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BackgroundThe incidence of systemic lupus in children with discoid lupus is unknown.ObjectiveThis study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE).MethodsMedical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of 1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P

Purpose: Major amputations of the lower extremity, specifically through and below the knee, are morbid procedures requiring general anesthesia typically followed by high doses of postoperative opioids. Many are performed on highly comorbid, chronic wound patients with a potential for increased opioid use following surgery. Given the current opioid epidemic, perioperative narcotic-reduction strategies are paramount. Our center instituted a protocol for major amputations that includes continuous regional anesthesia, for intraoperative and postoperative pain control, and targeted muscle reinnervation (TMR) nerve transfers to mitigate long-term pain. The aim of this study was to analyze the impact of continuous regional anesthesia and TMR on early postoperative opioid requirements after major lower extremity amputation at our limb salvage center. Methods: We retrospectively reviewed our center’s below-knee and through-knee-amputations from 2017-2019 for utilization of regional pain catheters and TMR nerve transfers. Opioid usage as morphine milligram equivalents (MMEs) was tracked for the first seven postoperative days. Baseline opioid dose was defined by the documented opioid use one day before amputation. Patients were categorized into one of four groups, based on whether regional pain catheter and/or TMR were used. Kruskal-Wallis testing was used to assess baseline opioid use between groups. Bivariate linear regression was used to assess postoperative opioid use of each group compared to the control group. Logistic regression analysis was conducted to examine association between TMR and changes in opioid use postoperatively versus baseline. Results: 198 patients were reviewed. 95 patients received perioperative regional anesthesia, of which 81 underwent TMR. 103 patients did not receive regional anesthesia, of which 30 underwent TMR. Average baseline opioid use was 40.6 MME in patients treated with TMR and regional anesthesia, 60.2 MME with TMR and without regional anesthesia, 28.7 MME without TMR and with regional anesthesia, and 132.6 MME without TMR and regional anesthesia (p=0.0004). Multivariate analysis showed that undergoing TMR, without regional anesthesia, significantly decreased postoperative opioid use by 111.7 MME, compared to the control group (p=0.006). Use of regional anesthesia, with TMR, provided an additive effect, significantly decreasing postoperative opioid use by 124.3 MME, compared to control (p

Background: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease., Objective: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began., Methods: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs., Results: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10 -35 and P = 1.1 × 10 -24 , respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors., Conclusions: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Competing Interests: Conflicts of interest Dr Brandling-Bennett has served as principal investigator for Lilly. Dr Arkin has received consulting fees from AbbVie, Regeneron, and Verrica. Dr Hebert has received research grants (paid to UTHealth McGovern Medical School) from LEO Pharma, Mayne Pharma, UCB, GSK, Ortho Dermatolgics, Amgen, Arcutis, AbbVie, and Pfizer; has received honoraria from Pfizer, Arcutis, UCB, Verrica, LEO Pharma, Novan, Incyte, Janssen, Mayne Pharma, and Castle Creek Bioscience; and has served on drug safety monitoring boards for Ortho Dermatologics, GSK, and Sanofi Regeneron. Dr Cordoro has served as a member of a scientific steering committee for Celgene. Dr Curran has served as an advisory board member for Novartis, receiving honoraria. Dr Dalrymple has served as an advisory board member for Novartis. Dr Flohr is chief investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754, EudraCT 2,015-002,013-29) and SOFTER (Clinicaltrials.gov: NCT03270566) trials as well as the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and a principal investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu/). He also leads the EU Trans-Foods Consortium. His department has received funding from Sanofi-Genzyme and Pfizer for host-microbiome research. Dr Gordon has received personal fees from AbbVie, Almirall, Amgen, BMS, Dermavant, Dermira, Lilly, Janssen, Kyowa Hakko Kirin, LEO Pharma, Novartis, Pfizer, Sun Pharma, and UCB and grants from BMS, Lilly, and UCB. Dr Irvine has received person fees from AbbVie, LEO Pharma, Lilly, Novartis, and Sanofi/Regeneron, and has received a grant from the UK National Institute for Health Research (research arm of the UK Department of Health) as co-principal investigator of a clinical trial comparing MTX with cyclosporine in children with severe atopic dermatitis. Dr Kirkorian has received honoraria from Verrica. Dr Lara-Corrales has served as an advisory board member for Ipsen, LEO Pharma, Lilly, Novartis, Pfizer, and Sanofi Genzyme; as a consultant for AbbVie, Avicanna, Janssen, Johnson & Johnson, Loreal, Pfizer, Pierre Fabre, Sanofi Genzyme, and Valeant; as a speaker for AbbVie, Amgen, Novartis, and Sanofi Genzyme; and has served as a site investigator for AbbVie, Clementia Pharmaceuticals, Janssen, Lilly, and, Mayne Pharma. Dr Jill Lindstrom has received consulting fees from AbbVie, AnaptysBio, Arena Pharmaceuticals, Aristea, Incyte, and Priovant. Dr Amy S. Paller has served as an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, and UCB; Consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer-Ingelheim, Bristol Myers Squibb, Castle Creek, Eli Lilly, Janssen, Krystal, LEO Pharma, Novartis, Regeneron, Sanofi/Genzyme, Seanergy, TWI Biotechnology, and UCB, and on the data safety monitoring board for AbbVie, Abeona, Catawba, Galderma, and InMed. Author Begolka has served as an advisory board member for Incyte and Pfizer, and has received a grant from Pfizer. Dr Tom has served as a site investigator for clinical trials for Janssen, Regeneron, Incyte, Pfizer, Dermira, Eli Lilly, and AbbVie, and has been on data safety committees for LEO Pharma. Dr Voorhees has received research grants from AbbVie, Celgene, and Lilly; has served as an advisory board member for BMS, Boehringer Ingelheim, Celgene, Novartis, and UCB; and had received consulting fees from Amgen. Dr Vleugels has received consulting fees from AbbVie, Pfizer, and Priovant. Dr Lee has received consulting fees from AbbVie and Krystal Biotech; served as an investigator for AbbVie, Amryt, Arcutis, BMS, Castle Creek Biosciences, Celgene, Galderma, Incyte, Janssen, Kiniksa, Lilly, Mayne Pharma, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Target Pharma, Trevi Therapeutics, and UCB; and has served as an advisory board member for Lilly, Novartis, Pfizer, and Regeneron. Dr Davies has received a fellow stipend from Pediatric Dermatology Research Alliance (PeDRA). Dr Siegfried has received consulting fees from AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica; has received honoraria from Regeneron, Sanofi Genzyme, and Verrica; has served on data safety monitoring boards for LEO Pharma, Novan, Pfizer, and UCB; participated in contracted research for AI Therapeutics; served as principal investigator for Janssen, and her institution has received fees related to clinical trials from Janssen, Lilly, Pierre Fabre, Regeneron, and Verrica and in support of a 2020-2021 pediatric dermatology fellowship from Pfizer. Dr Chiu, Dr Callen, Dr Castello-Soccio, Dr Co, Author Hanna, Dr Kim, and Dr Reyes have no conflicts of interest to declare.

