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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.

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.

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 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.

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.

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

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.

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.

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.

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.

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.

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.

An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological tongue changes and clarify whether the changes were reversible. Human recombinant IGF-I (640 microg/day) was continuously subcutaneously infused into ten-week-old male rats for four weeks (IGF-I group; n = 6). Control sham-operated animals were injected saline alone (control group; n = 6). Rats were sacrificed immediately on ending administration at the age of fourteen weeks. Another 12 rats (6 from each group) were housed for an additional four weeks after administration ended. Total IGF-I (human + rat) increased significantly during administration, returning to control levels afterwards. Tongue weights significantly increased with histopathological changes present (increases in the muscle-bundle width, spaces between muscle-bundles and epithelium thickness) in the IGF-I group compared to control rats. Tongue size returned to control levels after discontinuation of IGF-I administration. These findings suggest that the characteristic tongue enlargement was developed experimentally in our acromegaly-like rat model, and that such morphological and histopathological tongue changes are reversible on normalization of circulating IGF-I levels.

Histamine modulates immune responses. There are at least two ways histamine might be supplied: one is its release from cells that pool pre-formed histamine and the other is its de novo formation via induction of histidine decarboxylase (HDC). Lipopolysaccharide (LPS) and the proinflammatory cytokine interleukin (IL)-1 induce a marked elevation of HDC activity in various tissues or organs. To examine the contribution of mast cells to HDC induction in mice given LPS or IL-1, we examined the effects of LPS and IL-1 on HDC activity and/or histamine content in various organs (liver, lung, spleen or bone marrow) in mast cell-deficient mice (W/Wv), their normal littermates (+/+) and BALB/c mice deficient in IL-1alpha, IL-1beta and tumor necrosis factor (TNF)-alpha (IL-1alpha beta/TNFalphaKO mice). In non-stimulated mice, the histamine in the lung and spleen was contained largely within mast cells. The LPS-stimulated increase in HDC activity in a given organ was similar between +/+ and W/W(v) mice, and between IL-1alpha beta/TNFalphaKO BALB/c and control BALB/c mice, and led to increases in histamine. In W/Wv and +/+ mice, IL-1alpha also elevated HDC activity. These results suggest that (i) in liver, lung and spleen, either the major cells supplying histamine via HDC induction in response to LPS and IL-1 are not mast cells, or mast cells are not a prerequisite for the induction of HDC; (ii) the cells in which HDC is induced by LPS and IL-1 are similar or identical in a given organ; and (iii) neither IL-1 nor TNF-alpha is a prerequisite for the induction of HDC by LPS.

We experienced a case of multiple myeloma in a 62-year-old woman who visited our hospital with a chief complaint of paresthesia in the left lower lip, which was described as numb chin syndrome, as her initial symptom.

To evaluate the usefulness of heavily T(2) weighted (T2W) magnetic resonance (MR) images for the differential diagnosis of parotid tumours.Conventional T2W and heavily T2W images obtained from 43 patients with parotid tumours were reviewed retrospectively. Tumours were classified pathologically into three types: pleomorphic adenoma (25 cases), Warthin's tumour (7 cases) and malignant tumour (11 cases). During interpretation of each MR image, special attention was paid to the homogeneity and signal intensity displayed by the solid portions of the tumours.Heavily T2W images could distinguish pleomorphic adenoma from Warthin's tumour and malignant tumours based on the homogeneity and signal intensity of the solid portions, whereas conventional T2W images could not. On conventional T2W images, neither homogeneity nor signal intensity differed significantly among these three tumour types. On heavily T2W images, malignant and Warthin's tumours appeared more homogeneous than pleomorphic adenoma (P0.0061); signal intensity from pleomorphic adenoma was significantly different to signal intensity from malignant tumours (P0.05) and Warthin's tumour (P0.005).Heavily T2W MR images can be useful in distinguishing pleomorphic adenoma from Warthin's tumour and malignant tumours.

