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The purpose of the present study was to investigate the nervous control of gingival blood flow in cats. Gingival blood flow was measured by laser Doppler flowmeter in 75 cats during electrical stimulation and cutting or ligation of the inferior alveolar nerve and cervical sympathetic nerve without sympathectomy or pretreatment with adrenoceptor blocking agents. Three different patterns of responses in gingival blood flow were observed following electrical stimulation of the inferior alveolar nerve in cats. In 45 cats there was an increase in blood flow, in 4 cats a decrease in blood flow, and in 7 cats a biphasic change consisting of an initial decrease and a successive increase in blood flow. The vasodilator effect was significantly reduced by pretreatment with ( d -Pro 2 , d -Trp 7,9 )-substance P, tripelennamine, and methysergide. Pretreatment with cimetidine, atropine, hexamethonium, phentolamine, or propranolol had no effect on vasodilatation. The vasoconstrictor response was completely inhibited by pretreatment with phentolamine; in this case the vasodilator response appeared after stimulation of the inferior alveolar nerve. Ligation or cutting of the inferior alveolar nerve always elicited an increase in gingival blood flow. Cutting the cervical sympathetic nerve had no effect on gingival blood flow in 8 of 10 cats and caused an increase in gingival blood flow in 2 cats; however, electrical stimulation of the cervical sympathetic nerve always caused a decrease in gingival blood flow in the cats investigated. The present results suggest that cat gingival blood flow is controlled by sympathetic α-adrenergic fibers for vasoconstriction and by sensory fibers and mast cells for vasodilatation.

This study was designed to determine if sympathetic nerve fibers exist in dentinal tubules in rat normal dental pulp, and if they sprout into the dentinal tubules in response to artificial cavity preparation in dentin. Sympathetic nerve fibers in rat molar dental pulp were labeled using an anterograde axonal transport technique involving injection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into the superior cervical ganglion (SCG). They were then observed using light and electron microscopes. In normal dental pulp (control), scattered WGA-HRP reaction products were observed in unmyelinated nerve endings in the odontoblast layer and subodontoblastic region. In injured pulp 3 weeks after cavity preparation, reaction products were about 1.8-times more plentiful in the above areas (versus control pulp). However, no labeled nerve fibers were observed in the dentinal tubules in either control or injured dental pulp. These results indicate that although sympathetic nerve fibers do indeed sprout in rat dental pulp in response to cavity preparation, they do not penetrate into the dentinal tubules in which postganglionic nerve endings derived from the SCG were not originally present.

Background: The options for medical use of signaling molecules as stimulators of tissue regeneration are currently limited. Preclinical evidence suggests that fibroblast growth factor (FGF)-2 can promote periodontal regeneration. This study aimed to clarify the activity of FGF-2 in stimulating regeneration of periodontal tissue lost by periodontitis and to evaluate the safety of such stimulation. Methodology/Principal Findings: We used recombinant human FGF-2 with 3% hydroxypropylcellulose (HPC) as vehicle and conducted a randomized double-blinded controlled trial involving 13 facilities. Subjects comprised 74 patients displaying a 2- or 3-walled vertical bone defect as measured ?3 mm apical to the bone crest. Patients were randomly assigned to 4 groups: Group P, given HPC with no FGF-2; Group L, given HPC containing 0.03% FGF-2; Group M, given HPC cotaining 0.1% FGF-2; and Group H, given HPC Containing 0.3% FGF-2. Each patient underwent flap operation during which we administered 200 μL of the appropriate investigational drug to the bone defect. Before and for 36 weeks following administration, patients underwent periodontal tissue inspections and standardized radiography of the region under investigation. As a result, a significant difference (p = 0.021) in rate of increase in alveolar bone height was identified between Group P (23.92%) and Group H (58.62%) at 36 weeks. The linear increase in alveolar bone height at 36 weeks in Group P and H was 0.95 mm and 1.85 mm, respectively (p = 0.132). No serious adverse events attribute to the investigational drug were identified. Conclusions: Although no statistically significant differences were noted for gains in clinical attachment level and alveolar bone gain for FGF-2 groups versus Group P, the significant difference in rate of increase in alveolar bone height (p = 0.021) between Groups P and H at 36 weeks suggests that some efficacy could be expected from FGF-2 in stimulating regeneration of periodontal tissue in patients with periodontitis., PLoS ONE, 3(7), e2611; 2008

