Antibodies to histone have been associated in the adult literature with systemic lupus erythematosus(SLE) and drug induced lupus(DILE). Little data is available regarding the spectrum of pathology ...that antibodies to histone encompass in the pediatric population. Prior studies suggest an association with SLE, juvenile idiopathic arthritis(JIA), uveitis and linear scleroderma.
Patient charts were reviewed that contained positive anti-histone antibody testing during a consecutive three year period. Patient diagnosis along with the presence of: anti-histone antibody titer, ANA, and the presence of other autoantibodies to SSA, SSB, Sm, RNP, dsDNA and chromatin were obtained. The frequency of SLE, JIA and DILE was further investigated in specific subsets.
139 individual charts were reviewed containing 41 different diagnoses. The most common diagnosis was hypermobility arthralgia with 22 patients. The most frequent rheumatologic diagnosis was JIA(nonsystemic) with 19. 13 patients in this study were diagnosed with SLE and 2 with DILE. 18 patients had other autoantibody production, of these, 11 had SLE or DILE. Only one of 62 patients with a weak antihistone antibody titer(1.0-1.5) was diagnosed with SLE. When strong titers are present(> 2.5), the antihistone antibody test was associated with a greater than 50% incidence of an underlying rheumatologic disease and ten times higher incidence of SLE than a weak titer. In regards to the frequency of SLE, there was a statistically significant difference between weak and moderate titers and between weak and strong titers.
The presence of anti-histone antibody was observed in a variety of diagnoses in the pediatric population. Overall, the presence of anti-histone antibodies appears to have poor diagnostic utility for any specific condition. However, diagnostic utility for SLE does appear to improve with higher titers, when combined with other autoantibody positivity. Strength of titer did not appear to be a factor for JIA, but was the most frequently observed rheumatologic disease in this study.
An important outcome of plant thermogenesis is increased emissions of volatiles that mediate pollinator behaviour. We investigated whether the large increase in emissions, mainly the monoterpene ...ß‐myrcene (>90%), during daily thermogenic events of Macrozamia macleayi and lucida cycad cones are due solely to the influence of high cone temperatures or are, instead, a result of increased respiratory rates during thermogenesis. We concurrently measured temperature, oxygen consumption and ß‐myrcene emission profiles during thermogenesis of pollen cones under typical environmental temperatures and during experimental manipulations of cone temperatures and aerobic conditions, all in the dark. The exponential rise in ß‐myrcene emissions never occurred without a prior, large increase in respiration, whereas an increase in cone temperature alone did not increase emissions. When respiration during thermogenesis was interrupted by anoxic conditions, ß‐myrcene emissions decreased. The increased emission rates are not a result of increased cone temperature per se (through increased enzyme activity or volatilization of stored volatiles) but are dependent on biosynthetic pathways associated with increased respiration during thermogenesis that provide the carbon, energy (ATP) and reducing compounds (NADPH) required for ß‐myrcene production through the methylerythritol phosphate (MEP) pathway. These findings establish the significant contribution of respiration to volatile production during thermogenesis.
Investigations of thermogenesis in plant reproductive organs have focused on the effects of increased temperature on the release of the volatiles (volatilization) that mediate pollinator behavior, but the possible role of the increased respiration rate underlying the increase in temperature on volatile production and release has never been thoroughly tested. We measured concurrently the respiration, temperature and volatile emissions during the daily thermogenic events of Macrozamia cycad cones. The large surges in monoterpene (mainly β‐myrcene) emission rates during thermogenesis are shown to be driven primarily by pathways that are dependent on high respiration rates that occur only during a thermogenic event and are clearly not a result of high cone temperature alone. We propose that the large daily respiratory burst during thermogenesis increases the availability of ATP, NADPH and carbon substrates required for production of the monoterpenes via the methylerythritol phosphate pathway.