Objective: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes., Methods: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD., Results: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time., Conclusion: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials., (© 2023 American College of Rheumatology.)

Background: Bilateral Rasmussen encephalitis is a rare variant of a debilitating, typically unihemispheric disease with limited treatment options. Few cases with bilateral histopathology have been reported, all with poor seizure control following surgery. Here we report a favorable outcome following hemispherotomy in a four-year-old male with biopsy-confirmed bilateral disease., Case: The patient presented with right hemispheric focal seizures with behavioral arrest and over a year progressed to left lower extremity clonic seizures, epilepsia partialis continua, and loss of ambulation, with transient response to steroids and tacrolimus. Histopathology confirmed bilateral disease. The patient developed super-refractory status epilepticus and underwent right functional hemispherotomy 4.5 years after initial presentation. In a 2.5-year follow-up period, an Engel 1D outcome classification was observed with substantially improved quality of life., Conclusion: Previous reports of bilateral Rasmussen encephalitis describe universally poor outcomes, and hemispherotomy is often considered contraindicated. However, hemispherotomy in a patient with bilateral Rasmussen encephalitis may have a good outcome if seizures are unihemispheric., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acquired demyelinating syndromes (ADS) are a heterogenous group of inflammatory demyelinating conditions that include presentations of optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. They can be monophasic or can develop into relapsing episodes of the initial demyelinating event or evolve to include other types of demyelination. Significant progress has been made in differentiating subtypes of ADS that differ in their tendency to relapse and in which anti-inflammatory therapies are effective. Differentiating between these subtypes is important for the optimal management of these patients. Clinical features, labs (especially autoantibodies), and MRI findings can help to differentiate between the different ADS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Pleurotus ostreatus is an edible fungus with high nutritional value that uses industrial and agricultural lignocellulosic residues as substrates for growth and reproduction. Understanding their growth metabolic dynamics on agro-industrial wastes would help to develop economically viable and eco-friendly biotechnological strategies for food production. Thus, we used UHPLC/MS/MS and GNPS as an innovative approach to investigate the chemical composition of two strains of P. ostreatus, coded as BH (Black Hirataki) and WH (White Hirataki), grown on sisal waste mixture (SW) supplemented with 20 % cocoa almond tegument (CAT) or 20 % of wheat bran (WB). Metabolite dereplication allowed the identification of 53 metabolites, which included glycerophospholipids, fatty acids, monoacylglycerols, steroids, carbohydrates, amino acids, and flavonoids. This is the first report of the identification of these compounds in P. ostreatus, except for the steroid ergosterol. Most of the metabolites described in this work possess potential biological activities, which support the nutraceutical properties of P. ostreatus. Thus, the results of this study provide essential leads to the understanding of white-rot fungi chemical plasticity aiming at developing alternative biotechnologies strategies for waste recycling., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Autoimmune encephalitis is characterized by subacute onset of the altered mental status that can rapidly progress to autonomic instability and refractory seizures requiring intensive care. It is mediated by autoantibodies that bind to synaptic surface proteins and alter their function. In contrast to many autoimmune CNS diseases, there is often little detectable inflammatory damage to the brain making it difficult to diagnose. Early engagement of a multidisciplinary team is essential to obtaining a complete diagnostic workup and instituting definitive therapy as early as possible to optimize outcomes. Diagnosis, treatment, and monitoring for this devastating condition continue to evolve. Pathogenesis, diagnosis and both current and emerging therapies are reviewed., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Infections with pathogenic mycobacteria are controlled by the