Background: Previous findings suggest that antigen challenge (AC) may induce histidine decarboxylase (HDC) in cells other than mast cells (MCs) via MC-derived IL-1. We examined this hypothesis. Methods: Mice were sensitized to ovalbumin. After the sensitization, an AC was delivered intravenously. Results: In control mice, AC markedly induced HDC at a postanaphylactic time in the liver, lung, spleen, and ears. In MC-deficient W/Wv mice, AC also induced HDC, although the effect was weaker than in control mice. AC increased IL-1 in the tissues, the pattern being similar in W/Wv and control mice. AC induced HDC similarly in IL-1-deficient and control mice. In control mice, AC decreased histamine in the tissues (except the liver) for several hours. Conclusion: (1) AC induces HDC in both MC-dependent and MC-independent ways. (2) AC induces IL-1 mostly in non-MCs, but this IL-1 is not a prerequisite for the induction of HDC by AC. (3) HDC induction may contribute to the replenishment of the reduced pool of MC histamine in the anaphylactic period. (4) In the case of MC-dependent HDC induction, AC may stimulate MCs in such a way as to induce HDC within the MCs themselves, and/or AC-stimulated MCs may stimulate HDC induction in other cells, which will need to be directly identified in future studies.

Among the bisphosphonates, the nitrogen-containing bisphosphonates have much stronger anti-bone-resorptive activities than bisphosphonates containing no nitrogen, but nitrogen-containing bisphosphonates mostly have inflammatory side effects. Our previous murine-model experiments with a single intraperitoneal bisphosphonate injection demonstrated that (i) nitrogen-containing bisphosphonates induce various inflammatory reactions via an IL-1-dependent mechanism, (ii) alendronate (an nitrogen-containing bisphosphonate) produces a clear sclerotic line in the tibia that is easily detectable by radiography a few weeks later (tentatively called the bisphosphonate line, a useful marker for the anti-bone-resorptive activities of bisphosphonates), and (iii) clodronate (a non-nitrogen-containing bisphosphonate) reduces the inflammatory reactions induced by alendronate but does not reduce the bisphosphonate line formation induced by alendronate. We compared the effects of clodronate, aspirin and dexamethasone on the inflammatory reactions induced by alendronate (40 micromol/kg) (induction of the histamine-forming enzyme, accumulation of pleural exudate and splenomegaly) and on the bisphosphonate line formation induced by alendronate (0.1 micromol/kg). The effects of aspirin (833 micromol/kg) were weak. However, like clodronate, dexamethasone (10 micromol/kg, injected 5 min. after alendronate), strongly inhibited the alendronate-induced inflammatory reactions but did not reduce the alendronate-induced bisphosphonate line formation. Alendronate produced normal bisphosphonate lines in IL-1-deficient mice, too. These results suggest that clodronate and/or dexamethasone may be suitable for preventing or reducing the inflammatory side effects of nitrogen-containing bisphosphonates while preserving their powerful anti-bone-resorptive activities (although in practice the known side effects of dexamethasone may limit its use), and that the anti-bone resorptive activities of nitrogen-containing bisphosphonates are not influenced by IL-1.

