Dental Procedures: Is it a Risk Factor for Injectable Dermal Fillers?

Dental procedures done in the vicinity of dermal fillers may result in complications of the dermal fillers such as infections which may mimic a dental infection. These infections of dermal fillers must be differentiated from facial cellulitis or from dental infection as treatment for infection from dermal fillers may be prolonged with repeated use of antibiotics, incision and drainage or removal of the filler material itself. Dental surgeons need to be aware of this potential risk in order to recognize and manage it appropriately.

Tissue expanders in reconstruction of maxillofacial defects.

Tissue expansion in its natural ways had fascinated man from prehistoric times itself. But tissue expansion for medical purposes was first tried and reported only in the early half of twentieth century. Presently the principle of tissue expansion is being used in reconstruction of many hard and soft tissue defects of larger dimension, which were previously regarded as great challenge for maxillofacial and plastic surgeons. Making use of the viscoelastic nature of the skin, considerable amount of tissue expansion based tissue engineering is possible in the maxillofacial region. Here we present a case of a facial scar of large dimension with a central oro cutaneous fistula developed as a result of facial artery blow out in a 24 year old female for which esthetic correction was done using the excess tissue obtained from tissue expansion. In this case where other methods of reconstruction such as local flaps, free flaps and normal tissue grafts were assessed to be non viable, tissue expansion was found to be an apt solution for esthetic reconstruction.

Palmitoylation of LIM Kinase-1 ensures spine-specific actin polymerization and morphological plasticity.

Precise regulation of the dendritic spine actin cytoskeleton is critical for neurodevelopment and neuronal plasticity, but how neurons spatially control actin dynamics is not well defined. Here, we identify direct palmitoylation of the actin regulator LIM kinase-1 (LIMK1) as a novel mechanism to control spine-specific actin dynamics. A conserved palmitoyl-motif is necessary and sufficient to target LIMK1 to spines and to anchor LIMK1 in spines. ShRNA knockdown/rescue experiments reveal that LIMK1 palmitoylation is essential for normal spine actin polymerization, for spine-specific structural plasticity and for long-term spine stability. Palmitoylation is critical for LIMK1 function because this modification not only controls LIMK1 targeting, but is also essential for LIMK1 activation by its membrane-localized upstream activator PAK. These novel roles for palmitoylation in the spatial control of actin dynamics and kinase signaling provide new insights into structural plasticity mechanisms and strengthen links between dendritic spine impairments and neuropathological conditions.

Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity.

Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na(+)](i)) also exerts a regulatory influence on NMDAR channel activity, and [Na(+)](i) may, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na(+)](i) in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na(+)] and [Ca(2+)]. Pharmacological evaluation showed that PbTx-2-induced Ca(2+) influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca(2+) influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na(+)](i), up-regulation of NMDAR function, and engagement of downstream Ca(2+)-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.

κ-Opioid receptor inhibition of calcium oscillations in spinal cord neurons.

Mouse embryonic spinal cord neurons in culture exhibit spontaneous calcium oscillations from day in vitro (DIV) 6 through DIV 10. Such spontaneous activity in developing spinal cord contributes to maturation of synapses and development of pattern-generating circuits. Here we demonstrate that these calcium oscillations are regulated by κ opioid receptors (KORs). The κ opioid agonist dynorphin (Dyn)-A (1-13) suppressed calcium oscillations in a concentration-dependent manner, and both the nonselective opioid antagonist naloxone and the κ-selective blocker norbinaltorphimine eliminated this effect. The KOR-selective agonist (+)-(5α,7α,8ß)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69593) mimicked the effect of Dyn-A (1-13) on calcium oscillations. A κ-specific peptide antagonist, zyklophin, was also able to prevent the suppression of calcium oscillations caused by Dyn-A (1-13). These spontaneous calcium oscillations were blocked by 1 µM tetrodotoxin, indicating that they are action potential-dependent. Although the L-type voltage-gated calcium channel blocker nifedipine did not suppress calcium oscillations, the N-type calcium channel blocker ω-conotoxin inhibited this spontaneous response. Blockers of ionotropic glutamate receptors, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline and dizocilpine maleate (MK-801), also suppressed calcium oscillations, revealing a dependence on glutamate-mediated signaling. Finally, we have demonstrated expression of KORs in glutamatergic spinal neurons and localization in a presynaptic compartment, consistent with previous reports of KOR-mediated inhibition of glutamate release. The KOR-mediated inhibition of spontaneous calcium oscillations may therefore be a consequence of presynaptic inhibition of glutamate release.