formation of a unique structure known as a granuloma. The granuloma represents a host-pathogen interface where bacteria are killed and confined by the host response, but also where bacteria persist. Previous work has demonstrated that the T cell repertoire is heterogenous even at the single granuloma level. However, further work using pigeon cytochrome C (PCC) epitope-tagged BCG (PCC-BCG) and PCC-specific 5CC7 RAG -/- TCR transgenic (Tg) mice has demonstrated that a monoclonal T cell population is able to control infection. At the chronic stage of infection, granuloma-infiltrating T cells remain highly activated in wild-type mice, while T cells in the monoclonal T cell mice are anergic. We hypothesized that addition of an acutely activated non-specific T cell to the monoclonal T cell system could recapitulate the wild-type phenotype. Here we report that activated non-specific T cells have access to the granuloma and deliver a set of cytokines and chemokines to the lesions. Strikingly, non-specific T cells rescue BCG-specific T cells from anergy and enhance the function of BCG-specific T cells in the granuloma in the chronic phase of infection when bacterial antigen load is low. In addition, we find that these same non-specific T cells have an inhibitory effect on systemic BCG-specific T cells. Taken together, these data suggest that T cells non-specific for granuloma-inducing agents can alter the function of granuloma-specific T cells and have important roles in mycobacterial immunity and other granulomatous disorders.

Background/objectives: Clinically amyopathic juvenile dermatomyositis (CAJDM) is an uncommon but important subset of patients with juvenile dermatomyositis, characterized by pathognomonic cutaneous findings without clinically evident muscle weakness. With limited data available and lack of standardized management guidelines for CAJDM, we sought to describe common features, including early indicators that may be associated with progression of muscle disease, and review the course and treatment of these patients., Methods: A retrospective chart review of patients with CAJDM was conducted at four North American academic centers between the years 2000 and 2015., Results: Twenty-nine patients were included, of whom 21 (72%) were female. After a median follow-up of 4 years (IQR 1.8-5.8 years), 5 of the 29 (17%) patients with CAJDM evolved into classic juvenile dermatomyositis. Median time to develop weakness was 12 months (IQR 8-19 months) after diagnosis. The skin disease of CAJDM patients who did not develop weakness was often found to be recalcitrant with 58% of them requiring multiple systemic therapies to control their cutaneous disease., Conclusion: These results highlight the need for long-term monitoring for the development of myositis in CAJDM and for prospective studies on treatment of recalcitrant skin disease., (© 2021 Wiley Periodicals LLC.)

Objective: To document the need for additional Food and Drug Administration (FDA)-approved medications for the treatment of juvenile idiopathic arthritis (JIA)., Methods: The electronic medical records of JIA patients treated at Cincinnati Children's Hospital Medical Center (CCHMC) and data from JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry were included in this study. Unmet medication need was defined in 2 ways: (a) the presence of chronically uncontrolled JIA, defined as a physician global assessment of JIA activity ≥3 (on a 0-10 scale, where 0 = inactive) OR ≥3 joints with active arthritis OR a patient global assessment of well-being ≥3 (on a 0-10 scale, where 0 = very well), despite sequential use of ≥2 biologic disease-modifying antirheumatic drugs (bDMARDs); and (b) the use of ≥1 bDMARD not approved for any JIA category., Results: At CCHMC, 829 of 1,599 JIA patients (52%) were treated with ≥1 bDMARD, and 304 (19%) had been exposed to ≥1 unapproved bDMARD. In the CARRA Registry, 4,766 of 7,379 children (65%) had received ≥1 bDMARD, and 1,122 (15%) had been prescribed ≥1 unapproved bDMARD. Of those children treated with ≥2 bDMARDs for whom complete data were available, 52% (255 of 487) at CCHMC and 45% (527 of 1,159) in the CARRA Registry had chronically uncontrolled JIA despite the use of ≥2 bDMARDs., Conclusion: Despite the availability of bDMARDs currently approved for JIA, there is persistent need for additional therapies to control JIA signs and symptoms. Since FDA approval is critical to ensure access to bDMARDs, the study and licensing of new medications is critical to address the unmet medication need and to further improve JIA outcomes., (© 2020, American College of Rheumatology.)