Nitrogen-containing bisphosphonates (N-BPs), powerful anti-bone-resorptive drugs, have inflammatory side effects, while histamine is not only an inflammatory mediator, but also an immuno-modifier. In murine models, a single intraperitoneal injection of an N-BP induces various inflammatory reactions, including the induction of the histamine-forming enzyme histidine decarboxylase (HDC) in tissues important in immune responses (such as liver, lungs, spleen, and bone marrow). Lipopolysaccharide (LPS) and the proinflammatory cytokines IL-1 and TNF are also capable of inducing HDC. We reported previously that in mice, (i) the inflammatory actions of N-BPs depend on IL-1, (ii) N-BP pretreatment augments both LPS-stimulated IL-1 production and HDC induction, and (iii) the co-administration of clodronate (a non-N-BP) with an N-BP inhibits the latter's inflammatory actions (including HDC induction). Here, we add the new findings that (a) pretreatment with alendronate (a typical N-BP) augments both IL-1- and TNF-induced HDC elevations, (b) LPS pretreatment augments the alendronate-induced HDC elevation, (c) co-administration of clodronate with alendronate abolishes these augmentations, (d) alendronate does not induce HDC in IL-1-deficient mice even if they are pretreated with LPS, and (e) alendronate increases IL-1beta in all tissues tested, but not in the serum. These results suggest that (1) there are mutual augmentations between alendronate and immuno-stimulants (IL-1, TNF, and LPS) in HDC induction, (2) tissue IL-1beta is important in alendronate-stimulated HDC induction, and (3) combination use of clodronate may have the potential to reduce the inflammatory effects of alendronate (we previously found that clodronate, conveniently, does not inhibit the anti-bone-resorptive activity of alendronate).

Introduction: We have successfully treated skeletal open bite by intruding posterior teeth with the skeletal anchorage system. Our aim in this study was to morphologically and hemodynamically evaluate the changes in pulp tissues when molars are radically intruded. Methods: The mandibular fourth premolars of 9 adult beagle dogs were divided into 3 groups: a sham operated group (n = 6, 3 dogs), 4-month intrusion group (n = 6, 3 dogs), and a further 4-month retention group (n = 6, 3 dogs). We evaluated the morphological changes of the pulp and dentin—the amount of vacuolar degeneration in the odontoblast layer, the predentin width and nervous continuity in the pulp tissue, and the pulpal blood-flow response evoked by electrical stimulation in the dental pulp. Results: Extreme molar intrusion with the skeletal anchorage system caused slight degenerative changes in the pulp tissue, followed by recovery after the orthodontic force was released. Circulatory system and nervous functions were basically maintained during the intrusion, although a certain level of downregulation was observed. These morphologic and functional regressive changes in the pulp tissue after molar intrusion improved during the retention period. Conclusions: Histologic changes and changes in pulpal blood flow and function are reversible, even during radical intrusion of molars.

The purpose of this study was to investigate the effect of an increase in laser power on the transmitted laser signals from vital and non-vital teeth, in the hope of achieving a better assessment of human pulp vitality with the transmitted laser-light flowmeter. The experiments were carried out on total of 61 vital teeth with no restoration (19 upper central incisors, 16 upper lateral incisors, 16 upper canines, and 10 first premolars) and five non-vital upper central incisors (the root canals of which were filled with gutta-percha) in 15 subjects aged 22-28 years. For use with transmitted laser light, the fibers within the probe of a conventional laser Doppler flowmeter (LDF) apparatus were used, one for transmitting light onto the labial surface, the other for receiving it at the palatal surface of the same tooth, as reported previously. Laser output power was set at the original 2 mW and also at 5, 7, and 10 mW. The number of vital teeth displaying a blood flow (BF) signal at each laser power setting was: 1) 12/19 central incisors at 2 mW, 19/19 at 5, 7, and 10 mW, 2) 19/19 lateral incisors at 2, 5, 7, and 10 mW, 3) 0/16 canines at 2 mW, but eight, 12, and 14 at 5, 7, and 10 mW, 4) 0/10 first premolars at 2, 5, 7, and 10 mW. Thus, an increase in laser power increased BF detection from the thicker teeth (but not from premolars). In addition, clearer BF signals synchronized with heart rate, and greater passive BF changes secondary to blood pressure (BP) changes were observed at higher laser settings. In non-vital teeth, no signals synchronized with heart rate or BP changes were observed, indicating that no BF signal of non-pulpal origin was ever monitored with this ballistic light even when the laser power was increased. These results indicate that high-powered transmitted laser light could be a useful tool both for monitoring pulpal BF and for the assessment of tooth-pulp vitality.

