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Objective Oral lichen planus (OLP) displays various and complicated clinical presentations which often make their differential diagnosis challenging, and thus helpful clinical practice guidelines for the diagnosis and treatment of OLP have been long awaited. Methods The Japanese OLP Working Group (OLP-WG) has collected and analyzed a total of 393 OLP cases provided by 48 institutions nationwide from 2009 to 2011 toward the establishment of valuable clinical practice guidelines for OLP. Collected samples were classified according to their original diagnoses into three groups: bilateral reticular (Group 1); bilateral atrophic/erosive (Group 2); and unilateral (Group 3) buccal lesions. Ten OLP-WG members used intraoral pictures to categorize the cases into Andreasen’s six types, and then examined the biopsy specimens to make pathological and comprehensive diagnoses. Results When Andreasen’s reticular, plaque, and papular types were sorted into white (W) type, and when atrophic, erosive, and bullous types were sorted into red (R) type, they formed six clusters based on the number of the members’ judgments: W1 (W dominant), W/R (W-R competing), R1 (R dominant), UD (undeterminable dominant), W2 (boundary), and R2 (boundary). Both in the bilateral and unilateral lesion groups, proportions of cases which were comprehensively diagnosed as OLP were significantly higher in cluster W1 than those in cluster R1 (p Conclusions These results indicated that the simple W or R classification would be a better substitute for Andreasen’s in the clinical categorization of OLP.

Pulmonary mucormycosis (PM) is a life-threatening fungal infection in patients with hematologic malignancies, and early and accurate diagnostic modalities are urgently needed. We conducted a polymerase chain reaction (PCR) assay targeting these fungi in peripheral blood from four patients with hematologic malignancies who were strongly suspected of having PM. In these four patients, the Rhizopus species was identified in two patients, and the Cunninghamella and Absidia species in one each. Based on these molecular findings, all of the patients were successfully treated via targeted therapy with liposomal amphotericin B. In this report, a PCR analysis proved very useful for managing PM in patients with hematologic malignancies.

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.

Case Alcoholic ketoacidosis (AKA) usually occurs in patients with a history of prolonged alcohol abuse and recent binge drinking followed by abrupt cessation of alcohol consumption. Outcome A 61-year-old man was brought to our emergency department. He had a history of eating barbecued beef with beer the previous night. He had unexplained hypoglycemia with high anion gap metabolic acidosis and fatty liver, and we strongly suspected AKA. After hydration with saline solution, dextrose, and thiamine, given i.v., his metabolic acidosis rapidly improved. A history of alcohol abuse and high serum β-hydroxybutyrate concentration were subsequently confirmed, and the diagnosis of AKA was finally made. Conclusion Our case suggests that a high-fat meal can induce AKA without abrupt cessation of alcohol consumption and that AKA should be considered when encountering patients with unexplained high anion gap metabolic acidosis with hypoglycemia and fatty liver, even if the past history of alcohol abuse is unknown.

Objectives Invasive fungal diseases (IFDs) are life-threatening events in patients with haematologic disorders, and the spectrum of the aetiological pathogens continues to expand. This study aimed to evaluate the clinical utility of a panfungal polymerase chain reaction (PCR) assay for the management of IFDs in such patients. Methods We prospectively analysed 273 consecutive blood samples from 64 risk episodes in 51 patients with haematologic disorders at high risk for IFD who were treated at our hospital between April 2007 and October 2010. Results PCR-positive results were obtained in 18 of 64 risk episodes (35.3%). IFD was documented in 14 episodes (21.9%, 9 probable IFDs and 5 possible IFDs) according to the revised criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. PCR was positive in all of these 14 episodes, and in 4 of the 50 episodes with no IFD category. Sensitivity, specificity, positive predictive value, and negative predictive value of our assay were 100%, 92%, 78% and 100% respectively. A considerable number of fungi (44.4%) that are less common than Aspergillus and Candida species were positive by PCR. Molecular diagnoses of Cunninghamella species, Aspergillus ustus, Fusarium species, Scedosporium apiospermum, Rhodotorula species and Rhizopus species were beneficial in selecting suitable treatments. Conclusions Our panfungal PCR approach allows for the highly sensitive and specific detection and identification of a wide spectrum of fungal pathogens, which provides indispensable information for managing IFDs, especially refractory or breakthrough IFDs during antifungal therapy in high-risk patients with haematologic disorders.