Lipoatrophic panniculitis (LP) is a rare childhood panniculitis characterized by sclerotic, atrophic plaques on the extremities. We present a case of LP diagnosed during the inflammatory phase that was difficult to distinguish clinically from eosinophilic fasciitis. This report adds to the limited phenotypic spectrum of LP by differentiating the clinical features of disease activity from disease damage and highlighting the importance of biopsy in establishing a diagnosis., (© 2020 Wiley Periodicals, Inc.)

Background: Hypergammaglobulinemic purpura of Waldenström (HGPW), a rare cutaneous eruption characterized by the triad of recurrent episodes of lower extremity petechiae, symptoms of stinging and burning, and lower extremity edema, is poorly described in children. Some children have been reported to follow a benign course, while others are eventually diagnosed with fulminant rheumatologic disease., Objectives: To determine the distinguishing features of HGPW including the spectrum of disease manifestations and clinical outcomes., Methods: This is a multicenter, retrospective case series of six children with HGPW combined with a literature review of 45 previously published pediatric cases., Results: Most children were eventually diagnosed with systemic disease (63%) or developed autoantibody accumulation suggestive of evolving disease (71%). The most common diagnoses were Sjogren's syndrome and systemic lupus erythematosus. The mean duration between onset of cutaneous eruption and diagnosis of systemic disease was 5.6 years, underscoring that HPGW patients often present with a rash that precedes the development of systemic symptoms., Conclusions: Diagnosis of HGPW should prompt initial screening for rheumatologic disease with long-term rheumatology follow-up, as the majority of patients present with evolving manifestations of systemic disease., (© 2020 Wiley Periodicals, Inc.)

Immune-mediated diseases of the central nervous system show wide variability both symptomatically and with respect to underlying pathophysiology. Recognizing aberrant immunologic activity as the cause of neurologic dysfunction requires establishing as precise a neuroanatomic and functional phenotype as possible, and a diagnostic and therapeutic strategy that stabilizes the patient, excludes broad categories of disease via rapidly available diagnostic assays, and maintains a broad differential diagnosis that includes immune-mediated conditions. This process is aided by recognizing the appropriate clinical circumstances under which immune-mediated disease should be suspected, and how to differentiate these conditions from other causes of similar neurologic dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Pediatric patients can present with skin manifestations of dermatomyositis without overt weakness (clinically amyopathic juvenile dermatomyositis [JDM]), but it is unclear how often this happens and how often they have subclinical muscle inflammation., Objective: Our goal was to determine the frequency of clinically amyopathic JDM and the frequency with which a thorough evaluation uncovers subclinical myositis at a single institution., Methods: A retrospective review was performed of 46 patients diagnosed with JDM at Children's Hospital of Wisconsin., Results: Of 46 patients presenting with skin findings consistent with dermatomyositis, 10 patients (21.7%) did not have evidence of muscle involvement on history or exam, and these tended to be the younger patients. Of these 10, only 2 (4% of all the JDM patients) were truly amyopathic upon further evaluation (all five muscle enzymes [aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase and aldolase], magnetic resonance imaging [MRI], muscle biopsy). In our series, muscle biopsy was not helpful in identifying subclinical myositis. In contrast, MRI did uncover subclinical muscle disease., Conclusion: These data suggest that truly amyopathic JDM is rare and that a thorough workup that includes all five muscle enzymes and MRI may uncover occult myositis., (© 2016 Wiley Periodicals, Inc.)

Bullous eruptions in patients with underlying systemic lupus erythematosus (LE) can mimic toxic-epidermal necrolysis (TEN), a rapidly progressive mucocutaneous reaction usually associated with medication use. Differentiating between classic drug-induced TEN and TEN-like cutaneous LE is important but difficult. We report a series of 3 patients with pediatric systemic LE who were admitted with severe worsening of skin disease resembling TEN. However, the initial photo-distribution of the eruption, subacute progression, limited mucosal involvement, mild systemic symptoms, supportive biopsy and laboratory results, and lack of culprit drugs was more suggestive of a TEN-like cutaneous LE. These patients recovered with various systemic immunosuppressive medications including methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Our cases are rare and demonstrate key clinical and histologic features of TEN-like cutaneous LE in young patients and the importance of differentiating this entity from drug-induced TEN., (Copyright © 2016 by the American Academy of Pediatrics.)

Supplementation with epigallocatechin-3-gallate (EGCG), which restores metabolic profiles, has been proposed as an option for preventing and treating obesity. We investigated whether decaffeinated green tea extract rich in EGCG, attenuates high-fat diet (HFD)-induced metabolic alterations in Swiss mice. The mice were maintained on either a control diet (CD) or HFD for 8 weeks and supplemented with either a placebo or EGCG (50mg/kg/day). Body weight, serum lipid profiles, cytokine protein expression, and content in epididymal (EPI) and retroperitoneal (RET) adipose tissues, and adipocyte area were measured. The body weights of HFD + placebo-fed mice were increased compared with those of HFD + EGCG-fed mice (28 and 21%, respectively), whereas the body weights of CD + EGCG-fed mice were decreased 16% compared with those of the CD + placebo group. Serum triglyceride levels were decreased 32% in the CD + EGCG group compared with the CD + placebo group. Compared with the CD + placebo group, increased phosphorylation of AMPK and hormone-sensitive lipase in EPI and RET, respectively, was found in the CD + EGCG group. Increased acetyl-CoA carboxylase phosphorylation was observed in both adipose tissues. In addition, TNF-α and IL-10 levels in EPI and adiponectin levels were higher in the CD + EGCG group than in the CD + placebo group. TNF-α levels were lower in the HFD + EGCG group than in the HFD + placebo group. Furthermore, the CD + EGCG group exhibited a lower adipocyte area than the CD + placebo group. These indicate that the effects of decaffeinated green tea extract on body mass may be related to the crosstalk between lipolytic and inflammatory pathways in normolipidic diet-fed mice but not in HFD-fed mice., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Intracanal medications are fundamental for disinfection of the root canal system and participate in periapical repair, so their biocompatibility is of utmost importance to avoid tissue damage. This study evaluated the biocompatibility of a experimental paste of calcium hydroxide and propolis in the subcutaneous tissue of rats. The study was conducted on 15 male Wistar rats. Two incisions were made on the dorsal region of each animal for introduction of 4 tubes: one tube was empty; one contained zinc oxide-eugenol cement, and the two other tubes were filled with experimental paste. After 7, 14 and 30 days, the animals were euthanized and the specimens were subjected to histotechnical preparation. The hematoxylin and eosin-stained histological sections were analyzed by light microscopy. Scores were established according to the inflammatory process and statistically compared by the Tukey test (α = 5%). The analysis of histological sections showed non-significant or mild inflammatory reaction in the connective tissue in contact with the empty tubes in all study periods while the contact of subcutaneous tissue with zinc oxide-eugenol elicited moderate or severe inflammation similarly without significant difference among the study periods. The connective tissue was moderately inflamed at 7 days when contacting the experimental paste, but the inflammatory process was non-significant or mild at 14 and 30 days. The experimental paste was biocompatible with the tissues after 14 days of subcutaneous implantation.

To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease.

Adiponectin and interleukin 10 (IL-10) are adipokines that are predominantly secreted by differentiated adipocytes and are involved in energy homeostasis, insulin sensitivity, and the anti-inflammatory response. These two adipokines are reduced in obese subjects, which favors increased activation of nuclear factor kappa B (NF-κB) and leads to elevation of pro-inflammatory adipokines. However, the effects of adiponectin and IL-10 on NF-κB DNA binding activity (NF-κBp50 and NF-κBp65) and proteins involved with the toll-like receptor (TLR-2 and TLR-4) pathway, such as MYD88 and TRAF6 expression, in lipopolysaccharide-treated 3T3-L1 adipocytes are unknown. Stimulation of lipopolysaccharide-treated 3T3-L1 adipocytes for 24h elevated IL-6 levels; activated the NF-κB pathway cascade; increased protein expression of IL-6R, TLR-4, MYD88, and TRAF6; and increased the nuclear activity of NF-κB (p50 and p65) DNA binding. Adiponectin and IL-10 inhibited the elevation of IL-6 levels and activated NF-κB (p50 and p65) DNA binding. Taken together, the present results provide evidence that adiponectin and IL-10 have an important role in the anti-inflammatory response in adipocytes. In addition, inhibition of NF-κB signaling pathways may be an excellent strategy for the treatment of inflammation in obese individuals., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Juvenile dermatomyositis (JDM) is an autoimmune disease of the skin and muscle that affects children. The etiology is poorly understood, but genetic susceptibility, environmental triggers, and abnormal immune responses are each thought to play a part. T cells have traditionally been implicated in the immunopathogenesis of JDM, but dendritic cells, B cells, and microchimerism are increasingly associated. Additionally, myositis-specific autoantibodies (MSA) can be present in the sera of affected patients and may correlate with distinct clinical phenotypes. Given the role of humoral immunity and MSA, there has been recent interest in the use of rituximab to treat JDM. Early results are mixed, but it is hoped that a prospective clinical trial will shed light on the issue in the near future., (© 2011 Wiley Periodicals, Inc.)