Juvenile idiopathic arthritis (JIA) reflects a group of clinically heterogeneous, autoimmune disorders in children characterized by chronic arthritis and hallmarked by elevated levels of circulating ...immune complexes (CICs) and associated complement activation by-products in their sera. Immune complexes (ICs) have been detected in patients' sera with JIA utilizing a variety of methods, including the anti-human IgM affinity column, C1q solid-phase assay, polyethylene glycol precipitation, Staphylococcal Protein A separation method, anti-C1q/C3 affinity columns, and FcγRIII affinity method. As many as 75% of JIA patients have had IC detected in their sera. The CIC proteome in JIA patients has been examined to elucidate disease-associated proteins that are expressed in active disease. Evaluation of these ICs has shown the presence of multiple peptide fragments by SDS-PAGE and 2-DE. Subsequently, all isotypes of rheumatoid factor (RF), isotypes of anti-cyclic citrullinated peptide (CCP) antibodies, IgG, C1q, C4, C3, and the membrane attack complex (MAC) were detected in these IC. Complement activation and levels of IC correlate with disease activity in JIA, indicating their role in the pathophysiology of the disease. This review will summarize the existing literature and discuss the role of possible protein modification that participates in the generation of the immune response. We will address the possible role of these events in the development of ectopic germinal centers that become the secondary site of plasma cell development in JIA. We will further address possible therapeutic modalities that could be instituted as a result of the information gathered by the presence of ICs in JIA.
Preliminary studies suggest that a modified Paleolithic diet may benefit symptoms of fatigue in progressive multiple sclerosis (MS). However, this diet restricts the consumption of eggs, dairy, and ...gluten-containing grains, which may increase the risk of micronutrient deficiencies. Therefore, we evaluated the nutritional safety of this diet among people with progressive MS. Three nonconsecutive 24-h dietary recalls were collected from (
= 19) progressive MS participants in the final months of a diet intervention study and analyzed using Nutrition Data System for Research (NDSR) software. Food group intake was calculated, and intake of micronutrients was evaluated and compared to individual recommendations using Nutrient Adequacy Ratios (NARs). Blood was drawn at baseline and the end of the study to evaluate biomarker changes. Mean intake of fruits and vegetables exceeded nine servings/day and most participants excluded food groups. The intake of all micronutrients from food were above 100% NAR except for vitamin D (29.6 ± 34.6%), choline (73.2 ± 27.2%), and calcium (60.3 ± 22.8%), and one participant (1/19) exceeded the Tolerable Upper Limit (UL) for zinc, one (1/19) for vitamin A, and 37% (7/19) exceeded the chronic disease risk reduction (CDRR) for sodium. When intake from supplements was included in the analysis, several individuals exceeded ULs for magnesium (5/19), zinc (2/19), sodium (7/19), and vitamins A (2/19), D (9/19), C (1/19), B
(3/19), and niacin (10/19). Serum values of vitamins D, B
, K
, K
, and folate significantly increased compared to respective baseline values, while homocysteine and magnesium values were significantly lower at 12 months. Calcium and vitamin A serum levels did not change. This modified Paleolithic diet is associated with minimal nutritional risks. However, excessive intake from supplements may be of concern.
CD4+ T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor γ-chain FcRγ-Syk. A role for FcγRIIIa activation from immune complex ...(IC) ligation and sublytic terminal complement complex (C5b-9) in CD4+ T-cell responses is not investigated. In this study, we show that the ICs present in SLE patients by ligating to FcγRIIIa on CD4+ T-cells phosphorylate Syk and provide a co-stimulatory signal to CD4+ T-cells in the absence of CD28 signal. This led to the development of pathogenic IL-17A+ and IFN-γhigh CD4+ T-cells in vitro. Cytokines IL-1β, IL-6, TGF-β1, and IL-23 were the only requirement for the development of both populations. SLE patients CD4+ T-cells that expressed CD25, CD69, and CD98 bound to ICs showed pSyk and produced IFN-γ and IL-17A. This FcγRIIIa-mediated co-signal differentially up-regulated the expression of IFN pathway genes compared with CD28 co-signal. FcγRIIIa-pSyk up-regulated several toll-like receptor genes as well as the HMGB1 and MyD88 gene transcripts. ICs co-localized with these toll-like receptor pathway proteins. These results suggest a role for the FcγRIIIa-pSyk signal in modulating adaptive immune responses.
