. aureus or both. Mortality of groups S, P and OP after induction of pyelonephritis was 0%, 50% and 8.3% respectively. Tumour necrosis factor-alpha (TNFα) production by PBMCs was significantly lower in the OP group at 48 hours. E. coli bacterial load was similar in groups P and OP at death or sacrifice whereas the MPO activity of group OP was decreased. Production of TNFα was further decreased among dalbavancin treated rabbits; in these rabbits tissue MPO was increased. TNFα production decreased when healthy PBMCs pre-treated with bone homogenate, S. aureus (HKSA) or both were stimulated with E. coli (HKEC); production was further decreased in the presence of anti-TLR4 and anti-TLR9. It is concluded that staphylococcal osteomyelitis modulated the innate immune responses of the host leading to protection from death by highly virulent E. coli. Tolerance to TLR ligands is the most likely mechanism of action.

Chronic Implant-Related Bone Infections-Can Immune Modulation be a Therapeutic Strategy?

Chronic implant-related bone infections are a major problem in orthopedic and trauma-related surgery with severe consequences for the affected patients. As antibiotic resistance increases in general and because most antibiotics have poor effectiveness against biofilm-embedded bacteria in particular, there is a need for alternative and innovative treatment approaches. Recently, the immune system has moved into focus as the key player in infection defense and bone homeostasis, and the targeted modulation of the host response is becoming an emerging field of interest. The aim of this review was to summarize the current knowledge of impaired endogenous defense mechanisms that are unable to prevent chronicity of bone infections associated with a prosthetic or osteosynthetic device. The presence of foreign material adversely affects the immune system by generating a local immune-compromised environment where spontaneous clearance of planktonic bacteria does not take place. Furthermore, the surface structure of the implant facilitates the transition of bacteria from the planktonic to the biofilm stage. Biofilm formation on the implant surface is closely linked to the development of a chronic infection, and a misled adaption of the immune system makes it impossible to effectively eliminate biofilm infections. The interaction between the immune system and bone cells, especially osteoclasts, is extensively studied in the field of osteoimmunology and this crosstalk further aggravates the course of bone infection by shifting bone homeostasis in favor of bone resorption. T cells play a major role in various chronic diseases and in this review a special focus was therefore set on what is known about an ineffective T cell response. Myeloid-derived suppressor cells (MDSCs), anti-inflammatory macrophages, regulatory T cells (Tregs) as well as osteoclasts all suppress immune defense mechanisms and negatively regulate T cell-mediated immunity. Thus, these cells are considered to be potential targets for immune therapy. The success of immune checkpoint inhibition in cancer treatment encourages the transfer of such immunological approaches into treatment strategies of other chronic diseases. Here, we discuss whether immune modulation can be a therapeutic tool for the treatment of chronic implant-related bone infections.

Actinomycotic osteomyelitis of a long bone in an immunocompetent adult: a case report and literature review.

BACKGROUND: Actinomycosis is a rare, chronic granulomatous disease caused by Gram-positive anaerobic bacteria that colonize the oral cavity. Cervicofacial actinomycosis is the most frequent clinical presentation of actinomycosis, but hematogenous osteomyelitis at distant sites can occur in rare instance in immunocompromised or pediatric patients, only a few cases have been reported in healthy patients. Here we described a new case of distal femur osteomyelitis caused by Actinomyces in an adult patient who was immunocompetent and had no predisposing factors. CASE PRESENTATION: A woman aged 52 years with no history of trauma presented with severe pain, swelling, and increased local heat in the proximal area of the right knee 3 weeks after she first noticed discomfort. Magnetic resonance imaging showed persistent osteomyelitis of the distal metaphysis and diaphysis of the femur with a multifocal intraosseous abscess pocket. An incision and drainage of the abscess were conducted. The tissue culture, fungus culture, acid fast bacillus (AFB) culture, AFB smear, and tuberculosis polymerase chain reaction test results were negative. A pathologic examination confirmed the presence of actinomycosis. The patient was successfully treated with intravenous penicillin G for 8 weeks followed by oral amoxicillin-clavulanate for 6 weeks with repeated surgical debridement and drainage. After a 5-year follow up, the patient had no signs of recurring infection or complications and she had full range of movement in the affected knee. CONCLUSIONS: Although rare, actinomycotic osteomyelitis can occur in healthy people. Furthermore, actinomycotic osteomyelitis is easily misdiagnosed as tuberculosis in areas with a high prevalence of tuberculosis. To detect and identify the bacteria accurately, pathologic examination should be performed as well as culture tests, because the probability for culture confirmation of actinomycosis is quite low. The initial treatment is vital to a successful outcome without ostectomy or amputation.

Chronic Mycobacterium avium skin and soft tissue infection complicated with scalp osteomyelitis possibly secondary to anti-interferon-γ autoantibody formation.