We herein report the case of a 77-year-old woman who developed acute thrombocytopenia during the 23rd cycle of modified FOLFOX therapy. She developed a hypersensitivity reaction with nasal bleeding. The chemotherapy infusion was immediately discontinued. The patient's symptoms resolved with discontinuation of chemotherapy and the administration of supportive therapy. A complete blood count showed severe thrombocytopenia, and oxaliplatin-induced thrombocytopenia was diagnosed. The patient was admitted to the hospital, and the thrombocytopenia was corrected with a platelet transfusion followed by prednisolone. She was discharged after one week without requiring additional platelet transfusions. With the widespread use of oxaliplatin, the risk of oxaliplatin-induced acute thrombocytopenia should be considered an acute onset hematological emergency.

Invasive trichosporonosis is an extremely rare mycosis, but Trichosporon fungemia (TF) in patients with hematologic malignancies has been increasingly recognized to be a fulminant and highly lethal infection. Although the utility of azole therapy has been demonstrated in several observations, little is known about the efficacy of one of azoles, miconazole (MCZ). To assess its therapeutic role, we retrospectively investigated 6 cases of TF in patients with acute leukemia receiving MCZ containing regimens. Successful outcome was obtained in 4 patients [MCZ + amphotericin B (AmB) in 2, MCZ only and MCZ + fluconazole (FLCZ) + AmB in one each], but not in 2 (MCZ + FLCZ + AmB and MCZ + FLCZ in one each). Although MCZ and AmB exhibited good in vitro activities against isolates from all patients, FLCZ had such finding from only one patient. Considering the reportedly limited utility of AmB, MCZ seemed to play a critical role even in the combination therapies for TF. Despite the release of newer azoles and other classes of antifungals, the use of MCZ remains a potential therapeutic approach for TF in patients with acute leukemia.

Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.

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.

A 69-year-old man, who had been receiving prednisolone for 11 months for treatment of interstitial pneumonia, was diagnosed with acute myeloid leukemia. During induction therapy, he developed severe pneumonia. Although meropenem and micafungin were started, he died of circulatory failure owing to massive gastrointestinal bleeding. Autopsy specimens obtained from the stomach revealed fungal hyphae, which had invaded diffusely into submucosal vessels and caused the massive gastric bleeding. The same hyphae were also observed in both lungs. A diagnosis of disseminated zygomycosis was confirmed by its characteristic histopathological findings. Because zygomycetes are spontaneously resistant to the newer antifungal agents, such as voriconazole or micafungin, it seems likely that the prevalence of zygomycosis as a breakthrough infection may increase in the future. Zygomycosis is a rare, but life-threatening, deep fungal infection that appears in immunologically or metabolically compromised hosts. Its manifestations are clinically similar to those of invasive aspergillosis. In addition to the well-established epidemiology of zygomycosis, this case suggests the following new characteristics. (1) Although the gastrointestinal manifestation of zygomycosis is relatively rare, it is observed more frequently than invasive aspergillosis. (2) Gastrointestinal zygomycosis occasionally leads to the development of necrotic ulcers and may induce hemorrhagic shock.(3) We should be cautious of an occurrence of breakthrough zygomycosis when we use echinocandins for patients with known risk factors, especially steroid use and neutropenia. (4) For patients who are receiving broad-spectrum antibiotics and echinocandins, who are negative for culture studies and aspergillus antigen, and who present with unresolved fever, it is important to make a prompt clinical diagnosis of zygomycosis.