Lysophosphatidic Acid signals through specific lysophosphatidic Acid receptor subtypes to control key regenerative responses of human gingival and periodontal ligament fibroblasts.

BACKGROUND: We showed that the pluripotent platelet growth factor and mediator lysophosphatidic acid (LPA) controls key regenerative responses of human gingival fibroblasts (GFs) and periodontal ligament fibroblasts (PDLFs) and positively modulates their responses to platelet-derived growth factor (PDGF). This study determined which LPA receptor (LPAR) subtype(s) LPA signals through to stimulate mitogenic extracellular signal-regulated kinase (ERK) 1/2 signaling and chemotaxis and to elicit intracellular Ca(2+) increases in GFs and PDLFs because many healing responses are calcium-dependent. METHODS: Activation of mitogen-activated protein kinase was determined using Western blotting with an antibody to phosphorylated ERK1/2. Migration responses were measured using a microchemotaxis chamber. GF and PDLF intracellular Ca(2+) mobilization responses to multiple LPA species and LPAR subtype-specific agonists were measured by using a cell-permeable fluorescent Ca(2+) indicator dye. RESULTS: LPA stimulated ERK1/2 phosphorylation via LPA(1)(-3). For GFs, LPA(1) preferentially elicited chemotaxis, and LPA(1-3) for PDLFs, as confirmed using subtype-specific agonists. Elevation of intracellular calcium seems to be mediated through LPA(1) and LPA(3), with little, if any, contribution from LPA(2). CONCLUSIONS: To the best of our knowledge, this study provides the first evidence that LPA signals through specific LPAR subtypes to stimulate human oral fibroblast regenerative responses. These data, in conjunction with our previous findings showing that LPA modulates GF and PDLF responses to PDGF, suggest that LPA is a factor of emerging importance to oral wound healing.

Sodium channel activation augments NMDA receptor function and promotes neurite outgrowth in immature cerebrocortical neurons.

A range of extrinsic signals, including afferent activity, affect neuronal growth and plasticity. Neuronal activity regulates intracellular Ca(2+), and activity-dependent calcium signaling has been shown to regulate dendritic growth and branching (Konur and Ghosh, 2005). NMDA receptor (NMDAR) stimulation of Ca(2+)/calmodulin-dependent protein kinase signaling cascades has, moreover, been demonstrated to regulate neurite/axonal outgrowth (Wayman et al., 2004). We used a sodium channel activator, brevetoxin (PbTx-2), to explore the relationship between intracellular [Na(+)] and NMDAR-dependent development. PbTx-2 alone, at a concentration of 30 nM, did not affect Ca(2+) dynamics in 2 d in vitro cerebrocortical neurons; however, this treatment robustly potentiated NMDA-induced Ca(2+) influx. The 30 nM PbTx-2 treatment produced a maximum [Na(+)](i) of 16.9 +/- 1.5 mM, representing an increment of 8.8 +/- 1.8 mM over basal. The corresponding membrane potential change produced by 30 nM PbTx-2 was modest and, therefore, insufficient to relieve the voltage-dependent Mg(2+) block of NMDARs. To unambiguously demonstrate the enhancement of NMDA receptor function by PbTx-2, we recorded single-channel currents from cell-attached patches. PbTx-2 treatment was found to increase both the mean open time and open probability of NMDA receptors. These effects of PbTx-2 on NMDA receptor function were dependent on extracellular Na(+) and activation of Src kinase. The functional consequences of PbTx-2-induced enhancement of NMDAR function were evaluated in immature cerebrocortical neurons. PbTx-2 concentrations between 3 and 300 nM enhanced neurite outgrowth. Voltage-gated sodium channel activators may accordingly represent a novel pharmacologic strategy to regulate neuronal plasticity through an NMDA receptor and Src family kinase-dependent mechanism.