To help us investigate the time course of mandibular enlargement in acromegaly or acrogiantism to determine the most suitable period for occlusal treatment in this disease, our aim was to develop a rat model of acromegaly (acrogiantism). In this study, prominent mandibular enlargement was induced by continuous subcutaneous infusion of human recombinant insulin-like growth factor-I (IGF-I) (640 microg/day) in 10-week-old male rats for 4 weeks (n = 6); the control sham-operated group was injected with saline alone (n = 6). Circulating human IGF-I was clearly detectable in the IGF-I group during the four-week administration period, while endogenous rat IGF-I levels decreased. Total IGF-I (human + rat) increased significantly during administration, returning to control levels afterwards. The length of every bone examined (mandible, maxilla, and femur) showed a significant increase compared to control rats, especially the mandible. Although the mandible did not continue to grow after discontinuation of IGF-I administration, it did not return to control size, unlike the maxilla and femur, and disharmonious jaw size (between maxilla and mandible) persisted even after circulating IGF-I levels normalized. These findings in our rat model suggest that mandibular occlusal treatment should only be considered for acromegalic (acrogiantic) patients after serum IGF-I levels have normalized and bone growth has ceased.

As a new nonsurgical treatment for odontogenic maxillary sinusitis (OMS), irrigation of the maxillary sinus through the root canal of the causal tooth was carried out to the patient with OMS that had proved refractory to conservative treatments (i.e., root-canal treatment of the causal tooth and antibiotic therapy). Clinical signs, symptoms, and radiographs before and after the new treatment revealed evidence of good healing. The clinical signs and symptoms, such as oppressive pain in the cheek and retrorhinorrhoea, entirely disappeared immediately after the irrigation (which was done only once) without pain, and the obstructed ostiomeatal unit was aerated on the follow-up CT images. There was no side effect associated with saline irrigation, nor any recurrence of symptoms since the irrigation. We therefore propose the irrigation through the root canal of the causal tooth as a new treatment for periapical disease-induced maxillary sinusitis, a technique that should ensure proper ventilation and drainage by relieving obstruction of the ostiomeatal unit.

It has been shown earlier that electrical stimulation of the distal cut end of the inferior alveolar nerve (IAN) in the cat evokes three different patterns of pulpal blood-flow (PBF) response in the ipsilateral mandibular canine tooth (a decrease, a biphasic response, or an increase). The response to a given stimulus sometimes changed to another pattern even in one and the same experimental animal during the course of the experiment. It is known that the evoked decrease is due to activation of the sympathetics and that the increase is due to antidromic activation of sensory fibres; but, it is unknown why the response varies so much. It is hypothesised that the baseline blood-flow (BBF) modulates vasomotor responses in the dental pulp. To test this hypothesis, the effects of BBF on PBF responses elicited by the IAN stimulation mentioned above were investigated. Dynamic changes in PBF in cat mandibular canine teeth were elicited by electrical stimulation of the distal cut end of the IAN, at various BBF, with blood-flow monitored by laser Doppler flowmetry. The amplitude of the PBF vasodilator response increased as BBF was adjusted downwards (by cooling the tooth). In contrast, the amplitude of the PBF vasoconstrictor response increased as the BBF rose. Vasodilator responses could be transformed into vasoconstrictor responses, and vice versa, by alterations in the BBF. No systemic blood-pressure changes were elicited throughout the experiment. These results indicate that a consideration of baseline vascular tone is important, whenever the size of PBF responses to various stimuli is discussed or calculated.

Using laser-Doppler flowmetry we investigated whether reflex vasodilator responses would be evoked by the painful stimulation of the trigeminal region in human gingiva. GBF increases were elicited by the painful electrical stimulation to the tooth-pulp or gingiva, in addition to application by capsaicin onto the tongue, without an increase in systemic blood pressure. Thus, the pain of various oral tissues would cause the reflex vasodilatation in human gingiva.

