Studies on the Mechanism of Action of Nerve Growth Factor

In this study, explanted chick-embryo sensory ganglia were treated with nerve growth factor, and cellular concentrations of neurotubule protein were measured chemically by a colchicine-binding assay. Even after brief time periods, ganglia treated with growth factor were enriched in neurotubule protein, as compared with untreated (control) ganglia. Furthermore, studies with ganglia treated with both vincristine and growth factor demonstrated that neurotubule protein synthesis can occur even though neurite outgrowth is abolished. Several lines of evidence indicate that the growth factor stimulates de novo synthesis of neurotubule subunit protein, and that this effect precedes neurite extension. Like nerve growth factor, dibutyryl cyclic AMP also stimulates neurite outgrowth from embryonic sensory ganglia, yet it does not increase neurotubule protein levels. Available information suggests that the ability of growth factor to elicit rapid neurite outgrowth is closely related to its ability to increase cellular neurotubule levels. Cyclic AMP appears to stimulate neurite outgrowth by a different mechanism

Issues and Practices in Multiple Sclerosis

The objective of this roundtable discussion of experts in the field of multiple sclerosis (MS) was to summarize the current understanding of MS and its therapeutic options. The experts discussed subjects ranging from the etiology of MS to the current standards for patient care. Specific topics included the subtypes of MS, with a focus on the benign subtype, brain atrophy, the role of magnetic resonance imaging or “neuroimaging studies,” disease-modifying therapies, biological markers as indicators of drug efficacy, and combination therapies. In addition, the experts speculated as to what will be available in the near future for the improved diagnosis and management of MS. This review summarizes the main points of this discussion and is intended to serve as a reference for neurologists involved in the care of patients with MS

Rapid Immune Responses to a Botulinum Neurotoxin Hc Subunit Vaccine through In Vivo Targeting to Antigen-Presenting Cells▿

The clostridial botulinum neurotoxins (BoNTs) are the most potent protein toxins known. The carboxyl-terminal fragment of the toxin heavy chain (Hc) has been intensively investigated as a BoNT vaccine immunogen. We sought to determine whether targeting Hc to antigen-presenting cells (APCs) could accelerate the immune responses to vaccination with BoNT serotype A (BoNT/A) Hc. To test this hypothesis, we targeted Hc to the Fc receptors for IgG (FcγRs) expressed by dendritic cells (DCs) and other APCs. Hc was expressed as a fusion protein with a recombinant ligand for human FcγRs (R4) to produce HcR4 or a similar ligand for murine FcγRs to produce HcmR4. HcR4, HcmR4, and Hc were produced as secreted proteins using baculovirus-mediated expression in SF9 insect cells. In vitro receptor binding assays showed that HcR4 effectively targets Hc to all classes of FcγRs. APCs loaded with HcR4 or HcmR4 are substantially more effective at stimulating Hc-reactive T cells than APCs loaded with nontargeted Hc. Mice immunized with a single dose of HcmR4 or HcR4 had earlier and markedly higher Hc-reactive antibody titers than mice immunized with nontargeted Hc. These results extend to BoNT neutralizing antibody titers, which are substantially higher in mice immunized with HcmR4 than in mice immunized with Hc. Our results demonstrate that targeting Hc to FcγRs augments the pace and magnitude of immune responses to Hc

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema