Etanercept therapy in children with treatment‐resistant uveitis

Objective

To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment‐resistant uveitis.

Methods

Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3–12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months.

Results

At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted.

Conclusion

Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment‐resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.

     

Drug-induced impulse control disorders in Parkinson’s disease

Journal of Neurology -     

Differential effects of L-dopa and subthalamic stimulation on depressive symptoms and hedonic tone in Parkinson's disease

Patients with Parkinson's disease frequently have mild to moderate depression and exhibit low hedonic tone. The authors investigate the impact of a single L-dopa challenge and the acute effects of electric stimulation of the subthalamic nucleus (STN) on symptoms of depression and hedonic tone. Depressive symptoms improved with L-dopa and STN stimulation to the same extent. However, hedonic tone improved only with L-dopa. Most of the emotional changes did not correlate with changes in motor performance, indicating they were not just reactive but specific to the treatment. These results demonstrate a single dissociation of depressive symptoms and anhedonia in response to an acute L-dopa and STN-stimulation challenge.     

Ethnobotanical literature survey of medicinal plants in the Dominican Republic used for women's health conditions

This ethnobotanical literature survey is part of an on-going study in New York City investigating Dominican and Chinese healing systems and the herbal treatments used for the following women's conditions: uterine fibroids (benign tumors of uterine smooth muscle); menorrhagia (excessive uterine bleeding); endometriosis (growth of endometrial tissue outside of the uterus); and hot flashes (sudden brief sensations of heat commonly experienced during menopause). The objectives of this survey were: (1) to search literature on medicinal plants used in the Dominican Republic and identify those used for the above listed conditions and their symptoms; (2) to compare the use between herbal treatments reported in the literature with those prescribed by Dominican healers in New York City; and (3) to evaluate the extent to which healers may have changed their use of plants in order to adapt to availability in the New York City environment. A total of 87 plant species were reported in the Dominican literature for these conditions and symptoms. Nineteen species overlapped from the literature survey and the fieldwork with Dominican healers in New York City, representing 29% (n=65) of the plants prescribed by healers in New York City. This study offers a model to investigate changes in plant use as people migrate to urban centers where they are surrounded by diverse cultures, healing systems, and new environments.     

Acidic fibroblast growth factor signaling inhibits peroxynitrite-induced death of osteoblasts and osteoblast precursors.

After trauma injury to the musculoskeletal system, conditions such as ischemia and inflammation involve excess production of superoxide (O2*), nitric oxide (*NO), and their reaction product, peroxynitrite (ONOO-). Exposure of murine osteoblasts and rat-derived primary osteoblast precursors to ONOO- resulted in a dose- and time-dependent delayed cell death that was more characteristic of apoptosis than necrosis. Exposure of both cell populations to ONOO- immediately enhanced phosphorylation and nitration of tyrosine residues within several polypeptides. Treatment of osteoblasts and osteoblast precursors with exogenous acidic fibroblast growth factor (FGF-1) enhanced cellular growth, increased endogenous levels of tyrosine phosphorylation, and significantly induced expression of both osteopontin and osteocalcin messenger RNA (mRNA) as well as osteopontin protein. Pretreatment of both cell populations with exogenous FGF-1 prevented ONOO(-)-mediated death. Cell signaling induced by FGF-1 pretreatment had no major effect of total levels of tyrosine nitration after ONOO- treatment. Collectively, these in vitro efforts show that FGF-1 signaling renders osteoblasts and osteoblast precursors resistant to the cytotoxic effects of ONOO-. Consequently, results presented here predict the therapeutic use of this growth factor for promoting the progression of bone repair mechanisms after fracture trauma.     

Identification of novel susceptibility genes in childhood‐onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

Objective

Childhood‐onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood‐onset SLE and both of their parents.

Methods

Utilizing bioinformatic tools, a platform of 9,412 single‐nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high‐throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood‐onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections.

Results

Family‐based TDT showed a significant association of SLE with a N673S polymorphism in the P‐selectin gene (SELP) (P = 5.74 × 10⁻⁶) and a C203S polymorphism in the interleukin‐1 receptor–associated kinase 1 gene (IRAK1) (P = 9.58 × 10⁻⁶). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis.

Conclusion

SELP and IRAK1 were identified as novel SLE‐associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.

     

In vivo role for CREB signaling in the noradrenergic differentiation of sympathetic neurons

Signaling pathways involving cAMP and CREB have been implicated in several aspects of sympathetic neuron differentiation. Here, we used in vivo loss-of-function approaches in both mouse and chick embryos to characterize the physiological role of cAMP/CREB. Whereas sympathetic neuron development proceeds normally in CREB-deficient mouse embryos, a decrease in noradrenergic differentiation (TH, DBH) was observed in chick sympathetic ganglia in response to ACREB, a dominant-negative CREB variant which interferes with the function of all CREB family members. In contrast, expression of the generic neuronal marker SCG10 was not affected by ACREB. As the decrease in noradrenergic gene expression is compensated at later stages of development and TH expression in differentiated neurons is not CREB-dependent, a transient role for CREB is proposed, accelerating noradrenergic but not generic neuronal differentiation of sympathetic neurons.