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Chemotherapy-induced taste and smell alterations in cancer patients are associated with multiple adverse effects, namely, malnutrition, weight loss, and a diminished quality of life. The aim of this prospective study was to identify the incidence of taste alterations following epirubicin and cyclophosphamide (EC) chemotherapy in patients with breast cancer without previous history of cancer or chemotherapy. Forty-one patients undergoing EC chemotherapy for breast cancer at Tokai University Hospital were included. A subjective (questionnaire) and an objective (filter paper disk method) assessment for 5 basic tastes were administered on day 4 post-chemotherapy and immediately before the subsequent cycle of chemotherapy for each cycle, in addition to an olfactory evaluation and oral examination. The correlation between subjective and objective taste alterations and factors influencing these alterations were analyzed by statistical means. The mean incidence of subjective taste alteration on the 4th day after chemotherapy was 53%. In each of the 4 cycles, taste alterations decreased to about 9.0% immediately before the next cycle. A significant correlation between subjective and objective assessments was seen only for salty taste, suggesting important differences in subjective versus objective assessment outcomes. A multivariate analysis indicated that age and body surface area influenced taste alterations. EC chemotherapy induced taste alterations in more than 50% of patients, which decreased to less than 10% immediately before the next chemotherapy cycle. A combination of objective and subjective assessments is essential to evaluate taste alterations induced by EC chemotherapy. These could be used in routine clinical practice.

Objective We analysed the correlation between magnetic resonance images of the parotid and submandibular glands and the salivary flow rate in patients with Sjogren's syndrome. Methods We retrospectively reviewed magnetic resonance images (heterogeneous signal-intensity distribution and gland volume on T1- and fat-suppressed T2-weighted images, and multiple high-signal-intensity spots on magnetic resonance sialograms in the parotid and submandibular glands) obtained from 66 patients who were diagnosed with Sjogren's syndrome. We evaluated the relationship between these imaging features and their salivary flow rates in stimulated and unstimulated conditions. Results We found that as the disease progressed, both the heterogeneous signal-intensity distribution and the volumes of the parotid and the submandibular glands were significantly related to the stimulated and the unstimulated salivary flow rate. These imaging features were more highly correlated in assessments of the submandibular gland than in those of the parotid gland for both stimulated and unstimulated salivary flow rates. Conclusions Magnetic resonance image features of heterogeneity and smaller volume in the submandibular gland are reliable for predicting hyposalivation related to the progression of Sjogren's syndrome.

Type-2 bitter-taste receptors (TAS2Rs) are important for the evaluation of food quality and the nutritional control in animals. Mutations in some TAS2Rs including TAS2R38 are known to increase susceptibility to various diseases. However, the involvement of TAS2Rs in cancers has not been well understood. We conducted a pilot study by genotyping two TAS2R genes, TAS2R38 and TAS2R46, in Japanese cancer patients diagnosed with the following types of cancer: biliary tract cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer and gastric cancer. We selected the two TAS2Rs because they carry virtually non-functional alleles in human populations. We found that cancer risk is not associated with any TAS2R46 genotypes since there were no significant differences in genotype frequencies between cancer patients and controls. On the other hand, we confirmed that phenylthiocarbamide (PTC) non-tasters homozygous (AVI/AVI) for TAS2R38 were more frequent among Japanese cancer patients than those among controls as suggested in a previous study. The AVI/AVI genotype was therefore considered to increases cancer risk. In contrast, we also found that homozygous (PAV/PAV) PTC tasters are less frequent among cancer patients, suggesting that the PAV/PAV is a cancer resistant genotype that decreases cancer risk. Genotype frequencies for heterozygous AVI/PAV genotype were not significantly different between the two groups. It is suggested that the risk and resistance of cancers is antagonistically controlled by the two TAS2R38 alleles, PAV and AVI, rather than by the AVI allele alone.

Dendritic cells (DCs) in lymphoid and non-lymphoid tissues are professional antigen-presenting cells that are essential for effective immunity and tolerance. However, the presence and characteristics of DCs in steady-state salivary glands (SGs) currently remain unknown. We herein identified CD64- CD11c+ classical DCs (cDCs) as well as CD64+ macrophages among CD45+ MHC class II+ antigen-presenting cells in steady-state murine SGs. SG cDCs were divided into CD103+ CD11b- and CD103- CD11b+ cDCs. CD103+ CD11b- cDCs expressed XCR1, CLEC9A, and interferon regulatory factor 8, whereas CD103- CD11b+ cDCs strongly expressed CD172a. Both cDC subsets in SGs markedly expanded in response to the Flt3 ligand (Flt3L), were replenished by bone marrow-derived precursors, and differentiated from common DC precursors, but not monocytes. Furthermore, ovalbumin-pulsed SG CD103+ CD11b- cDCs induced the proliferation of naive ovalbumin-specific CD8+ T cells and production of interferon-γ from proliferating T cells. SG CD103+ CD11b- cDCs expanded by Flt3L in vivo exhibited the same properties. These results indicate that bona fide cDCs reside in steady-state murine SGs and cDCs with the CD103+ CD11b- phenotype possess antigen cross-presenting capacity. Moreover, Flt3L enhances protective immunity by expanding cDCs. Taken together, SG cDCs might play an important role in maintaining immune homeostasis in the tissues.

Loss of umami taste sensation affects quality of life and causes weight loss and health problems, particularly in the elderly. We recently expanded the use of the filter paper disc method to include assessment of umami taste sensitivity, using monosodium glutamate as the test solution. This test showed high diagnostic performance for discriminating between normal taste function and disorders in sensation of the umami taste, according to established cut-off values. The test also revealed: (1) some elderly patients suffered from specific loss of umami taste sensation with preservation of the other four taste sensations (sweet, salty, sour, and bitter); (2) umami taste disorder caused a loss of appetite and decline in weight, resulting in poor health; (3) appetite, weight and overall health improved after appropriate treatment for umami taste disorder. Because of the subjective nature of the test, however, it may not be useful for patients who cannot express which taste sensation is induced by a tastant, such as those with dementia. Most recently, using tissue samples collected from the tongue by scraping the foliate papillae, we showed that evaluation of umami taste receptor gene expression may be clinically useful for the objective genetic diagnosis of umami taste disorders.