Cycad cone thermogenesis and its associated volatiles are intimately involved in mediating the behavior of their obligate specialist pollinators. In eastern Australia, thrips in the Cycadothrips ...chadwicki species complex are the sole pollinators of many Macrozamia cycads. Further, they feed and reproduce entirely in the pollen cones. M. miquelii, found only in the northern range of this genus, is pollinated only by a C. chadwicki cryptic species that is the most distantly related to others in the complex. We examined the volatile profile from M. miquelii pollen and ovulate (receptive and non-receptive) cones to determine how this mediates pollination mechanistically, using GC-MS (gas chromatography-mass spectrometry) and behavioral tests. Monoterpenes comprise the bulk of M. miquelii volatile emissions, as in other Macrozamia species, but we also identified compounds not reported previously in any cycad, including three aliphatic esters (prenyl acetate and two of uncertain identity) and two aliphatic alcohols. The two unknown esters were confirmed as prenyl (3-methylbut-2-enyl) esters of butyric and crotonic ((E))-but-2-enoic) acids after chemical synthesis. Prenyl crotonate is a major component in emissions from pollen and receptive ovulate cones, is essentially absent from non-receptive cones, and has not been reported from any other natural source. In field bioassays, Cycadothrips were attracted only to those volatile treatments containing prenyl crotonate. We discuss M. miquelii cone odorants relative to those of other cycads, especially with respect to prenyl crotonate being a species-specific signal to this northern C. chadwicki cryptic species, and how this system may have diversified.
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•Cones of Macrozamia miquelii, an Australian endemic, emit novel cycad volatiles.•Two are hemiterpenes, commonly found in other plants.•Three are prenyl esters: acetate, butyrate and crotonate.•Prenyl crotonate, a major component, is not known from any other natural source.•Prenyl crotonate attracts the species-specific thrips pollinator of M. miquelii.
Background A shorter dosing regimen of imiquimod for the treatment of actinic keratosis may be effective, with long-term clinical benefits. Objective Imiquimod in one or two shorter courses of ...treatment was evaluated. Methods Patients with actinic keratosis lesions on the head applied imiquimod or vehicle cream 3×/wk for 4 weeks (course 1). Patients with remaining lesions received another course of treatment. Complete and partial clearance rates were evaluated after course 1, after course 2 (overall), and 1 year later. Results Complete clearance rates were 26.8% (course 1) and 53.7% (overall). Partial clearance rates were 36.6% (course 1) and 61.0% (overall). One-year follow-up recurrence rates were 39% (imiquimod) and 57% (vehicle). Limitations Blinded investigators may have been biased toward patients treated with imiquimod identified by treatment site reactions. Conclusion Imiquimod 3×/wk in one or two courses of treatment appears to be effective for the treatment of actinic keratoses on the head, providing long-term clinical benefits. Some recurrences do occur, so long-term follow-up is recommended.
Whether or not CD4+ T-cells express low affinity receptor FcγRIIIa (CD16a) in disease pathology has not been examined in great detail. In this study, we show that a subset of activated CD4+ T-cells ...in humans express FcγRIIIa. The ligation of FcγRIIIa by immune complexes (ICs) in human CD4+ T-cells produced co-stimulatory signal like CD28 that triggered IFN-γ production. The induced expression of FcγRIIIa on CD4+ helper T-cells is an important finding since these receptors via ITAM contribute to intracellular signaling. The induced expression of FcγRIIIa on CD4+ T helper cells and their ability to co-stimulate T-cell activation are important and novel findings that may reveal new pathways to regulate adaptive immune responses during inflammation and in autoimmunity.
Background: Fcγ-receptors play an important role in the immune responses.
Results: We show that upon activation by immune complexes peripheral CD4+ T-lymphocytes express FcγRIIIa and produce a subset that express high levels of IFN-γ.
Conclusion: We describe for the first time a role for FcγRIIIa in CD4+ T-cell differentiation.
Significance: This CD4+FcγRIIIa+IFN-γhigh subset will be critical in understanding the underlying autoimmune pathologies.
Urinary tract infection (UTI) is a frequent infection in childhood. The diagnosis is usually made by history and physical examination and confirmed by urine analysis. Cystitis is infection or ...inflammation confined to the bladder, whereas pyelonephritis is infection or inflammation of kidneys. Pyelonephritis can cause renal scarring, which is the most severe long-term sequela of UTI and can lead to accelerated nephrosclerosis, leading to hypertension and chronic renal failure. The role of imaging is to guide treatment by identifying patients who are at high risk to develop recurrent UTIs or renal scarring. This document provides initial imaging guidelines for children presenting with first febrile UTI with appropriate response to medical management, atypical or recurrent febrile UTI, and follow-up imaging for children with established vesicoureteral reflux. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
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