Sympathetic regulation of periodontal ligament blood flow (PLBF) is well-attested; however, vasodilator responses mediated by parasympathetic nerve fibers have yet to be conclusively demonstrated in the periodontal ligament (PL). The present study was designed to determine whether parasympathetic vasodilator mechanisms do or do not exist in the cat PL. In our cats, the cervical sympathetic trunks were sectioned bilaterally prior to any stimulation in order to eliminate sympathetic effects on the vascular beds under study. Dynamic changes in PLBF, with mandibular lip blood flow (LBF) recorded for comparison, were investigated in cat mandibular canine teeth using laser Doppler flowmetry. The peripheral cut ends of the facial and glossopharyngeal nerve roots, which have been reported to contain parasympathetic nerve fibers to the oral tissues, were electrically stimulated intracranially. Such stimulation caused blood flow to increase in the ipsilateral PL and lip, without an increase in systemic blood pressure. These vasodilator responses in the PL and lip were sensitive to ganglion blockade (with hexamethonium), indicating vasodilation via activation of parasympathetic vasodilator fibers. In contrast, although intracranial stimulation of the trigeminal nerve root also induced increases in both PLBF and LBF, these were unaffected by hexamethonium, but reduced by tripelennamine, indicating antidromic vasodilatation via the trigeminal sensory nerve. These results suggest that parasympathetic vasodilator mechanisms do exist in feline PL.

The existence and nature of parasympathetic nerve fibers in the dental pulp have long been a subject for discussion; indeed, vasodilator responses mediated by such nerve fibers have yet to be conclusively demonstrated in the dental pulp. This study was designed to determine whether parasympathetic vasodilator mechanisms do or do not exist in the cat dental pulp. Dynamic changes in pulpal blood flow (PBF), with mandibular lip blood flow (LBF) recorded as a control, were investigated in cat mandibular canine teeth by means of laser Doppler velocimetry. Peripheral trigeminal afferents (see below) were stimulated electrically to confirm that somato-parasympathetic reflex vasodilatation could be induced. The peripheral cut ends of the facial and glossopharyngeal nerve roots, which have been reported to contain parasympathetic nerve fibers to the oral tissues, were then stimulated intracranially. Electrical stimulation of trigeminal afferents (in the infra-orbital nerve or the maxillary buccal gingiva) caused no change in PBF but did increase ipsilateral LBF. Neither facial nor glossopharyngeal nerve root stimulation caused a PBF increase, though both elicited increases in ipsilateral LBF. The vasodilator responses in the lip were sensitive to ganglion blockade (with hexamethonium), indicating vasodilatation via activation of parasympathetic vasodilator fibers. In contrast, intracranial stimulation of the trigeminal nerve root induced increases in both PBF and LBF which were reduced by pre-treatment with tripelennamine, indicating antidromic vasodilatation via the trigeminal sensory nerve. These results suggest that a parasympathetic vasodilator mechanism is not present in feline dental pulp.

We recently reported that anti-IL-15 neutralizing mAb has been shown to inhibit production of MCP-1 in response to IL-2 from normal human gingival fibroblasts (HGF), the major constituent of gingival tissue. In the present study, we examined the expression of IL-2R and IL-15R subunits in HGF from normal and inflamed regions and the role of endogenous IL-15 in IL-2-mediated signaling. Normal HGF expressed IL-2Rβ and common γ-chain (γ c ) but not IL-2Rα or IL-15Rα, whereas inflamed HGF expressed IL-2Rα, IL-15Rα, IL-2Rβ, and γ c , as assessed by RT-PCR and flow cytometry. Exogenous IL-2 and IL-15 induced production of MCP-1 but not IL-8 in normal HGF, and induced the production of both chemokines in inflamed HGF. Both HGF constitutively transcribed the 48 aa-IL-15 isoform, and the isoform was not actively secreted but rather existed as a membrane-bound form. Pretreatment with anti-IL-15 neutralizing mAb for 24 h completely inhibited the production of MCP-1 induced by IL-2 and IL-15 and IL-2-induced phosphorylation of Jak 1 and 3 in HGF. The pretreatment and RNA interference targeted to IL-15 mRNA resulted in total inhibition of the IL-2Rβ and γ c expression at mRNA and protein levels. Furthermore, excess amounts of IL-2 restored the inhibitory effect of anti-IL-15, inhibition of NF-κB abrogated the expression of IL-2Rβ and γ c , and IL-2-induced-nuclear translocation of NF-κB was completely inhibited by the RNA interference in HGF. These results suggest that endogenous membrane-bound IL-15 sustains recruitment of IL-2Rβ and γ c through activation of NF-κB in HGF.