The jugular ganglion (JG) contains sensory neurons of the vagus nerve which innervate somatic and visceral structures in cranial and cervical regions. In this study, the number of sensory neurons in the human JG was investigated. And, the morphology of sensory neurons in the human JG and nodose ganglion (NG) was compared. The estimated number of JG neurons was 2721.8–9301.1 (average number of sensory neurons ± S.D. = 7975.1 ± 3312.8). There was no significant difference in sizes of the neuronal cell body and nucleus within the JG (cell body, 1128.8 ± 99.7 μ m2; nucleus, 127.7 ± 20.8 μ m2) and NG (cell body, 963.8 ± 225.7 μ m2; nucleus, 123.2 ± 32.3 μ m2). These findings indicate that most of sensory neurons show the similar morphology in the JG and NG. Our immunohistochemical method also demonstrated the distribution of ion channels, neurotransmitter agents and calcium-binding proteins in the human JG. Numerous JG neurons were immunoreactive for transient receptor potential cation channel subfamily V member 1 (TRPV1, mean ± SD = 19.9 ± 11.5 %) and calcitonin gene-related peptide (CGRP, 28.4 ± 6.7 %). A moderate number of JG neurons contained TRPV2 (12.0 ± 4.7 %), substance P (SP, 15.7 ± 6.9 %) and secreted protein, acidic and rich in cysteine-like 1 (SPARCL1, 14.6 ± 7.4 %). A few JG neurons had vesicular glutamate transporter 2 (VGLUT2, 5.6 ± 2.9 %) and parvalbumin (PV, 2.3 ± 1.4 %). SP- and TRPV2-containing JG neurons had mainly small and medium-sized cell bodies, respectively. TRPV1- and VGLUT2- containing JG neurons were small to medium-sized. CGRP- and SPARCL1-containing JG neurons were of various cell body sizes. Sensory neurons in the human JG were mostly free of vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH) and neuropeptide Y (NPY). In the external auditory canal skin, subepithelial nerve fibers contained TRPV1, TRPV2, SP, CGRP and VGLUT2. Perivascular nerve fibers also had TRPV1, TRPV2, SP, CGRP, VIP, NPY and TH. However, PV- and SPARCL1-containing nerve endings could not be seen in the external auditory canal. It is likely that sensory neurons in the human JG can transduce nociceptive and mechanoreceptive information from the external auditory canal. Theses neurons may be also associated with neurogenic inflammation in the external auditory canal and ear-cough reflex through the vagus nerve.

Oral cancer and smoking are closely related, because the oral cavity, which is the route of ingestion of tobacco smoke, is in direct contact with the oral mucosa. Nicotine, one of the components of tobacco, can diffuse rapidly to the central nervous system and is responsible for tobacco addiction. Nicotine is present in high concentrations in the bloodstream of smokers; while the addictive effects of this alkaloid have extensively been studied, its effect on tumorigenesis is not clear yet. Therefore, in this study, we examined the effect of nicotine on cell proliferation and the signaling pathways it activates. The human oral squamous cell carcinoma cell line HSC-2 was used as a model system. We demonstrated the correlation between nicotine and epidermal growth factor receptor (EGFR) signaling. Nicotine treatment induced HSC-2 cell proliferation and migration and the phosphorylation of EGFR. Furthermore, nicotine treatment activated the EGFR downstream effectors phosphatidylinositol-3 kinase/AKT and p44/42 mitogen-activated protein kinases (ERK), which, in turn, promoted cell proliferation. Overall, our study suggests that nicotine promotes cell growth and migration through epidermal growth factor (EGF) signaling and plays an important role in oral cancer progression.

We investigated the efficacy, safety, and clinical significance of trafermin, a recombinant human fibroblast growth factor (rhFGF)-2, for periodontal regeneration in intrabony defects in Phase III trials. Study A, a multicenter, randomized, double-blind, placebo-controlled study, was conducted at 24 centers. Patients with periodontitis with 4-mm and 3-mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 328 patients were randomly assigned (2:1) to receive 0.3% rhFGF-2 or placebo, and 323 patients received the assigned investigational drug during flap surgery. One of the co-primary endpoints, the percentage of bone fill at 36 weeks after drug administration, was significantly greater in the rhFGF-2 group at 37.131% (95% confidence interval [CI], 32.7502 to 41.5123; n = 208) than it was in the placebo group at 21.579% (95% CI, 16.3571 to 26.8011; n = 100; p < 0.001). The other endpoint, the clinical attachment level regained at 36 weeks, was not significantly different between groups. Study B, a multicenter, randomized, blinded (patients and evaluators of radiographs), and active-controlled study was conducted at 15 centers to clarify the clinical significance of rhFGF-2. Patients with 6-mm and 4-mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 274 patients were randomly assigned (5:5:2) to receive rhFGF-2, enamel matrix derivative (EMD), or flap surgery alone. A total of 267 patients received the assigned treatment during flap surgery. The primary endpoint, the linear alveolar bone growth at 36 weeks, was 1.927 mm (95% CI, 1.6615 to 2.1920; n = 108) in the rhFGF-2 group and 1.359 mm (95% CI, 1.0683 to 1.6495; n = 109) in the EMD group, showing non-inferiority (a prespecified margin of 0.3 mm) and superiority of rhFGF-2 to EMD. Safety problems were not identified in either study. Therefore, trafermin is an effective and safe treatment for periodontal regeneration in intrabony defect, and its efficacy was superior in rhFGF-2 compared to EMD treatments.

The effects and mechanisms of tastes on labial minor salivary gland (LMSG) secretion were investigated in 59 healthy individuals. Stimulation with each of the five basic tastes (i.e., sweet, salty, sour, bitter, and umami) onto the tongue induced LMSG secretion in a dose-dependent manner. Umami and sour tastes evoked greater secretion than did the other tastes. A synergistic effect of umami on LMSG secretion was recognized: a much greater increase in secretion was observed by a mixed solution of monosodium glutamate and inosine 5′-monophosphate than by each separate stimulation. Blood flow (BF) in the nearby labial mucosa also increased following stimulation by each taste except bitter. The BF change and LMSG secretion in each participant showed a significant positive correlation with all tastes, including bitter. Administration of cevimeline hydrochloride hydrate to the labial mucosa evoked a significant increase in both LMSG secretion and BF, while adrenaline, atropine, and pirenzepine decreased LMSG secretion and BF. The change in LMSG secretion and BF induced by each autonomic agent was significantly correlated in each participant. These results indicate that basic tastes can induce the gustatory-salivary reflex in human LMSGs and that parasympathetic regulation is involved in this mechanism.

Objectives The aim of this study was to compare cone-beam computed tomography (CBCT) with intraoral radiography (parallel and bisecting techniques) for their detection capabilities of various horizontal angle root fractures in human teeth.

Taste perception is influenced by several factors. However, the relation between taste perception and food culture is unclear. This study compared taste thresholds between populations with different food culture, i.e. Thai and Japanese. A matched case-control study was conducted in 168 adults (84 for each; aged between 50 and 90 years). The age, sex, systemic disease, medication, smoking, xerostomia, and oral hygiene of both groups were not different. Recognition thresholds (RTs) of sweet, salty, sour, bitter, and umami were measured using filter paper disc (FPD). Detection taste thresholds were measured using electrogustometry. Spicy preference was measured by calibrated questionnaires. Higher RTs of all tastes and higher detection taste thresholds were found in Thai as compared to those of Japanese (P < 0.0001). Separate analyses of healthy and unhealthy persons confirmed the significant differences between 2 countries. The average thresholds for sweet, salty, sour, and bitter in Thai and Japanese were 4 and 2, respectively. The average threshold for umami in Thai and Japanese was 5 and 3, respectively. Moreover, Thai population had stronger preference for spicy food (P < 0.0001) with 70% mild- or moderate and 10% strong lovers, compared to over 90% non- or mild-spicy lovers in Japanese. In addition, 70% of Thai consumed spicy food weekly, whilst 80% of Japanese consumed it monthly. Our findings suggested that population with stronger spicy preference such as Thai had much poorer taste sensitivity and perception than that with milder preference like Japanese. Extensive international survey is needed to conclude the influence of food culture on taste perception.

The enjoyment of tastes should be one of the greatest pleasures in life. Without the sense of taste, one cannot enjoy one's food. The result would then be poor appetite, eating less and weight loss. As the elderly population in Japan increases, the number of patients suffering from taste disorder has also increased. While changes in the ability to distinguish tastes are partly associated with advancing age, they occur moreover in response to secondary influences, such as the side effects of drugs, or the effects of some diseases including periodontal disease/oral infections, nervous disorders, nutritional impairment, and endocrine disorders. Some drugs affect sensitivity to taste by directly stimulating the taste receptors, not only altering the normal transmission process and cellular functions, but also altering the salivary flow. The reduction of salivary flow strongly correlates with a decline in taste perception. In cases of taste disorder, early detection and treatment are important because the appreciation of taste is vital for overall health and long life.

Type-2 bitter-taste receptors (TAS2Rs) are important for the evaluation of food quality and the nutritional control in animals. Mutations in some TAS2Rs including TAS2R38 are known to increase susceptibility to various diseases. However, the involvement of TAS2Rs in cancers has not been well understood. We conducted a pilot study by genotyping two TAS2R genes, TAS2R38 and TAS2R46, in Japanese cancer patients diagnosed with the following types of cancer: biliary tract cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer and gastric cancer. We selected the two TAS2Rs because they carry virtually non-functional alleles in human populations. We found that cancer risk is not associated with any TAS2R46 genotypes since there were no significant differences in genotype frequencies between cancer patients and controls. On the other hand, we confirmed that phenylthiocarbamide (PTC) non-tasters homozygous (AVI/AVI) for TAS2R38 were more frequent among Japanese cancer patients than those among controls as suggested in a previous study. The AVI/AVI genotype was therefore considered to increases cancer risk. In contrast, we also found that homozygous (PAV/PAV) PTC tasters are less frequent among cancer patients, suggesting that the PAV/PAV is a cancer resistant genotype that decreases cancer risk. Genotype frequencies for heterozygous AVI/PAV genotype were not significantly different between the two groups. It is suggested that the risk and resistance of cancers is antagonistically controlled by the two TAS2R38 alleles, PAV and AVI, rather than by the AVI allele alone.

The purpose of this study was to clarify the diagnostic value of capsule-like rim enhancement (CLRE) on magnetic resonance imaging (MRI) for distinguishing malignant from benign tumours of the parotid gland. We retrospectively evaluated contrast-enhanced T1-weighted images of 100 patients with malignant and benign parotid tumours for the presence, completeness, and irregularity of CLRE and its maximum thickness. We investigated any correlation of imaging and histopathological findings for 51 cases showing CLRE with available histology. The presence and completeness of CLRE did not differ significantly between benign and malignant tumours. Malignant tumours had more irregular CLRE than benign tumours (P

Background Alveolar bone is often lost after tooth extraction. Few studies have assessed the longitudinal changes in bone volume that occur within these extraction sites. Purpose To investigate the longitudinal morphological changes in extraction sockets following sustained continuous subcutaneous infusion of human recombinant insulin-like growth factor I (IGF-I). Materials and Methods Fourteen rats were subjected to right mandibular first molar extraction. Experimental rats (n = 7) received a continuous subcutaneous infusion of human recombinant IGF-I (320 mg/day) for 3 weeks by osmotic minipump. Control animals were treated with saline via the same method (n = 7). All rats were then housed for an additional 3 weeks. Micro-CT scanning was performed immediately after tooth extraction and at 1, 2, 3, and 6 weeks after extraction. Results New bone formation was markedly higher in the IGF-I-treated group as compared with the control group. The loss in alveolar ridge height in the IGF-I group was significantly lower than that in the control group at each time point after extraction on the buccal side and at 2, 3, and 6 weeks on the lingual side. Conclusions IGF-I treatment increases the volume of newly formed bone and reduces the loss in alveolar ridge height following tooth extraction.