BACKGROUND: Nontuberculous mycobacterial (NTM) disease is commonly an opportunistic infection frequently found in immunocompromised individuals, but sometimes can also be found in the immunocompetent hosts, especially in East Asians. The NTM separation rate in China is increasing, which reminds us to focus on NTM infections in immunocompromised populations. CASE PRESENTATION: A 43-year-old woman with a recurrent fever for more than 8-month and a right forehead surgical wounds unhealed for more than 6-month was admitted to our hospital on February 22, 2018. On arrival, several elliptic ulcers were obvious on the right forehead with pus and fibrin exudation, and the skin around the lesions was tender, reddish, no sense of fluctuation. The result of HIV serology test was negative. CD4+ T cell count was normal and tuberculosis antibody was negative. CT of the chest and head showed bone destruction. Skin biopsy on the right forehead was performed on March 13, 2018, and pathological examination of the excisional biopsy specimen found inflammatory granuloma and suppurative inflammatory changes. Broad-spectrum antibiotics were treated but the effect seemed discontent. Then debridement and skin grafting were performed on the right frontal ulcer under general anesthesia on April 3, 2018. The skin tissue culture that resected on March 13, 2018 found Nontuberculous mycobacteria grown after 78 days, so clarithromycin, ethambutol, protionamide, and amoxicillin clavulanate potassium were prescribed for anti-nontuberculous mycobacteria treatment beginning on May 31, 2018. In reviewing the case, Mycobacterium avium (M. avium) was identified in the skin tissue resected on April 3, 2018 by polymerase chain reaction (PCR) and the serum test of anti-interferon-γ autoantibodies was positive. CONCLUSIONS: This is a case report of "Mycobacterium avium SSTI (skin and soft tissue infection) and OM (osteomyelitis) with possible secondary immunodeficiency syndrome induced by anti-interferon-γ autoantibody".

Inflammasome-Dependent Cytokines at the Crossroads of Health and Autoinflammatory Disease.

As key regulators of both innate and adaptive immunity, it is unsurprising that the activity of interleukin (IL)-1 cytokine family members is tightly controlled by decoy receptors, antagonists, and a variety of other mechanisms. Additionally, inflammasome-mediated proteolytic maturation is a prominent and distinguishing feature of two important members of this cytokine family, IL-1ß and IL-18, because their full-length gene products are biologically inert. Although vital in antimicrobial host defense, deregulated inflammasome signaling is linked with a growing number of autoimmune and autoinflammatory diseases. Here, we focus on introducing the diverse inflammasome types and discussing their causal roles in periodic fever syndromes. Therapies targeting IL-1 or IL-18 show great efficacy in some of these autoinflammatory diseases, although further understanding of the molecular mechanisms leading to unregulated production of these key cytokines is required to benefit more patients.

Immunoprecipitation high performance liquid chromatographic analysis of healing process in chronic suppurative osteomyelitis of the jaw.

PURPOSE: Chronic suppurative osteomyelitis (CSO) of the jaw is one of the most difficult infectious diseases to manage, because it causes progressive bony destruction and is associated with bacterial inhabitation of the sequestra. A combination of antibiotic therapy and surgical debridement is often used to treat CSO. Nevertheless, various systemic conditions can lead to life-threatening complications. METHODS: The present study aimed to explore the wound healing progress in 16 cases of CSO through protein expression analysis of postoperative exudates (POE) that were collected 6 h, 1 day, and 2 days after saucerization and/or decortication. A bony lesion was removed during surgery and then examined pathologically, and the CSO POE was examined by immunoprecipitation thus high performance chromatography (IP-HPLC). The POE at 6 h was used as a comparative control. RESULTS: Histologically the CSO lesion showed a necrotic granulomatous lesion heavily infiltrated with polymorphonuclear leukocytes, macrophages, and plasma cells, admixed with multiple sequestra inhabited by bacterial colonies. The IP-HPLC analysis displayed a slight increase in innate immunity-related proteins, i.e., NFkB, TNFα, IL-1, IL-6, IL-28, and LL-37, but a gradual decrease of bacteria-related inflammatory proteins, i.e., IL-8, IL-12, CD31, CD68, and lysozyme. The angiogenesis-related proteins, i.e., VEGF-A and VEGF-C, were slightly decreased but TGF-ß1 and bFGF were markedly increased on day 2. The osteogenesis-related proteins, i.e., OPG and ALP, were slightly increased, while the osteoclastogenesis-related protein, RANKL was slightly decreased compared to the control. CONCLUSION: These findings indicate that the infected CSO undergoes a rapid wound healing process with active osteogenesis and a gradual decrease in bacteria-related inflammation, predicting a favorable prognosis after surgery. Moreover, IP-HPLC can be useful in monitoring the POE and wound healing processes during the postoperative period.

Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment.

PURPOSE OF REVIEW: Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO. RECENT FINDINGS: Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues. CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.