Influence of lipid-soluble gating modifier toxins on sodium influx in neocortical neurons.

The electrical signals of neurons are fundamentally dependent on voltage-gated sodium channels (VGSCs), which are responsible for the rising phase of the action potential. An array of naturally occurring and synthetic neurotoxins have been identified that modify the gating properties of VGSCs. Using murine neocortical neurons in primary culture, we have compared the ability of VGSC gating modifiers to evoke Na+ influx. Intracellular sodium concentration ([Na+](i)) was monitored using the Na+-sensitive fluorescent dye, sodium-binding benzofuran isophthalate. All sodium channel gating modifier compounds tested produced a rapid and concentration-dependent elevation in neuronal [Na+](i). The increment in [Na+](i) exceeded 40 mM at high concentrations of brevetoxins, batrachotoxin, and the novel lipopeptide, antillatoxin. The maximal increments in neuronal [Na+](i) produced by neurotoxin site 2 alkaloids, veratridine and aconitine, and the pyrethroid deltamethrin were somewhat lower with maximal [Na+](i) increments of less than 40 mM. The rank order of efficacy of sodium channel gating modifiers was brevetoxin (PbTx)-1 > PbTx-desoxydioxolane > batrachotoxin > antillatoxin > PbTx-2 = PbTx-3 > PbTx-3alpha-naphthoate > veratridine > deltamethrin > aconitine > gambierol. These data demonstrate that the ability of sodium channel gating modifiers to act as partial agonists is shared by compounds acting at both neurotoxin sites 2 and 5. The concentration-dependent increases in [Na+](i) produced by PbTx-2, antillatoxin, veratridine, deltamethrin, aconitine, and gambierol were all abrogated by tetrodotoxin, indicating that VGSCs represent the sole pathway of Na+ entry after exposure to gating modifier neurotoxins.

Brevetoxin-induced phosphorylation of Pyk2 and Src in murine neocortical neurons involves distinct signaling pathways.

Brevetoxins (PbTx-1 to PbTx-10) are potent lipid soluble polyether neurotoxins produced by the marine dinoflagellate Karenia brevis. Brevetoxins bind to site 5 of the alpha-subunit of voltage-gated sodium channels (VGSCs) and augment Na(+) influx. In neocortical neurons brevetoxins elevate intracellular Ca(2+) and augment NMDA receptor signaling. In this study, we explored the effects of PbTx-2 on Pyk2 and Src activation in neocortical neurons. We found that both Pyk2 and Src were activated following PbTx-2 exposure. PbTx-2-induced Pyk2 Tyr402 phosphorylation was dependent on elevation of Ca(2+) influx through NMDA receptors. Moreover, Pyk2 Tyr402 phosphorylation was also found to require PKC activation inasmuch as RO-31-8425 and GF 109203x both attenuated the response. In contrast, PbTx-2-induced Src Tyr416 phosphorylation involved a Gq-coupled receptor inasmuch as U73122, a specific PLC inhibitor, abolished the response. This Gq-coupled receptor appears to be mGluR 5. The PKCdelta inhibitor rottlerin abolished PbTx-2-induced Src activation demonstrating that this isoform of PKC is involved in the activation of Src by PbTx-2. Considered together these data suggest that although activation of neuronal Pyk2 and Src result from PbTx-2 stimulation of VGSC, engagement of these two non-receptor tyrosine kinases involves distinct signaling pathways.