Immunohistochemistry for several neurochemical substances, the transient receptor potential cation channel subfamily V member 1 (TRPV1) and 2 (TRPV2), P2X3 receptor, and parvalbumin (PV), was performed on the nodose ganglion, pharynx, and epiglottis in human cadavers. The nodose ganglion was situated beneath the jugular foramen, and had a spindle shape with the long rostrocaudal axis. The pharyngeal branch (PB) issued from a rostral quarter of the nodose ganglion, whereas the superior laryngeal nerve (SLN) usually originated from a caudal half of the ganglion. In the nodose ganglion, sensory neurons were mostly immunoreactive for TRPV1 (89 %) or P2X3 (93.9 %). About 30 % of nodose neurons contained TRPV2 (35.7 %)-or PV (29.9 %)-immunoreactivity (-IR). These neurons mainly had small to medium-sized cell bodies, and were distributed throughout the ganglion. Neurodegenerative profiles such as shrinkage or pyknosis could not be detected in the examined ganglion. Occasionally, TRPV2-IR nerve fibers surrounded blood vessels in the epiglottis as well as in the nasal and oral parts of the pharynx. Isolated TRPV2-IR nerve fibers were also located beneath the epithelium. TRPV1-, P2X3-, or PV-IR nerve endings could not be detected in the pharynx or epiglottis. In the PB and SLN, however, numerous nerve fibers contained TRPV1-, TRPV2-, P2X3-, and PV-IR. The present study suggests that TRPV1-, TRPV2-, P2X3-, and PV-IR neurons in the human nodose ganglion innervate the pharynx and epiglottis through the PB and SLN. These neurons may respond to chemical, thermal, and mechanical stimuli during respiration and swallowing.

Periodontal disease is a chronic inflammatory disease that results in the breakdown of the tooth-supporting tissues, and can ultimately lead to resorption of the alveolar bone. Recently, several studies have shown a close relationship between increased interleukin-18 (IL-18) levels and the pathogenesis of chronic periodontitis, a major cause of tooth loss. However, it has yet to be shown whether chronic periodontitis results from or causes an increase in IL-18 after bacterial infection. In the present study, we investigated how IL-18 overexpression relates to periodontal disease using IL-18 transgenic (Tg) mice. IL-18Tg and wild-type mice were inoculated intraorally with Porphyromonas (P.) gingivalis, which has been implicated in the etiology of chronic periodontitis. Seventy days after P. gingivalis infection, alveolar bone loss and gingival cytokine levels were assessed using histo-morphological analysis and enzyme-linked immuno-absorbent assay, respectively. Periodontal bone loss was evoked in IL-18Tg mice, but not in wild-type mice. Interestingly, levels of bone-resorptive cytokines, including IL-1α, IL-1β, tumor necrosis factor-α, and IL-6, were unchanged in the gingival tissues of IL-18Tg mice infected with P. gingivalis, although levels of interferon γ (a proinflammatory T-helper 1 cytokine) decreased. RT-PCR analysis showed elevated expression of mRNAs for receptor activator of nuclear factor kappa-B ligand (a key stimulator of osteoclast development and activation) and CD40 ligand (a marker of T cell activation) in the gingiva of IL-18Tg mice infected with P. gingivalis. We conclude that increased IL-18 in the gingival tissues evokes chronic periodontitis after bacterial infection, presumably via a T cell-mediated pathway.

Introduction The purpose of this article was to test the theory that short miniscrews will decrease the possibility of damaging the root, but the failure rate will increase. Methods One hundred eighty-six miniscrews (diameter, 1.3 × 5 mm, n = 63; 6 mm, n = 62; 7 mm, n = 61) were placed in 105 consecutive patients. Multislice computed tomography and cone-beam computed tomography scans were taken before and after miniscrew placement. Insertion torque was measured at miniscrew placement. Results The success rate of the miniscrews in the maxilla (93.4%) was higher than that in the mandible (70.3%). A significantly lower success rate with 5-mm miniscrews was observed compared with 6-mm and 7-mm miniscrews in the mandible. Miniscrews placed in less than approximately 3.8 mm of bone and those within 1.4 mm of the root had significantly higher failure rates. Miniscrews placed with insertion torque greater than 10 Ncm had a tendency for a lower success rate. Conclusions The optimum lengths of miniscrews of a diameter of 1.3 mm are 5 mm in the maxilla and 6 mm in the mandible. They should be placed at a distance from the root with insertion torque less than 10 Ncm for safe orthodontic anchorage without failure.

Dendritic cells (DCs) in lymphoid and non-lymphoid tissues are professional antigen-presenting cells that are essential for effective immunity and tolerance. However, the presence and characteristics of DCs in steady-state salivary glands (SGs) currently remain unknown. We herein identified CD64