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 the case of a 75-year-old man with acute myeloid leukemia who developed hyponatremia after linezolid administration. Because induction therapy did not achieve complete remission for this man, we initiated re-induction therapy with enocitabin and daunomycin. Seven days after chemotherapy, the patient experienced a catheter-related blood stream infection (CRBSI) due to methicilin resistant staphylococcus aureus (MRSA). When treatment with albekacin and fosfomycin was in effective, linezolid was administrated intravenously and he became afebrile. On day 8 after linezolid administration, however, he reported general fatigue and slight consciousness disturbance. His serum sodium concentration was 119 mEq/L and his urinary sodium excretion rose to 143 mEq/day, although intravenous sodium intake was 98 mEq/day. Because of the sufficiency of urine volume and weight loss, we surmise that inappropriate ADH secretion (SIADH) syndrome was unlikely. We diagnosed renal salt wasting syndrome (RSWS) based on calculation of the amount of sodium intake and the amount of sodium excreted from the kidneys. After linezolid was discontinued and aggressive treatment with sodium supplement begun, his consciousness cleared as his low serum sodium level rose. This is, to the best of our knowledge, the first case reported on the development of RSWS after linezolid treatment. Although the process remains unclear, our case suggests that linezolid may induce RSWS after intensive chemotherapy.

A 67-year-old woman with systemic lupus erythematosus (SLE) was admitted to our hospital because of lupus nephritis. Methylprednisolone minipulse therapy dramatically reduced her proteinuria; however; she then complained of general fatigue with low-grade fever. Radiological and culture studies revealed no infectious focus, but she was treated with meropenem and micafungin, considering her immunosuppressive state. Cytomegalovirus antigenemia was later determined and ganciclovir was added. She became afebrile, but complained of nausea and headache, and disorientation, without meningeal signs. Because a brain computed tomography (CT) scan showed no abnormality, we initially suspected some kind of drug interaction. Despite the discontinuation of all drugs, however, she still suffered from disturbance of consciousness. A lumbar puncture revealed yeast cells stained by India ink. A diagnosis of cryptococcal meningitis was confirmed. Though fluconazole and meropenem were administered, the patient died. Autopsy findings revealed disseminated cryptococcosis concomitant with pulmonary aspergillosis. Micafungin is a recently approved echinocandin-class antifungal agent that is now widely used in Japan because of its minimal toxicity and broadspectrum activity. However, such echinocandins have limited activity against a number of fungi. Indeed, breakthrough trichosporonosis is becoming a significant problem in patients with hematological malignancies who are receiving echinocandins. To the best of our knowledge, breakthrough cryptococcosis, as seen in our patient, has not been reported previously in patients who were receiving micafungin as an empiric antifungal therapy. This case highlights that cryptococcosis should be kept in mind as a possible breakthrough infection during the administration of echinocandins, especially in patients with cellular immunodeficiency.

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.

We report the case of a 59-year-old man with thymic adenocarcinoma who was treated with colon cancer chemotherapy. He was referred to our hospital for an anterior mediastinal mass and multiple bone metastases that were found by computed tomography. Needle biopsy of the mediastinal tumor revealed a caudal-type homeobox 2 (CDX2)-positive adenocarcinoma. Neither upper nor lower gastrointestinal endoscopic examinations revealed any evidence of a primary tumor. The patient was administered CapeOX (capecitabine and oxaliplatin) and FOLFIRI (fluorouracil, leucovorin and irinotecan)/cetuximab. He died 6 months after diagnosis. Primary thymic adenocarcinoma was confirmed by autopsy. As far as we know, this is the first report in which colon cancer chemotherapy was used to treat CDX2-positive metastatic thymic adenocarcinoma.

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.