A transistor pH electrode (pH-ISFET electrode) was placed in each of four human mouths and bacteria were allowed to accumulate on it for 1, 2 or 3 days. Changes of plaque pH were measured in situ after application of sucrose solution (0.1, 1 or 3%) and, then, quick pH recovery by mouth-rinses with water was estimated. Although the acidic pH after application of 0.1% sucrose was easily and quickly recovered from by a few mouth-rinses with water, rather frequent mouth-rinses with water were required to recover from the acidic pH of 2- or 3-day-old plaque after the application of a 1 or 3% sucrose solution. For example, 15 (mean, n = 4) mouth-rinses with water were required for the 3 day-old plaque pH to recover after the application of 3% sucrose solution.

Dynamic changes of pulpal blood flow (PBF) and gingival blood flow (GBF) induced by intra-venous injection of two kinds of vasoactive drugs were observed in dogs by means of Laser Doppler Velocimetry. Intra-venous injection of norepinephrine caused PBF to increase, corresponding to the blood pressure (BP) increase, while GBF decreased. Orciprenaline sulfate caused PBF to decrease parallel to the BP decrease, as compared with a GBF increase. The effects of these vasoactive drugs lasted longer on GBF than on PBF and BP. These results indicate that the regulation of blood flow in the dental pulp is more dependent on systemic blood pressure than on local vasoconstriction or vasodilation.

To ascertain whether steroid therapy evokes dentin hypersensitivity (DH)-like tooth pain, we performed a study based on compelling evidence from patients receiving steroid therapy. An exploratory study was conducted using a questionnaire for 220 patients prescribed steroids who attended the Department of Hematology and Rheumatology of Tohoku University Hospital. Group comparisons between patients with and without steroid pulse therapy were analysed by statistical means. In this study, any DH-like tooth pain that commenced subsequent to steroid treatment was defined as steroid-derived (SD) tooth pain. The prevalence of SD tooth pain was 17.7% (39/220 patients). SD tooth pain was triggered in many vital teeth by cold and/or hot water (84.2% and 23.7%, respectively) with the pain characterised as continuous, in contrast to typical DH tooth pain. SD tooth pain was significantly more frequent in pulse therapy patients than in non-pulse therapy patients (p

Oral epithelium might be the first barrier against oral bacteria in periodontal tissue. We hypothesized that oral epithelium is endowed with innate immune receptors for bacterial components, which play roles in host defense against bacterial infection without being accompanied by excessive inflammatory responses. We found clear expression of Toll-like receptor (TLR)4 as well as TLR2, and strong expression of NOD1 and NOD2 in normal oral epithelial tissues by immunohistochemical analysis. We also showed that primary oral epithelial cells in culture expressed these molecules using PCR, flow cytometry, and immunostaining. In inflamed oral epithelium, cell-surface localizations of TLR2 and TLR4 were more clearly observed than in healthy tissue. Upon stimulation with synthetic ligands for these receptors, the expression of β-defensin 2 was markedly up-regulated. These findings indicate that these molecules in oral epithelial cells are functional receptors that induce antibacterial responses.

There is a close relationship between an individual’s perception of umami taste and that individual’s physical condition. Our newly developed umami taste sensitivity test revealed the loss of only the umami taste sensation with preservation of the other four basic taste sensations (sweet, salty, sour, and bitter) in some elderly patients. All such patients complained of appetite and weight loss, resulting in poor overall health. We also found that treatment of hyposalivation diminishes hypogeusia, indicating that salivation is essential to the maintenance of normal taste function. Based on these findings, we consider that improvement in salivary flow may serve as a treatment for patients with taste disorders. Umami taste stimulation increases the salivary flow rate because of the gustatory–salivary reflex. We used Japanese Kobucha (kelp tea: tea made of powdered tangle seaweed) to stimulate umami taste and promote reflexive salivation. Improvements were noted in salivation, taste function, appetite, weight, and overall health. Maintenance of umami taste function contributes not only to the preservation of good oral health but also to the general overall health in elderly people.