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is a member of the osteonectin family of proteins. In this study, immunohistochemistry for SPARCL1 was performed to obtain its distribution in the human brainstem, cervical spinal cord, and sensory ganglion. SPARCL1-immunoreactivity was detected in neuronal cell bodies including perikarya and proximal dendrites, and the neuropil. The motor nuclei of the IIIrd, Vth, VIth, VIIth, IXth, Xth, XIth, and XIIth cranial nerves and spinal nerves contained many SPARCL1-immunoreactive (-IR) neurons with medium-sized to large cell bodies. Small and medium-sized SPARCL1-IR neurons were distributed in sensory nuclei of the Vth, VIIth, VIIIth, IXth, and Xth cranial nerves. In the medulla oblongata, the dorsal column nuclei also had small to medium-sized SPARCL1-IR neurons. In addition, SPARCL1-IR neurons were detected in the nucleus of the trapezoid body and pontine nucleus within the pons and the arcuate nucleus in the medulla oblongata. In the cervical spinal cord, the ventral horn contained some SPARCL1-IR neurons with large cell bodies. These findings suggest that SPARCL1-containing neurons function to relay and regulate motor and sensory signals in the human brainstem. In the dorsal root (DRG) and trigeminal ganglia (TG), primary sensory neurons contained SPARCL1-immunoreactivity. The proportion of SPARCL1-IR neurons in the TG (mean ± SD, 39.9 ± 2.4%) was higher than in the DRG (30.6 ± 2.1%). SPARCL1-IR neurons were mostly medium-sized to large (mean ± SD, 1494.5 ± 708.3 μm(2); range, 320.4-4353.4 μm(2)) in the DRG, whereas such neurons were of various cell body sizes in the TG (mean ± SD, 1291.2 ± 532.8 μm(2); range, 209.3-4326.4 μm(2)). There appears to be a SPARCL1-containing sensory pathway in the ganglion and brainstem of the spinal and trigeminal nervous systems.

Immunohistochemistry for transient receptor potential melastatin-8 (TRPM8), the cold and menthol receptor, was performed on the rat soft palate, epiglottis and pharynx. TRPM8-immunoreactive (IR) nerve fibers were located beneath the mucous epithelium, and occasionally penetrated the epithelium. These nerve fibers were abundant in the posterior portion of the soft palate and at the border region of naso-oral and laryngeal parts of the pharynx. The epiglottis was free from such nerve fibers. The double immunofluorescence method demonstrated that TRPM8-IR nerve fibers in the pharynx and soft palate were mostly devoid of calcitonin gene-related peptide-immunoreactivity (CGRP-IR). The retrograde tracing method also demonstrated that 30.1 and 8.7 % of sensory neurons in the jugular and petrosal ganglia innervating the pharynx contained TRPM8-IR, respectively. Among these neurons, the co-expression of TRPM8 and CGRP-IR was very rare. In the nodose ganglion, however, pharyngeal neurons were devoid of TRPM8-IR. Taste bud-like structures in the soft palate and pharynx contained 4-9 TRPM8-IR cells. In the epiglottis, the mucous epithelium on the laryngeal side had numerous TRPM8-IR cells. The present study suggests that TRPM8 can respond to cold stimulation when food and drinks pass through oral and pharyngeal cavities.

The aim of this study was to assess the efficacy of magnetic resonance imaging (MRI) for the differential diagnosis of basal cell adenocarcinoma (BCAC) and basal cell adenoma (BCA) in the salivary gland. Magnetic resonance imaging findings and pathological correlations were studied retrospectively in three cases of pathologically verified BCA and one case of BCAC. The MRI findings from previously reported cases (16 cases of BCA, 1 case of BCAC) were reviewed. All three BCAs showed well-defined margins, a round or ovoid shape, homogeneous hypointense signal on T1-weighted imaging (T1WI), and moderate contrast enhancement on contrast-enhanced T1WI. T2-weighted imaging showed heterogeneous hyperintense signals in two cases and a hypointense signal in one. The BCAC displayed MRI findings similar to those of the BCAs, with histopathologically verified partial invasion into the surrounding tissue remaining undetected. Time-signal intensity curves on dynamic MRI displayed rapid enhancement followed by a low washout pattern in all BCA cases, and a gradual enhancement pattern in the BCAC case. Both of these patterns are nonspecific and are commonly seen in other salivary tumors. Both the BCAs and the BCAC showed nonspecific findings on MRI, making it difficult to distinguish between these entities, even with dynamic MRI.

Platelets are reportedly causal in hepatitis. We previously showed that in mice, lipopolysaccharide (LPS) induces a reversible and macrophage-dependent hepatic platelet accumulation (HPA), including translocation of platelets into Disse spaces and their entry into hepatocytes. Concanavalin A (ConA), which induces hepatitis in mice via both T cells and macrophages, also induces HPA. Here, we examined the relationship between HPA and ConA-hepatitis. ConA-hepatitis and HPA were evaluated by serum transaminases, hepatic 5-hydroxytryptamine, and/or electron microscopy. Unlike LPS-induced HPA, ConA-induced HPA was only moderately dependent on phagocytic macrophages. Against expectations, platelet-depletion significantly exacerbated ConA-hepatitis, and anti-P-selectin antibody and P-selectin receptor blockade reduced both ConA-induced HPA and hepatitis. Prior induction of HPA by pretreatment with low-dose LPS powerfully reduced ConA-hepatitis. Such protection by LPS-pretreatment was not effective in mice depleted of phagocytic macrophages. In platelet-depleted mice, LPS-pretreatment severely exacerbated ConA-hepatitis. In mice depleted of both macrophages and platelets, neither ConA nor LPS-pretreatment + ConA induced hepatitis. In mice deficient in IL-1α and IL-1β (but not in TNFα), ConA-induced hepatitis was mild, and a protective effect of LPS was not detected. These results suggest that (i) there are causal and protective types of HPA, (ii) the causal type involves hepatic aggregation of platelets, which may be induced by platelet stimulants leaked from injured hepatocytes, (iii) the protective type is inducible by administration of prior low-dose LPS in a manner dependent on phagocytic (or F4/80-positive) macrophages, and (iv) IL-1 is involved in both the causal and protective types.

Candida species were detected and identified in samples from the buccal mucosa, dorsal surface of the tongue and supragingival plaque of subjects with oral lichen planus (OLP). The Candida in the samples were cultured on selection agars, and identified by sequence analyses of 18S, 5.8S and 25/28S rRNA. The isolation frequency of Candida was higher in subjects with OLP than in those with healthy oral mucosa. Non-C. albicans were only isolated from people with OLP. These results support the notion that subjects with OLP are more likely to have oral colonization with Candida, and that non-C. albicans are specifically present in subjects with this condition.

