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Objective: The current study aimed to explore the interplay between food insecurity, fast-food outlet exposure and dietary quality in disadvantaged neighbourhoods., Design: In this cross-sectional study, main associations between fast-food outlet density and proximity, food insecurity status and dietary quality were assessed using Generalized Estimating Equation analyses. We assessed potential moderation by fast-food outlet exposure in the association between food insecurity status and dietary quality by testing for effect modification between food insecurity status and fast-food outlet density and proximity., Setting: A deprived urban area in the Netherlands., Participants: We included 226 adult participants with at least one child below the age of 18 years living at home., Results: Fast-food outlet exposure was not associated with experiencing food insecurity (fast-food outlet density: b = -0·026, 95 % CI = -0·076; 0·024; fast-food outlet proximity: b = -0·003, 95 % CI = -0·033; 0·026). Experiencing food insecurity was associated with lower dietary quality (b = -0·48 per unit increase, 95 % CI = -0·94; -0·012). This association was moderated by fast-food outlet proximity (Pinteraction = 0·008), and stratified results revealed that the adverse effect of food insecurity on dietary quality was more pronounced for those with the nearest fast-food outlet located closer to the home., Conclusions: Food insecurity but not fast-food outlet density is associated with dietary quality. However, the association between food insecurity and dietary quality may be modified by the food environment. These findings could inform policymakers to promote a healthier food environment including less fast-food outlets, with particular emphasis on areas with high percentages of food insecure households.

In the last decade, early-onset of affective illness has been recognized as a major public health problem. However, clinical studies indicate that although children experience the symptoms of anxiety and depression in much the same way as adults, they display and react to those symptoms differently (Bostic et al., 2005). Recently, we have demonstrated that similar differences in symptoms are found also between adult and juvenile rats (Jacobson-Pick and Richter-Levin, 2010). Especially the hippocampus is believed to be vulnerable to stress-related illness, as this brain region has a high density of corticoid receptors. The hippocampus is known to finalize its development, and particularly that of GABA-related functions, into adolescence (Bergmann et al., 1991; Harris et al., 1992; Nurse and Lacaille, 1999; Lopez-Tellez et al., 2004; Jacobson-Pick et al., 2008) and may thus be differentially sensitive to environmental challenges in childhood and in adulthood. In this study we explored the differences in activity and plasticity of the dentate gyrus between pre-pubertal and adult rats in vivo. Furthermore, we have examined the impact of exposure to stress either during pre-puberty or in adulthood on dentate gyrus electrophysiology. In both male and female rats, marked differences were found for intrinsic excitability and local circuit activity between pre-pubertal and adult animals. Exposure to forced swim stress resulted in significant alterations of dentate gyrus activity and plasticity in male rats with differences between adult and pre-pubertal animals. Stress had far less impact on females' dentate electrophysiology. The results are in agreement with the differences in behavioral response to stress between pre-pubertal and adult rats, and with reported differences for the sensitivity of male and female rats in performing hippocampus-dependent tasks under stress, such as the active avoidance task., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Gangliosides are sialylated glycosphingolipids that are present in high density on neuronal membranes, especially at synapses, where they are assumed to play functional or modulating roles. Mice lacking GM2/GD2-synthase express only the simple gangliosides GD3 and GM3 and develop progressive motor behaviour deficits upon ageing, apparently due to failing complex ganglioside-dependent maintenance and/or repair processes or, alternatively, toxic GM3/GD3 accumulation. We investigated the function of neuromuscular junctions (NMJs) of aged (>9 month-old) GM2/GD2-synthase null-mutant mice, because synaptic dysfunction might develop with age and could potentially contribute to the late-onset motor phenotype. In addition, we studied NMJs of old mice lacking GD3-synthase (expressing only O- and a-series gangliosides), which do not show an overt neurological phenotype but may develop subclinical synaptic deficits. Detailed electrophysiological analyses showed subtle changes in presynaptic neurotransmitter release. Acetylcholine release at 40 Hz nerve stimulation at aged GM2/GD2-synthase null-mutant NMJs ran down slightly more pronounced than at wild-type NMJs, and spontaneous acetylcholine release rate at GD3-synthase null-mutant NMJs was somewhat higher than at wild-type, selectively at 25 °C bath temperature. Interestingly, we observed faster kinetics of postsynaptic electrophysiological responses at aged GD3-synthase null-mutant NMJs, not previously seen by us at NMJs of young GD3-synthase null-mutants or other types of (aged or young) ganglioside-deficient mice. These kinetic changes might reflect a change in postsynaptic acetylcholine receptor behaviour. Our data indicate that it is highly unlikely that transmission failure at NMJs contributes to the progressive motor defects of aged GM2/GD2-synthase null-mutants and that, despite some kinetic changes of synaptic signals, neuromuscular transmission remains successful in aged GD3-synthase null-mutant mice. Apparently, mutual redundancy of the different gangliosides in supporting presynaptic function, as observed previously by us in young mice, remains adequate upon ageing or, alternatively, gangliosides have only relatively little direct impact on neuromuscular synaptic function, even in aged mice., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Neuronal membrane gangliosides, forming a large family of sialylated glycosphingolipids, have been hypothesized to play important roles in synaptic transmission. We studied the ex vivo electrophysiological function of neuromuscular junctions of GM2/GD2-synthase*GD3-synthase compound null-mutant mice after acute removal of GM3, the only remaining ganglioside in this mouse, by in vitro treatment with neuraminidase. We found 16% enhancement of the acetylcholine release per nerve impulse at low-rate (0.3 Hz) nerve stimulation. Conversely, the treatment reduced the acetylcholine release evoked by high-rate (40 Hz) nerve stimulation. Also, 25 ms paired-pulse facilitation of endplate potentials was reduced by the neuraminidase-treatment. These effects may indicate a modest modulatory influence of the negative electrical charges carried by the sialic acid molecules of gangliosides on the function of presynaptic Ca(v)2.1 channels, affecting the magnitude and kinetics of the Ca(2+) influx that induces neurotransmitter release from the motor nerve terminal. Our results show that gangliosides are to some extent involved in neurotransmission at the neuromuscular junction, but that their presence is not an absolute requirement in this process.

Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.

Gangliosides are a family of sialylated glycosphingolipids enriched in the outer leaflet of neuronal membranes, in particular at synapses. Therefore, they have been hypothesized to play a functional role in synaptic transmission. We have measured in detail the electrophysiological parameters of synaptic transmission at the neuromuscular junction (NMJ) ex vivo of a GD3-synthase knockout mouse, expressing only the O- and a-series gangliosides, as well as of a GM2/GD2-synthase*GD3-synthase double-knockout (dKO) mouse, lacking all gangliosides except GM3. No major synaptic deficits were found in either null-mutant. However, some extra degree of rundown of acetylcholine release at high intensity use was present at the dKO NMJ and a temperature-specific increase in acetylcholine release at 35 degrees C was observed in GD3-synthase knockout NMJs, compared with wild-type. These results indicate that synaptic transmission at the NMJ is not crucially dependent on the particular presence of most ganglioside family members and remains largely intact in the sole presence of GM3 ganglioside. Rather, presynaptic gangliosides appear to play a modulating role in temperature- and use-dependent fine-tuning of transmitter output.

Recent research into the Guillain-Barré syndromes (GBS) has focused on anti-ganglioside antibodies that correlate with specific clinical phenotypes. Our increasing understanding of the role of antibodies in mediating GBS has naturally focused our attention on complement involvement in the pathological procession. We have studied the axonal and glial components of the murine motor nerve terminal as a model site of antibody and complement mediated injury. Such studies are providing us with clear information on the molecular components underlying our clinicopathological model for GBS and have lead us to the testing of emerging complement therapeutics that are potentially suitable for human use.

Guillain-Barré syndrome and its clinical variants, including the anti-GQ1b ganglioside-mediated Miller Fisher syndrome (MFS), comprise the world's leading cause of acute neuromuscular paralysis. Presently, no specific drug therapies exist. The complement cascade, which is activated in these patients, forms an attractive drug target. In this study, we tested whether the complement C5-inhibiting recombinant protein, rEV576, was able to prevent neural injury in a previously developed in vitro mouse model for MFS. Mouse hemidiaphragm preparations were treated with anti-GQ1b antibody and normal human serum as a source of complement with added rEV576 or control protein. Immunohistology in control tissue showed deposition of C3c and membrane attack complex at neuromuscular junctions (NMJs), along with terminal motor axonal neurofilament degradation as well as ethidium homodimer-2 staining showing perisynaptic Schwann cell (pSC) injury. Electrophysiological and functional analyses showed block of synaptic transmission at the NMJ after an initial period of a dramatically high level of asynchronous acetylcholine release. In tissue treated with rEV576, all these indicators of motor neuronal damage were absent, except for the presence of C3c, indicating effective inhibition of C5. These results demonstrate that rEV576 effectively prevents development of neuronal and pSC damage in experimental murine neuropathy.

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain-Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.