Mast cells and basophils are believed to trigger allergic reactions and anaphylaxis. They rapidly release histamine (H), a typical mediator of inflammation, in response to antigens. In the mouse, platelets contain much 5-hydroxytryptamine (5HT), an additional inflammatory mediator, while human platelets contain both H and 5HT. Here, we examined the response of platelets in sensitized mice to antigen challenge. Platelets accumulated in the lung and liver almost immediately after intravenous injection of ovalbumin (OVA), in mice sensitized to it, and platelet degranulation occurred during these reactions. These responses of platelets preceded H release from mast cells and/or basophils, occurred at doses of OVA lower than those inducing H release, and contributed to the signs of shock. We reported previously that intravenous injection into mice of LPS (a membrane constituent of gram-negative bacteria) induces a similar platelet response (accumulation of platelets in the lung and liver) and shock. Blood that has passed through the body (other than the digestive tract) passes first to the lungs before being recirculated by the heart, and blood that has passed through the digestive tract passes next to the liver. Thus, our findings suggest that in addition to their role in haemostasis, platelets, tiny anuclear cytoplasts, may be important in both innate and acquired immunity, and that the lung and liver may be the fronts at which platelets wage war on pathogens. British Journal of Pharmacology (2002) 137, 146–152. doi:10.1038/sj.bjp.0704852

Fourteen patients with oral chronic graft-versus-host disease (GVHD) who received allogenic bone marrow transplantation were clinically and histopathologically studied. Most patients had lichenoid lesions on the oral mucosa and xerostomia. Two patients displayed multiple superficial mucoceles of the buccal mucosa as vesicular lesions. These clinical features resembled those of autoimmune diseases, such as lichen planus and Sjogren's syndrome. Histopathologically, all cases showed oral mucosal and minor salivary gland involvement characteristic of chronic GVHD, irrespective of the presence or absence of systemic lesions. The oral mucosa showed subepithelial lymphocytic infiltration with epithelial recessive changes, and the minor salivary glands displayed inflammatory changes or fibrosis with destructive alteration of epithelial cells. Immunohistochemically, CD3-positive cells were more numerous than CD79α-positive cells in the oral mucosa, while CD3- and CD79α-positive cells were equally observed in the minor salivary glands. CD4- and CD8-positive cells were detected equally in both the oral mucosa and the minor salivary glands. CD1a- and CD68-positive cells were scattered throughout the oral mucosa and the minor salivary glands. Cellular and humoral immune systems may differ between the oral mucosa and salivary glands in patients with chronic GVHD. CD1a- and CD68-positive cells may play a role in antigen presentation in oral lesions involved in chronic GVHD.

There is a close relationship between perception of umami, which has become recognized as the fifth taste, and the human physical condition. We have developed a clinical test for umami taste sensitivity using a filter paper disc with a range of six monosodium glutamate (MSG) concentrations. We recruited 28 patients with taste disorders (45–78 years) and 184 controls with no taste disorders (102 young [18–25 years] and 82 older [65–89 years] participants). Filter paper discs (5 mm dia.) were soaked in aqueous MSG solutions (1, 5, 10, 50, 100 and 200 mM), then placed on three oral sites innervated by different taste nerves. The lowest concentration participants correctly identified was defined as the recognition threshold (RT) for MSG. This test showed good reproducibility for inter- and intra-observer variability. We concluded that: (1) The RT of healthy controls differed at measurement sites innervated by different taste nerves; that is, the RT of the anterior tongue was higher than that of either the posterior tongue or the soft palate in both young and older individuals. (2) No significant difference in RT was found between young adults and older individuals at any measurement site. (3) The RT of patients with taste disorders was higher before treatment than that of the healthy controls at any measurement site. (4) The RT after treatment in these patients improved to the same level as that of the healthy controls. (5) The cutoff values of RT, showing the highest diagnostic accuracy (true positives + true negatives), were 200 mM MSG for AT and 50 mM MSG for PT and SP. The diagnostic accuracy at these cutoff values was 0.92, 0.87 and 0.86 for AT, PT and SP, respectively. Consequently, this umami taste sensitivity test is useful for discriminating between normal and abnormal umami taste sensations.

Prednisolone is a member of synthetic glucocorticoids which are widely used to treat chronic inflammatory diseases. In this study, neuronal degeneration and cell death, and glial reaction were investigated in the rat trigeminal ganglion (TG) and brainstem after subcutaneous injection of prednisolone for 7 days. Expression of c-Jun activating transcription factor 3 and caspase-3 was absent or infrequent in the TG, and cranial sensory and motor nuclei of saline- and prednisolone-treated animals. In these animals, distribution of calcitonin gene-related peptide-immunoreactive (-IR) neurons and nerve fibers was similar in the brainstem. In addition, the number of Iba1- and glial fibrillary acidic protein (GFAP)-IR cells with some processes in the brainstem was barely affected by prednisolone treatment. However, the treatment increased ramification of Iba1-IR processes in the subnucleus caudalis of the trigeminal sensory complex. Prednisolone scarcely influenced the morphology of GFAP-IR cells in the brainstem. Expression of p38 mitogen-activated protein kinase was very rare in the brainstem of saline- and prednisolone-treated animals. The present study suggests that microglia are activated by prednisolone in the subnucleus caudalis of the trigeminal sensory complex. The glucocorticoid may affect nociceptive transmission in the brainstem.