Background: It is well known that high fat diets (HFDs) induce obesity and an increase in proinflammatory adipokines. Interleukin-6 (IL-6) is considered the major inflammatory mediator in obesity. Obesity is associated with a vitamin deficiency, especially of vitamins E and D3. We examined the effects of vitamin D3 and vitamin E supplementation on levels of IL-6 and IL-10 (as a marker of anti-inflammatory cytokines since, a balance between pro- and anti-inflammatory cytokines is maintained) protein expression in adipose tissue of mice provided with an HFD. Additionally, we measured the effects of vitamin E and vitamin D3 treatment on LPS-stimulated 3T3-L1 adipocytes IL-6 and IL-10 secretion., Results: IL-6 protein levels and the IL-6/IL-10 ratio were decreased in epididymal white adipose tissue in groups receiving vitamins E and D3 supplementation compared to the HFD group. A 24-hour treatment of vitamin D3 and vitamin E significantly reduced the IL-6 levels in the adipocytes culture medium without affecting IL-10 levels., Conclusions: Vitamin D3 and vitamin E supplementation in an HFD had an anti-inflammatory effect by decreasing IL-6 production in epididymal adipose tissue in mice and in 3T3-L1 adipocytes stimulated with LPS. Our results suggest that vitamin E and D3 supplementation can be used as an adjunctive therapy to reduce the proinflammatory cytokines present in obese patients.

The present study examined the effects of aerobic training and energy restriction on adipokines levels in mesenteric (MEAT) and retroperitoneal (RPAT) white adipose tissue from obese rats. Male Wistar rats were fed with standard laboratory diet (Control group) or high fat diet (HFD). After 15 weeks, HFD rats were randomly assigned to the following groups: rats submitted to HFD, which were sedentary (sedentary HFD, n=8) or trained (trained HFD, n=8); or submitted to energy-restriction (ER), which were sedentary (sedentary ER, n=8) or trained (trained ER, n=8). Trained rats ran on a treadmill at 55% VO(2max) for 60 min/day, 5 days/week, for 10 weeks. ER rats were submitted to a reduction of 20% daily caloric ingestion compared to the Control group. ER and aerobic training decreased body weight, MEAT and RPAT absolute weight, and fat mass. IL-6, IL-10 and TNF-α levels were decreased and adiponectin did not change in RPAT in response to ER protocol. On the other hand, ER and the aerobic training protocol decreased IL-6, TNF-α and adiponectin levels in MEAT. Absolute MEAT weight showed a positive correlation with IL-6 (r=0.464), TNF-α (r=0.508); and adiponectin (r=0.342). These results suggest a tissue-specific heterogeneous response in adipokines level. The combination of the protocols (aerobic training and energy restriction) did not induce an enhanced effect., (Published by Elsevier Ltd.)

Introduction: Cytokines (IL-6, IL-10 and TNF-α) are increased after exhaustive exercise in the rat retroperitoneal (RPAT) and mesenteric adipose tissue (MEAT) pads. On the other hand, these cytokines show decreased expression in these depots in response to a chronic exercise protocol. However, the effect of exercise with overload combined with a short recovery period on pro- and anti-inflammatory cytokine expression is unknown. In the present study, we investigated the regulation of cytokine production in the adipose tissue of rats after an overtraining-inducing exercise protocol., Methods: Male Wistar rats were divided into four groups: Control (C), Trained (Tr), Overtrained (OT) and recovered overtrained (R). Cytokines (IL-6, TNF-α and IL-10) levels and Toll Like Receptor 4 (TLR4), Nuclear Factor kBp65 (NF-kBp65), Hormone Sensitive Lipase (HSL) and, Perilipin protein expression were assessed in the adipose tissue. Furthermore, we analysed plasma lipid profile, insulin, testosterone, corticosterone and endotoxin levels, and liver triacylglycerol, cytokine content, as well as apolipoprotein B (apoB) and TLR4 expression in the liver., Results: OT and R groups exhibited reduced performance accompanied by lower testosterone and increased corticosterone and endotoxin levels when compared with the control and trained groups. IL-6 and IL-10 protein levels were increased in the adipose tissue of the group allowed to recover, in comparison with all the other studied groups. TLR-4 and NF-kBp65 were increased in this same group when compared with both control and trained groups. The protein expression of HSL was increased and that of Perilipin, decreased in the adipose in R in relation to the control. In addition, we found increased liver and serum TAG, along with reduced apoB protein expression and IL-6 and IL-10 levels in the of R in relation to the control and trained groups., Conclusion: In conclusion, we have shown that increases in pro-inflammatory cytokines in the adipose tissue after an overtraining protocol may be mediated via TLR-4 and NF-kBp65 signalling, leading to an inflammatory state in this tissue.

The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-gamma)-producing LCMV-specific T cells in liver granulomas and increased local IFN-gamma. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

CD4(+) T cells are central in mediating granuloma formation and limiting growth and dissemination of mycobacterial infections. To determine whether T cells responding to influenza infection can interact with T cells responding to Mycobacterium bovis bacille Calmette-Guérin (BCG) infection and disrupt granuloma formation, we infected mice containing two monoclonal T cell populations specific for the model Ags pigeon cytochrome c (PCC) and hen egg lysozyme (HEL). These mice were chronically infected with PCC epitope-tagged BCG (PCC-BCG) and acutely infected with HEL epitope-tagged influenza virus (HEL-flu). In these mice, PCC-BCG infection is much more abundant in the liver than the lung, whereas HEL-flu infection is localized to the lung. We observe that both T cells have access to both inflammatory sites, but that PCC-specific T cells dominate the PCC-BCG inflammatory site in the liver, whereas HEL-specific T cells dominate the HEL-flu inflammatory site in the lung. Influenza infection, in the absence of an influenza-specific T cell response, is able to increase the activation state and IFN-gamma secretion of PCC-BCG-specific T cells in the granuloma. Activation of HEL-specific T cells allows them to secrete IFN-gamma and contribute to protection in the granuloma. Ultimately, infection with influenza has little effect on bacterial load, and bacteria do not disseminate. In summary, these data illustrate complex interactions between T cell responses to infectious agents that can affect effector responses to pathogens.

Neuroinflammation often starts with the invasion of T lymphocytes into the CNS leading to recruitment of macrophages and amplification of inflammation. In this study, we show that dendritic cells (DCs) facilitate T-T cell help in the CNS and contribute to the amplification of local neuroinflammation. We adoptively transferred defined amounts of naive TCR-transgenic (TCR) recombination-activating gene-1-deficient T cells into another TCR-transgenic mouse strain expressing different Ag specificity. Following adoptive transfers, we coinjected DCs that presented one or multiple Ags into the brain and followed the activation of T cells with defined specificities simultaneously. Injection of DCs presenting both Ags simultaneously led to significantly higher infiltration of T cells into the brain compared with injection of a mixture of DCs pulsed with two Ags separately. DCs mediated either cooperative or competitive interactions between T cell populations with different specificities depending upon their MHC-restricting element usage. These results suggest that DC-mediated cooperation between brain-infiltrating T cells of different Ag specificities in the CNS plays an important role in regulation of neuroinflammation. This work also implies that blocking Ag-specific responses may block not only the targeted specificities, but may also effectively block their cooperative assistance to other T cells. Therefore, these data justify more attention to Ag-specific therapeutic approaches for neuroinflammation.

Chronic infection with mycobacteria is controlled by the formation of granulomas. The failure of granuloma maintenance results in reactivation of disease. Macrophages are the dominant cell type in granulomas, but CD4+ T cells are the master organizers of granuloma structure and function. Recent work points to an unrecognized role for nonspecific T cells in maintaining granuloma function in the chronic phase of infection. In addition, it has become clear that mycobacteria and host T cells collaborate in formation of granulomas. Further understanding of how nonspecific T cells contribute to granuloma formation, as well as how bacteria and T cells maintain a harmonious relationship over the life of the host, will facilitate the development of new strategies to treat mycobacterial disease.

Granulomatous inflammation is a form of delayed type hypersensitivity reaction that is involved in protection against chronic infections. Granulomatous inflammation can also occur without any clear inciting stimulus such as in sarcoidosis. An in depth knowledge of granuloma formation is essential to our understanding of protection against chronic infection as well as the dysregulation which occurs in granulomatous diseases of unknown origin. Granuloma formation is a complex and dynamic process involving the recruitment and coordination of diverse cell types. This review is focused on the important roles that T cells play in initiating and building the granuloma as well as in mediating effector functions and eventually resolving granulomatous inflammation. CD4(+) T cells emerge as the central mediators of this process, with T cells from other subsets also participating in the later phases of granuloma formation.