Enjoying taste should be one of the greatest pleasures in human life. However, aging is sometimes associated with decreased taste sensitivity, also known as hypogeusia. The loss of taste not only affects quality of life, but can also cause weight loss and health problems in the elderly. Our recent study has shown that 37% of test subjects over 65 years of age exhibited hypogeusia. Further, whole saliva secretion, including minor salivary secretion, was significantly decreased in elderly patients with gustatory impairment, but was normal in all elderly subjects with normal taste thresholds. These data indicate that hyposalivation is closely related to hypogeusia. Moreover, clinical studies have shown that treatment of hyposalivation diminishes hypogeusia, indicating that salivation is essential to maintain normal taste function. However, many medications for relief of dry mouth, such as parasympathomimetic (cholinomimetic) drugs, have serious adverse effects. Palpitation, sweating, nausea, diarrhea and dizziness have all been observed in elderly patients taking parasympathomimetic drugs. To circumvent this problem, glutamate, which produces umami taste, was demonstrated to increase salivary secretion and thereby improve hypogeusia by enhancing the gustatory-salivary reflex. Our data suggests that umami is an effective tool for the relief of hypogeusia without the side effects of parasympathomimetic drugs.

Objective The accuracies of intraoral radiography (IOR), multidetector helical computerized tomography (MDHCT) at slice thicknesses 0.63 mm and 1.25 mm, and limited cone-beam computerized tomography (LCBCT) were compared for detection of horizontal tooth root fracture. Study design In 7 beagle dogs, 28 maxillary anterior teeth were used, of which 13 had artificially induced horizontal root fracture. The specimens were examined by the above-mentioned 4 modalities. Diagnosis of root fracture was based on direct visualization of radiolucent line in each image by 6 radiologists. Results Sensitivity, negative predictive value, and diagnostic accuracy (true positives + true negatives) for detecting fracture lines in LCBCT (0.96 ± 0.04, 0.97 ± 0.03, 0.93 ± 0.04, respectively) were significantly higher than MDHCT at 0.63 mm (0.76 ± 0.09, 0.8 ± 0.05, 0.8 ± 0.05, respectively), MDHCT at 1.25 mm (0.49 ± 0.09, 0.66 ± 0.04, 0.69 ± 0.05, respectively), and IOR (0.51 ± 0.18, 0.67 ± 0.08, 0.69 ± 0.08, respectively). Specificity and positive predictive value showed no significant intermethod difference among the 4 modalities. Conclusion Limited cone-beam CT is more useful than the other 3 radiographic modalities for diagnostic imaging of horizontal tooth root fracture.

Aging is sometimes associated with decreased sensitivity to tastants, i.e., hypogeusia. The loss of taste sense induces not only the decreased quality of life (QOL), but also weight loss or health problems in the elderly. In our recent study, whole saliva secretion including minor salivary secretion, was found to be significantly decreased in the elderly with gustatory impairment, while it was normal in all of the elderly with normal taste thresholds, indicating that hyposalivation is closely related to hypogeusia. Moreover, clinical studies have shown that treatment for hyposalivation alleviates hypogeusia, even that due to the side effects of prescribed drugs or the effects of disease, e.g., nervous disorders or endocrine disorders. Thus, salivation is essential for maintenance of the normal taste function. Many medications for relief of dry mouth, primarily parasympathomimetic drugs, have serious adverse effects such as palpitation, sweating, nausea, diarrhea or dizziness, particularly in the elderly. To circumvent this problem, we use glutamate (umami taste) in an attempt to increase salivary secretion and to alleviate hypogeusia. An umami stimulus might be an effective method for the alleviation of hypogeusia through improvement of hyposalivation or dry mouth without side effects in aged patients. Consequently, attempts should be made to remedy hypogeusia by alleviation of hyposalivation so as to maintain and promote the health of the elderly.

Objective To investigate morphological changes in the dental arches of acromegaly-like rats recently developed by means of exogenous IGF-I administration. Design Human recombinant IGF-I (640 μg/day) was continuously administered subcutaneously for 4 weeks by osmotic mini-pumps to 10-week-old male rats ( n = 6). Control animals were injected with saline alone ( n = 6). After administration, all the rats were housed for 4 more weeks. Arch width ( W ), length ( L ) and angle ( θ ) in the mandible and maxilla were measured once a week during and after IGF-I administration. Results The concentration of circulating IGF-I, and W and θ in the mandible were significantly increased as compared with the control rats. Although the mandibular dental arch stopped expanding once administration ended, it did not return to the control size. Conclusions In our acromegaly-like rat model, mandibular dental arch growth is greater in the lateral than antero-posterior direction during and after IGF-I administration.

IL-18 is a proinflammatory cytokine and plays an important pathogenic role in inflammatory and autoimmune disorders. IL-17 is also a proinflammatory cytokine and IL-17-secreting Th17 cells are involved in autoimmunity. However, the pathological roles of IL-18 and Th17 cells in Sjögren’s syndrome (SS) remain to be elucidated. This study showed that the expression of IL-18 was detected in acinar cells, intraducts, and CD68+ macrophages in salivary glands of SS patients, but not in those of healthy subjects or patients with chronic graft-vs-host disease, by immunohistochemistry, and immunoblot analysis revealed that 24-kDa precursor form of IL-18 (proIL-18) and 18-kDa mature IL-18 were detected in SS salivary glands. The majority of the infiltrating cells in the salivary glands of SS patients were CD4+ T cells, and CD8+ T cells were infiltrated to a lesser extent. The predominant expression of IL-17 was found in infiltrating CD4+ T cells, whereas a small number of infiltrating CD8+ T cells expressed IL-17. Human salivary gland HSY and acinar AZA3 cells constitutively expressed proIL-18 and caspase-1, and a calcium ionophore A23187 induced the secretion of IL-18 from the cells. HSY and AZA3 cells expressed IL-18R and IL-17R on the cell surface, and IL-18 amplified the secretion of IL-6 and IL-8 that were induced by low amounts of IL-17. Primary salivary gland cells from normal subjects partially confirmed these findings. These results suggest that IL-18 and Th17 cells detected in the salivary glands in SS patients are associated with the pathogenesis of SS in the salivary glands.

