Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7-10). We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e., mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5±4.8 weeks) and 16 non-PVL controls (36.7±5.2 weeks) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared to controls (19%; 3/16)(p=0.01), with substantial involvement of the mediodorsal and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL. Keywords limbic system; mediodorsal nucleus; oxidative stress; prefrontal cortex; reticular nucleus; working memory Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors (1). Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors (2-6). Prevention of these deficits depends upon a firm understanding of their neuropathologic basis directly in the developing human brain. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants (7-10). While long tract involvement by periventricular necrosis readily explains cerebral palsy (7), it is uncertain how PVL accounts Copyright © 2008 International Pediatric Research Foundation, Inc. All rights reserved.Corresponding Author: Hannah C. Kinney, MD, Department of Pathology, Enders Building, Room 1112, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, Email: E-mail: Hannah.Kinney@childrens.harvard.edu, Telephone: 617 919-4508, FAX: 617 730-0168. Pediatric Research Articles Ahead of Print contains articles in unedited manuscript form that have been peer-reviewed and accepted for publication. As a service to our readers, we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting and review of the resulting proof before it is published in its final definitive form. Please note that during the production process errors may be discovered, which could affect the content, and all legal disclaimers that apply to the journal pertain. [11][12][13]. In a recent survey of the neuropathology of premature infants dying in the perinatal period (14), we reported semi-quantitative evidence of neuronal loss in the thalamus in 38% of the cases with PVL, in contrast ...
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high autoantibody levels and multiorgan tissue damage, including kidney and skin. Cutaneous manifestations are frequent in patients with SLE, yet the etiology and pathogenesis of skin injury in SLE remains unclear. We reasoned that lupus serum containing high levels of autoreactive Ig contributes to skin injury. In this article, we report that serum from SLE patients and lupus-prone mice induces skin inflammation following intradermal injection into normal mice. Lupus serum depleted of IgG failed to cause skin inflammation. Monocytes, but not lymphocytes, were found to be crucial in the development of lupus serum-induced skin inflammation, and lupus serum IgG induced monocyte differentiation into dendritic cells (DCs). TNF-α and TNFR1, but not TNFR2, were required for the development of lupus serum-induced skin inflammation. TNFR1, not TNFR2, represented the main molecule expressed in the skin lesions caused by injected lupus serum. Our studies demonstrated that lupus serum IgG causes skin injury by involving the TNFR1 signaling pathway and monocyte differentiation to DCs. Accordingly, disruption of the TNFR1-mediated signaling pathway and blockade of DC generation may prove to be of therapeutic value in patients with cutaneous lupus erythematosus.
Objective. Spleen tyrosine kinase (Syk) is involved in membrane-mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB ؋ NZW)F 1 lupus-prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus-prone mice and whether they result in improvement in skin disease and modification of established disease.Methods. Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.Results. We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.Conclusion. Syk inhibition suppresses the development of lupus skin and kidney disease in lupus-prone mice, suppresses established disease in lupus-prone mice, and may represent a valuable treatment for patients with SLE.
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