B-Cell Pathology in Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of different diseases. Due to the promising results of B-cell depleting therapies in rheumatoid arthritis the role of B-cells in autoimmune diseases has to be discussed in a new context. Additionally, experiments in mouse models have shed new light on the antibody-independent role of B-cells in the development of autoimmune diseases. In this review we will discuss the importance of B-cells in the pathogenesis of JIA appraising the question for an immunological basis of B-cell targeted therapy in JIA

Impact of Different Metabolic Uncouplers on the Specific Degradation Rate of Toluene in a Differential Biofiltration Reactor

In this work, a differential biofiltration reactor was used to explore the potential of metabolic uncouplers to improve pollutant (toluene) degradation rates. Metabolic uncouplers were reported to reduce the cell mass in activated sludge systems, but are untested in biofilters and the current work is the first to report the impact of different metabolic uncouplers in a biofilter. Initially soil was used as a biofilter bed and later experiments were conducted in pure cultures in a biofilm reactor. A simple diffusion system was developed to generate the desired concentration of toluene to the system. Gas chromatography and a carbon dioxide analyzer were connected online to the reactor which improved the precision of the data collected and also the robustness of the measurements. Preliminary experiments including effect of substrate concentration, different nutrients and temperature were done to optimize the conditions before starting the metabolic uncoupler screening studies in soil. Based on the results, inlet toluene concentration between 180 ppm and 250 ppm was used throughout the studies. Also it was found that the toluene degraders were nitrogen limited. Temperature studies showed that the elimination capacity (EC) increased with increasing temperature, from 34 ± 1.4 g.m-3.h-1 to 49.8 ± 2.6 g.m-3.h-1 for temperatures of 20 to 45 oC, respectively. Nine potential metabolic uncouplers were screened in batch serum bottles. The nine uncouplers tested were dinitrophenol (dNP), p-nitrophenol (pNP), benzoic acid (BA), carbonylcyanide p-trifluoromethoxy phenylhydrazone (FCCP), carbonylcyanide m-chloromethoxy phenylhydrazone (CCCP), pentachlorophenol (PCP), malonic acid (MA), m-chlorophenol (mCP) and 2, 4, 6-trichlorophenol (TCP). Other than dNP and pNP (nitrogen containing uncouplers), seven other uncouplers were further tested in the differential biofilter reactor. Only PCP and TCP increased the toluene degradation rate significantly. PCP increased the toluene degradation rate by 35% at 140 µM, whereas 4051 µM TCP increased the rate by 18%. Though FCCP behaved as a classical uncoupler when compared with others, the EC increase was not significant. Five toluene degraders were isolated from soil subjected to toluene and were identified using 16s rDNA/18s rDNA analysis. Out of five, two potential toluene degraders, Stenotrophomonas maltophilia and Pseudomonas putida were used to develop a biofilm reactor. PCP, TCP and CCCP were tested in the biofilm reactors and found that PCP increased the surface elimination capacity (SEC) by 85% at 140 µM in S. maltophilia biofilm reactor and CCCP increased the SEC by 27% at 1 µM in P. putida biofilm reactor. Finally a simple model was developed to calculate the energy uncoupling coefficient for non-growth systems like ours to quantitatively represent the uncoupling mechanism

Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment

Introduction: Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported. Methods: Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome. Results: Naproxen treatment was highly effective in general, inducing a symptom-free status in 43% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67% of them were clinically silent. Conclusions: Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics

New Insights into Adult and Paediatric Chronic Non-bacterial Osteomyelitis CNO

Purpose of Review To describe in detail the clinical synopsis and pathophysiology of chronic non-bacterial osteomyelitis and SAPHO syndrome. Recent Findings Chronic non-bacterial osteomyelitis (CNO) has been identified as a disease entity for almost 50 years. This inflammatory bone disorder is characterized by osteolytic as well as hyperostotic/osteosclerotic lesions. It is chronic in nature, but it can present with episodic flairs and phases of remission, which have led to the denomination “chronic recurrent osteomyelitis”, with its severe multifocal form “chronic recurrent multifocal osteomyelitis” (CRMO). For almost three decades, an infectious aetiology had been considered, since especially Propionibacterium acnes had been isolated from bone lesions of individual patients. However, this concept has been challenged since long-term antibiotic therapy did not alter the course of disease and modern microbiological techniques (including PCR) failed to confirm bone infection as an underlying cause. Over recent years, a profound dysregulation of cytokine expression profiles has been demonstrated in innate immune cells of CNO patients. A hallmark of monocytes from CNO patients is the failure to produce immune regulatory cytokines interleukin-10 (IL-10) and IL-19, which have been linked with genetic and epigenetic alterations. Subsequently, a significant upregulation of pro-inflammatory, NLRP3 inflammasome-dependent cytokines (IL-1β and TNF-α), has been demonstrated. Summary The current knowledge on CNO, the underlying molecular pathophysiology, and modern imaging strategies are summarized; differential diagnoses, treatment options, outcome measures, as well as quality of life studies are discussed

Thymus transplantation for complete DiGeorge syndrome: European experience

Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods: Twelve patients with cDGS were transplanted with allogeneic cultured thymus. Objective: To confirm and extend the results previously obtained in a single centre. Results: Two patients died of pre-existing viral infections without developing thymopoeisis and one late death occurred from autoimmune thrombocytopaenia. One infant suffered septic shock shortly after transplant resulting in graft loss and the need for a second transplant. Evidence of thymopoeisis developed from 5-6 months after transplantation in ten patients. The median (range) of circulating naïve CD4 counts (x10663 /L) were 44(11-440) and 200(5-310) at twelve and twenty-four months post-transplant and T-cell receptor excision circles were 2238 (320-8807) and 4184 (1582 -24596) per106 65 T-cells. Counts did not usually reach normal levels for age but patients were able to clear pre-existing and later acquired infections. At a median of 49 months (22-80), eight have ceased prophylactic antimicrobials and five immunoglobulin replacement. Histological confirmation of thymopoeisis was seen in seven of eleven patients undergoing biopsy of transplanted tissue including five showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator (AIRE) expression was also demonstrated. Autoimmune complications were seen in 7/12 patients. In two, early transient autoimmune haemolysis settled after treatment and did not recur. The other five suffered ongoing autoimmune problems including: thyroiditis (3); haemolysis (1), thrombocytopaenia (4) and neutropenia (1). Conclusions: This study confirms the previous reports that thymus transplantation can reconstitute T cells in cDGS but with frequent autoimmune complications in survivors

Association Between Renal Failure and Foot Ulcer or Lower-Extremity Amputation in Patients With Diabetes

OBJECTIVE—The objective of this study was to evaluate the association between foot ulcers (DFU) and lower-extremity amputation (LEA) and chronic kidney disease (CKD) in patients with diabetes