We report here a case of masticatory disturbance evoked by trigeminal schwannoma, in which we have evaluated the changes in occlusal force and masticatory sensation before and after treatment for the tumour. The patient was a 43-year-old woman and her chief complaint was a loss of masticatory sensation on her left side. MR imaging revealed an enhanced tumour in the left cavernous sinus/Meckel's cave. The left masseter muscle function and occlusal force showed remarkable decreases before treatment; however, the sensory thresholds of her facial skin and dental pulp were not significantly different from the control side, indicating that her loss of masticatory sensation was not due to sensory disturbance but to occlusal force weakness. Gamma-knife radiosurgery resulted in a significant improvement in masticatory sensation following an increase in occlusal force.

Objective To determine the optimal scan settings (scan mode and position of field of view [FOV]) for cone beam computed tomography to reduce root fracture-like artifacts that are often observed in teeth filled with gutta-percha cones (GPCs). Study Design Fracture-like artifacts that appeared on cone beam computed tomography images of 9 extracted human mandibular premolars filled with GPCs were analyzed using I-mode (FOV, 102 mm; voxel size, 0.2 mm) and D-mode (FOV, 51 mm; voxel size, 0.1 mm) settings. Results The artificial lines were more obvious in I-mode than in D-mode. Increased distance between the center of the FOV and the GPCs produced stronger artificial lines in both I-mode and D-mode. Conclusion To reduce fracture-like artifacts, it is critical to use a mode with small voxel size and to place the target tooth in the center of the FOV.

Microbial infection is thought to modulate allergic disorders, and we previously demonstrated that not only mast cells (which release histamine), but also platelets are involved in the anaphylaxis induced in mice sensitised to ovalbumin (OVA). Here, we examined the effects of a lipopolysaccharide (LPS) from the oral bacterium Prevotella intermedia (Pi) on OVA-induced anaphylaxis. Upon intraperitoneal co-injection of Pi-LPS plus OVA into BALB/c mice, the Pi-LPS displayed a potent adjuvant effect comparable to that of alum (a standard adjuvant) in terms of its abilities to induce both anaphylactic shock and histamine-release following an antigen (OVA)-challenge. Moreover, an injection of Pi-LPS given to OVA+alum-sensitised mice shortly before an OVA-challenge augmented the shock-response. This LPS-pretreatment did not affect histamine-release, but did augment pulmonary platelet accumulation. Histamine was not by itself causal for shock-induction in sensitised mice. These results suggest that oral bacteria and/or their constituents (such as LPS) may help to sensitise the host to an antigen or exacerbate the host's allergic reactions ("aggravation effect"), probably by enhancing the platelet response to the antigen OVA.

IL-18, an important regulator of immune responses, is expressed in activated macrophages and also in nonimmune cells, such as keratinocytes and epithelial cells. Increased levels of serum IL-18 are reported in patients with a wide variety of diseases, but it is unclear which type of cell is the major source of serum IL-18. Here, we showed that the administration of liposomes encapsulating clodronate (Clo-lip) in mice selectively depleted F4/80+ phagocytic macrophages in the liver and spleen. Serum levels of mature IL-18 with 18 kDa were increased markedly in mice treated with Propionibacterium acnes and LPS, whereas administration of Clo-lip and gadolinium chloride, another widely used macrophage inactivator, showed no obvious effect on serum IL-18 levels, which were marginal in the liver, lung, and spleen and more pronounced in the intestines, especially in the duodenum. Treatment with P. acnes alone induced IL-18 more than twofold in each organ, and P. acnes and LPS induced a marked increase in IL-18 levels in the liver and spleen but decreased in the intestines. The administration of Clo-lip showed only a marginal effect on the IL-18 levels in these organs. Furthermore, serum levels of liver enzymes and TNF-α and liver injury (necrotic change and granuloma formation) induced by P. acnes and LPS were reduced moderately by Clo-lip. These results suggest that phagocytic macrophages do not actively contribute to the induction of serum IL-18 and liver injury in mice treated with P. acnes and LPS.

Nitrogen-containing bisphosphonates (NBPs) are powerful anti-bone-resorptive drugs, but they frequently induce various inflammatory side effects. Recent clinical applications have disclosed an unexpected new side effect, jaw-bone necrosis and exposure. In vitro studies suggest that the inflammatory effects of NBPs are due to Vgamma2Vdelta2 T-cells, stimulated directly and/or indirectly [the latter via isopentenylpyrophosphate (IPP) in the mevalonate pathway]. Rats and mice, however, lack Vgamma2Vdelta2 T-cells, yet NBPs still induce necrotic and inflammatory reactions. In mice, NBPs induce IL-1-dependent inflammatory reactions, such as inductions of histidine decarboxylase (HDC, the histamine-forming enzyme) in the liver, lung, spleen, and bone marrow, an increase in granulocytic cells in the peritoneal cavity, pleural exudation, and splenomegaly. Here, we examined the involvement of IPP, TNF, macrophages, and T-cells in the inflammatory actions of alendronate (a typical NBP) in mice. Various statins (mevalonate-synthesis inhibitors) suppressed the alendronate-induced HDC inductions, while mevalonate itself augmented such inductions. IPP injection also induced HDC. Like IL-1-deficient mice, TNF-deficient mice were resistant to alendronate-stimulated HDC induction. Alendronate-stimulated HDC inductions were significantly weaker in macrophage-depleted mice and in nude mice than in control mice. Similar, though generally less clear-cut, results were obtained when other alendronate-induced inflammatory reactions were examined. These results suggest that (i) inhibition of the mevalonate pathway causes and/or modifies at least some inflammatory actions of alendronate in mice, (ii) in addition to IL-1, TNF is also involved in the inflammatory actions of alendronate, and (iii) alendronate may act on a variety of cells, including macrophages and T-cells.

