Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical 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 <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >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 < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

Novel inhibitors of the Plasmodium falciparum electron transport chain.

Due to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc 1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.

Keratinocyte Carcinoma as a Marker of a High Cancer-Risk Phenotype.

Keratinocyte carcinoma (KC) (also referred to as nonmelanoma skin cancer) is by far the most common form of human cancer. A personal history of KC is well established to be associated with increased risk of recurrent KC and malignant melanoma, a less common yet more fatal form of skin cancer. More surprising is that a substantial body of epidemiologic evidence now indicates that a personal history of KC is significantly associated with an overall elevated risk of noncutaneous malignancies. This association is not limited to one or a few types of cancer but applies across many different types of malignancy. This association has been consistently observed in prospective studies across genders for both major histologic types of KC, basal cell carcinoma and squamous cell carcinoma. The risk of other cancers has been even stronger in those with younger compared with older age of onset of KC. A robust body of evidence lends support to the notion that KC may be a marker of a high cancer-risk phenotype. The underlying mechanisms for this association remain to be elucidated, but the cross-cutting nature of this association across numerous malignancies suggests that research to uncover these mechanisms is a promising line of inquiry that could potentially yield valuable insight into human carcinogenesis.

Phytophthora ramorum on Quercus ilex in the United Kingdom.

Phytophthora ramorum causes bleeding cankers of trunks of trees native to the west coast of the United States (i.e., Quercus kelloggii, Q. parvula var. shrevei, and Lithocarpus densiflorus). In the United Kingdom so far, bleeding cankers caused by inner bark infections have been found on Aesculus hippocastanum, Fagus sylvatica, Q. cerris, Q. falcata, and Q. petraea ( http://rapra.csl.gov.uk [2005]). Shoot tip dieback (ramorum dieback) and foliar necrosis (ramorum leaf blight) are other diseases caused by the pathogen on understory and ornamental plants (3). Inoculum is produced on infected shoots and leaves of foliar hosts but not on bole cankers (1). Foliar hosts are thus critical in initiating and maintaining epidemics of tree mortality resulting from lethal bark cankers. Ramorum dieback and blight occurs in Europe on genera Rhododendron, Camellia, Kalmia, Pieris, and Viburnum (http://rapra.csl.gov.uk [2005]), and now we report these diseases on foliage and shoots of holm oaks (Quercus ilex) in Cornwall (UK). First discovered in November 2003, infected young leaves had a water-soaked, dull gray appearance, and petioles were blackened. Lesions started at leaf margins, tips, or petioles, often progressing into the midrib veins. Initial infections also occurred on shoots and extended into the petioles. If shoots were infected, they were blackened at first, but later in the season clusters of dry, dead leaves and twigs characterized branch tips. Infected mature leaves bore dry, reddish-brown, restricted lesions. P. ramorum (A1 sexual compatibility type belonging to the European population) was isolated and confirmed by morphological studies, ITS sequence (GenBank Accession No. AY924253), and amplified fragment length polymorphism analyses. Lesions developed on detached leaves dipped for 10 sec in inoculum (4 × 105 zoospores per ml) and incubated in moist chambers at 20°C for 6 days (2). Two isolates were used (four leaves per isolate). The pathogen was reisolated, and the tests were repeated twice. Koch's postulates were also successfully completed once on foliage attached to saplings. To our knowledge, this is the first report of P. ramorum on holm oak. So far, at least 24 holm oaks are infected at various woodland and garden sites in the United Kingdom; infected rhododendrons have also been found at these sites. P. ramorum has also been recorded on saplings in nurseries. The high sporulation potential, the evergreen nature of leaves, and susceptible shoots indicate that holm oak could be a significant source of inoculum for other hosts. References: (1) J. M. Davidson et al. Phytopathology 95:587, 2005. (2) S. Denman et al. Plant Pathol. 54:512, 2005. (3) E. M. Hansen et al. Plant Dis. 89:63, 2005.

Identification of three distinct receptor binding sites of murine interleukin-11.

Interleukin-11 (IL-11) is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of which contain at least one molecule of the transmembrane signaling receptor gp130. A complex of IL-11 and the IL-11 receptor (IL-11R) has been shown to interact with gp130, with high affinity, and to induce gp130- dependent signaling. In this study, we have identified residues crucial for the binding of murine IL-11 (mIL-11) to both the IL-11R and gp130 by examining the activities of mIL-11 mutants in receptor binding and cell proliferation assays. The location of these residues, as predicted from structural studies and a model of IL-11, reveals that mIL-11 has three distinct receptor binding sites. These are structurally and functionally analogous to the previously defined receptor binding sites I, II, and III of interleukin-6 (IL-6). This supports the hypothesis that IL-11 signals via the formation of a hexameric receptor complex and indicates that site III is a generic feature of cytokines that signal via association with gp130.

Interleukin-11 signals through the formation of a hexameric receptor complex.

Interleukin-11 (IL-11) is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of which contain at least one molecule of the transmembrane signaling receptor gp130. IL-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the IL-11 receptor (IL-11R) and gp130. Site-directed mutagenesis studies have identified three distinct receptor binding sites of IL-11, which enable it to form this high affinity receptor complex. Here we present data from immunoprecipitation experiments, using differentially tagged forms of ligand and soluble receptor components, which show that multiple copies of IL-11, IL-11R, and gp130 are present in the receptor complex. Furthermore, it is demonstrated that sites II and III of IL-11 are independent gp130 binding epitopes and that both are essential for gp130 dimerization. We also show that a stable high affinity complex of IL-11, IL-11R, and gp130 can be resolved by nondenaturing polyacrylamide gel electrophoresis, and its composition verified by second dimension denaturing polyacrylamide gel electrophoresis. Results indicate that the three receptor binding sites of IL-11 and the Ig-like domain of gp130 are all essential for this stable receptor complex to be formed. We therefore propose that IL-11 forms a hexameric receptor complex composed of two molecules each of IL-11, IL-11R, and gp130.