Our newly developed umami taste sensitivity test revealed the loss of only the umami taste sensation in some elderly patients, whereas the other four basic taste sensations (sweet, salty, sour, bitter) were normal. Such patients all complained of appetite loss and weight loss, resulting in poor overall health. As a treatment for taste disorder patients, improvement of salivary flow has been adopted in our clinic. Umami taste stimulation increases salivary flow rate of not only major but also minor salivary glands. After treatment with umami taste stimulation, patients remarkably regained their appetite, weight and overall health. Sensitivity to umami taste seems to contribute to good overall health in elderly people.

Patients with gustatory disorders often complain of persistent impairment of umami taste, a synonym for savory or broth-like flavor, even after the recovery of the other four basic taste sensations (sweet, salty, sour, and bitter). Umami taste is important for maintaining not only the quality of life but also good health, and therefore, it seems important to assess and treat the impairment of umami taste perception. At present, however, there is no clinical test for umami taste, even though tests for the other four basic tastes have been widely used in quantitative gustometry. We have developed a new method to clinically assess the sensitivity of umami taste using a filter paper disc (FPD) with monosodium glutamate (MSG) as the prototype umami substance. We found that some elderly patients complained only of the loss of umami taste sensation, whereas the sensation of the other four basic tastes (sweet, salty, sour, and bitter) was normal. Those patients without normal umami taste sensitivity were all over 65 years old, and complained of appetite and weight loss, resulting in poor general health. After treatment, their umami taste threshold recovered, and they regained appetite and weight.

Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness), elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained.

Objective Minor salivary gland flow rate (MF) has been proposed as a key feature of xerostomia (subjective feeling of dry mouth). To assess its diagnostic performance, MF was compared in xerostomia and control subjects. Design Sixty-six subjects with xerostomia and 30 controls were enrolled. MF was measured in the lower labial mucosa using the iodine–starch filter paper method. Stimulated whole salivary flow rates were also measured using the gum test (stimulated-WF). Results Both labial-MF and stimulated-WF were significantly lower in xerostomia subjects than in controls. There was a positive correlation between labial-MF and stimulated-WF in control but not xerostomia subjects. In xerostomia subjects compared to controls, there was a significantly larger reduction in labial-MF than in stimulated-WF. Xerostomia was most accurately diagnosed using a labial-MF cutoff value of 0.25 μL/cm2/min. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy at this cutoff value were 1.00, 0.87, 0.93, 1.00, and 0.96, respectively. Compared to respective values of 0.64, 1.00, 1.00, 0.56, and 0.75 for stimulated-WF at the traditional cutoff of 1.0 mL/min, these data indicate the higher sensitivity, negative predictive value, and diagnostic accuracy of labial-MF. Conclusions Xerostomia was more strongly related to reduction of labial-MF than to that of stimulated-WF. Xerostomia was most likely triggered at a labial-MF cut-off value of 0.25 μL/cm2/min based on results from the iodine–starch method.

Mandibular protrusion accompanies acromegaly or acrogigantism. To clarify the detailed mechanisms, we used an acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I). Human recombinant IGF-I (640 microg/day) continuously was infused subcutaneously to 10-week-old male rats (n=12) for four weeks. Control, sham-operated animals (n=12) were injected with saline alone. Twelve rats (six from each group) were killed immediately after ending administration at age 14 weeks. Another 12 rats (six from each group) were housed for an additional four weeks after treatment ended. Mandibular condylar length increased significantly in the IGF-I rats compared with the control rats, but no significant intergroup difference was found in the lengths of the coronoid and angular processes. Cartilaginous layer width, bone matrix volume, and the number of osteoblasts in the mandibular condyle increased significantly in the IGF-I group. These histopathological changes in the condyle disappeared after IGF-I administration was discontinued; however, the morphological change in condylar length remained. These findings suggest that mandibular protrusion in patients with acromegaly or acrogigantism may be evoked by superfluous elongation of the mandibular condyle and that such elongation can be induced by endochondral ossification caused by high IGF-I serum levels.

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

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.

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.

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.

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