Factors which regulate expression of the haptoglobin (acute phase reactant) gene in adipocytes have been examined using 3T3-L1 cells. Haptoglobin expression was observed by Northern blotting in each of the major white adipose tissue depots of mice (epididymal, subcutaneous, mesenteric, and perirenal) and in interscapular brown fat. Expression occurred in mature adipocytes, but not in the stromal-vascular fraction. In 3T3-L1 cells, haptoglobin mRNA was detected from day 4 after the induction of differentiation into adipocytes. Lipopolysaccharide and the cytokines, TNFalpha and interleukin-6, resulted in substantial increases in haptoglobin mRNA in 3T3-L1 adipocytes; the increase (7-fold) was highest with TNFalpha. Increases in haptoglobin mRNA level were also induced by dexamethasone, noradrenaline, isoprenaline, and a beta3-adrenoceptor agonist. In contrast, haptoglobin mRNA was reduced by nicotinic acid and the PPARgamma agonist, rosiglitazone. RT-PCR showed that the haptoglobin gene was expressed in human adipose tissue (subcutaneous, omental). It is concluded that haptoglobin gene expression in adipocytes is stimulated by inflammatory cytokines, glucocorticoids, and the sympathetic system, while activation of the PPARgamma nuclear receptor is strongly inhibitory.

Infectious agents have been proposed to influence susceptibility to autoimmune diseases such as multiple sclerosis. We induced a Th1-mediated central nervous system (CNS) autoimmune disease, experimental autoimmune encephalomyelitis (EAE) in mice with an ongoing infection with Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) to study this possibility. C57BL/6 mice infected with live BCG for 6 weeks were immunized with myelin oligodendroglial glycoprotein peptide (MOG(35-55)) to induce EAE. The clinical severity of EAE was reduced in BCG-infected mice in a BCG dose-dependent manner. Inflammatory-cell infiltration and demyelination of the spinal cord were significantly lessened in BCG-infected animals compared with uninfected EAE controls. ELISPOT and gamma interferon intracellular cytokine analysis of the frequency of antigen-specific CD4(+) T cells in the CNS and in BCG-induced granulomas and adoptive transfer of MOG(35-55)-specific green fluorescent protein-expressing cells into BCG-infected animals indicated that nervous tissue-specific (MOG(35-55)) CD4(+) T cells accumulate in the BCG-induced granuloma sites. These data suggest a novel mechanism for infection-mediated modulation of autoimmunity. We demonstrate that redirected trafficking of activated CNS antigen-specific CD4(+) T cells to local inflammatory sites induced by BCG infection modulates the initiation and progression of a Th1-mediated CNS autoimmune disease.

The hallmark of Schistosoma mansoni infection is the formation of liver granulomas around deposited ova. The initiation of granuloma formation is T cell-dependent since granulomas are not formed in their absence. We investigated whether a few T cells arrive to initiate the inflammatory lesion and subsequently expand locally, or whether a large repertoire of systemically activated T cells home to the delayed type hypersensitivity reaction induced by the ova. The TCR repertoire of single granulomas from the same liver were analyzed by PCR using Vbeta-specific primers and CDR3 analysis. Each granuloma has a very diverse TCR repertoire indicating that most of the T cells recruited to these lesions are activated systemically. At the same time, sequence analysis of individually sized CDR3 products from single granuloma indicate that a fraction of T cells expand locally at the lesion site. Using TCR transgenic mice containing a pigeon cytochrome c-specific T cell population or lymphocytic choriomeningitis virus infection tracked with lymphocytic choriomeningitis virus-specific tetramers, we demonstrated that nonspecific T cells home to the granuloma if they are activated. However, recombinase-activating gene 2(-/-) pigeon cytochrome c-specific TCR transgenic mice fail to form granulomas in response to S. mansoni ova even after T cell activation, suggesting a requirement for egg-specific T cells in the initiation of these inflammatory lesions. Understanding the mechanism of T cell recruitment into granulomas has important implications for the rational design of immunotherapies for granulomatous diseases.

We have generated transgenic mice by pronuclear microinjection of a murine satellite DNA-based artificial chromosome (SATAC). As 50% of the founder progeny were SATAC-positive, this demonstrates that SATAC transmission through the germline had occurred. FISH analyses of metaphase chromosomes from mitogen-activated peripheral blood lymphocytes from both the founder and progeny revealed that the SATAC was maintained as a discrete chromosome and that it had not integrated into an endogenous chromosome. To our knowledge, this is the first report of the germline transmission of a genetically engineered mammalian artificial chromosome within transgenic animals generated through pronuclear microinjection. We have also shown that murine SATACs can be similarly introduced into bovine embryos. The use of embryo microinjection to generate transgenic mammals carrying genetically engineered chromosomes provides a novel method by which the unique advantages of chromosome-based gene delivery systems can be exploited.