The beta-2 subunit of the mammalian brain voltage-gated sodium channel (SCN2B) was examined in the rat trigeminal ganglion (TG) and trigeminal sensory nuclei. In the TG, 42.6 % of sensory neurons were immunoreactive (IR) for SCN2B. These neurons had various cell body sizes. In facial skins and oral mucosae, corpuscular nerve endings contained SCN2B-immunoreactivity. SCN2B-IR nerve fibers formed nerve plexuses beneath taste buds in the tongue and incisive papilla. However, SCN2B-IR free nerve endings were rare in cutaneous and mucosal epithelia. Tooth pulps, muscle spindles and major salivary glands were also innervated by SCN2B-IR nerve fibers. A double immunofluorescence method revealed that about 40 % of SCN2B-IR neurons exhibited calcitonin gene-related peptide (CGRP)-immunoreactivity. However, distributions of SCN2B- and CGRP-IR nerve fibers were mostly different in facial, oral and cranial structures. By retrograde tracing method, 60.4 and 85.3 % of TG neurons innervating the facial skin and tooth pulp, respectively, showed SCN2B-immunoreactivity. CGRP-immunoreactivity was co-localized by about 40 % of SCN2B-IR cutaneous and tooth pulp TG neurons. In trigeminal sensory nuclei of the brainstem, SCN2B-IR neuronal cell bodies were common in deep laminae of the subnucleus caudalis, and the subnuclei interpolaris and oralis. In the mesencephalic trigeminal tract nucleus, primary sensory neurons also exhibited SCN2B-immunoreactivity. In other regions of trigeminal sensory nuclei, SCN2B-IR cells were very infrequent. SCN2B-IR neuropil was detected in deep laminae of the subnucleus caudalis as well as in the subnuclei interpolaris, oralis and principalis. These findings suggest that SCN2B is expressed by various types of sensory neurons in the TG. There appears to be SCN2B-containing pathway in the TG and trigeminal sensory nuclei.

Objective We analyzed the diagnostic performance of the MR imaging findings of the parotid, submandibular, and sublingual glands to discriminate between patients with and without Sjogren's syndrome. Methods We retrospectively analyzed the correlation between the MR imaging and histopathological findings obtained from 69 patients with clinically suspected Sjogren's syndrome. We evaluated the heterogeneous signal intensity distribution on T1- and T2-weighted images, the multiple high-signal-intensity spots on MR sialograms, and the volume of the parotid, submandibular, and sublingual salivary glands. Results The multiple high-signal-intensity spots in the parotid gland showed the highest sensitivity and diagnostic accuracy (82% and 83%, respectively). In addition, the multiple high-signal-intensity spots and the heterogeneous signal intensity distribution in the submandibular gland showed high specificity (100% and 88%, respectively). The volume of the submandibular gland, but not that of the parotid or sublingual gland, was smaller in patients with Sjogren's syndrome. Conclusions The presence of multiple high-signal-intensity spots on an MR sialogram in the parotid gland should be considered the best diagnostic indicator for Sjogren's syndrome. The presence of spots, heterogeneity, and the change to smaller volumes in the submandibular gland were also helpful because of their high specificity, particularly in advanced cases. This article is protected by copyright. All rights reserved.

Patients with dry mouth are increasing in Japan due to the country's super-aging society and stressful modern society. Dry mouth affects quality of life, including difficulty with speech or swallowing, and also causes aspiration pneumonia and, respiratory infection. Moreover, dry mouth closely relates to taste dysfunction, resulting in malnutrition, a common risk of nursing care in the elderly. Against these backgrounds, dry mouth has recently been a target of social concern. Drugs for dry mouth such as M3, a muscarinic agonist, have been widely used: however, these drugs have serious side effects, such as vomiting, sweating and/or digestive disorders. We examined the gustatory-salivary reflex to explore a remedy for dry mouth. We have demonstrated that umami stimulation increases saliva from both minor- and major salivary-glands, and that the effect is longer-lasting than with the other four basic tastes. Stimulating the umami response could therefore be a safe and useful remedy for dry mouth.

To examine the potential role of the histamine-forming enzyme, histidine decarboxylase (HDC), in oral inflammation and disease, we studied HDC activity in oral tissue after induction by bacterial agents. Following injection of E. coli-derived lipopolysaccharide (LPS) into mice, we measured the quantitative changes in HDC activity over time in dental pulp and gingiva. Oral tissue taken from individual mice was insufficient for detecting precise HDC activity, thus, we combined dental pulp or gingival tissues from four mice and assayed them over the course of 24 h. Our results indicate that LPS stimulated marked elevations of HDC activity in dental pulp and gingiva. This increase reached a maximum at 6 h after LPS injection and remained detectable at for least 24 h. Since mast cells are known to produce histamine through a difference mechanism than HDC induction, we compared LPS-induced HDC activity in dental pulp and gingiva to that in ear skin (a tissue rich in mast cells) and liver (a tissues lacking in mast cells). LPS also induced a marked increase in the HDC activity in liver and ear skin at 6 h after LPS injection. By contrast, saline injection had no effect on the HDC activity in any of the four tissues, although basal levels of HDC activity in ear skin was markedly higher than basal HDC activity in the other three kinds of tissues. Still, the relative increase in LPS-induced HDC activity in dental pulp and gingiva were much greater than that in ear skin. Since liver are devoid of mast cells and ear skin is considered the tissue richest in mast cells, the differences in HDC activity between tissues indicates that histamine induced by LPS may be produced by cells other than mast cells through another mechanism of action. These results also suggest that histamine produced in oral tissues in response to bacterial agents such as LPS could be involved in development of pulpitis or gingivitis (periodontitis), the most common diseases in the dental clinic, and that efforts to inhibit HDC activity, which elevates histamine levels in oral tissues, might offer the basis for novel treatment strategies.