Activated neutrophils produce serine proteases, which activate cells through protease-activated receptor 2 (PAR2). As proteinase 3 (PR3) induces the secretion of interleukin (IL)-18 from epithelial cells in combination with lipopolysaccharide (LPS) in vitro, we examined whether neutrophils, serine proteases, and PAR2 are involved in the induction of serum IL-18 and IL-18-dependent liver injury in mice treated with heat-killed Propionibacterium acnes and LPS. LPS-induced serum IL-18 levels in P. acnes-primed mice were reduced significantly by anti-Gr-1 injection (depletion of neutrophils and macrophages) but not by a macrophage “suicide” technique, using liposomes encapsulating clodronate. The IL-18 induction was decreased significantly by coadministration of a serine protease inhibitor [Nafamostat mesilate (FUT-175)] with LPS. Serum levels of tumor necrosis factor α and liver enzymes induced by P. acnes and LPS were abolished by anti-Gr-1 treatment, and concomitantly, liver injury (necrotic change and granuloma formation) and Gr-1+ cell infiltration into the liver were prevented by the treatment. A deficiency of PAR2 in mice significantly impaired IL-18 induction by treatment with P. acnes and LPS, and only slight pathological changes in hepatic tissues occurred in the PAR2-deficient mice treated with P. acnes and LPS. Furthermore, coadministration of exogenous murine PR3 or a synthetic PAR2 agonist (ASKH95) with LPS in the anti-Gr-1-treated mice restored the serum IL-18 levels to those in control mice treated with P. acnes and LPS. These results indicate that neutrophil recruitment and PAR2 activation by neutrophil serine proteases are critically involved in the induction of IL-18 and IL-18-dependent liver injury in vivo.

Peptidoglycan recognition proteins (PGRPs), a novel family of pattern recognition molecules involved in innate immunity conserved from insects to mammals, recognize bacterial cell wall peptidoglycan (PGN) and have been suggested to act as anti-bacterial factors. In humans, four kinds of PGRPs (PGRP-L, -Iα, -Iβ and -S) have been cloned and all four of them bind PGN. Chemically synthesized pathogen-associated molecular patterns (PAMPs) in bacterial cell surface components (synthetic lipopeptide [TLR2 agonist], synthetic lipid A [TLR4 agonist], synthetic iE-DAP [NOD1 agonist], and muramyldipeptide [MDP, NOD2 agonist]) markedly upregulated the mRNA expressions of the four PGRPs and cell surface expressions of PGRP-Iα and -Iβ, but did not induce either mRNA expression or the secretion of inflammatory cytokines in oral epithelial cells. Suppression of the expressions of TLR2, TLR4, NOD1 and NOD2 by RNA interference specifically inhibited the upregulation of PGRP mRNA expression induced by lipopeptide, lipid A, iE-DAP and MDP, respectively. In addition, these PAMPs definitely activated nuclear factor (NF)-κB in the epithelial cells, and suppression of NF-κB activation clearly prevented the induction of PGRP mRNA expression induced by these PAMPs in the cells. These findings suggested that bacterial PAMPs induced the expression of PGRPs, but not proinflammatory cytokines. Although the function of human PGRPs has not been clarified so far, in contrast to insect PGRPs, human PGRPs might be also involved in host defence against bacterial invasion without accompanying inflammatory responses. Further studies are required to elucidate the function of human PGRPs.

To investigate the role of human gingival fibroblasts (HGF) in periodontitis, we examined the expression of interleukin-2 receptor (IL-2R) and IL-15R subunits in HGF from normal and inflamed regions and the role of endogenous IL-15 in IL-2-mediated signaling. Normal HGF expressed IL-2Rβ and common γ-chain (γc) but not IL-2Rα or IL-15Rα, whereas inflamed HGF expressed IL-2Rα, IL-15Rα, IL-2Rβ and γc. Exogenous IL-2 and IL-15 induced production of monocyte chemoattractant protein-1 (MCP-1) but not IL-8 in normal HGF, and induced the production of both chemokines in inflamed HGF. Both HGF constitutively transcribed 48aa-IL-15 isoform, and the isoform existed as a membrane-bound form. Pretreatment with anti-IL-15 neutralizing mAb completely inhibited the production of MCP-1 induced by IL-2 and IL-15 and IL-2-induced phosphorylation of Janus tyrosine kinase 1 and 3 in HGF. The pretreatment and RNA interference targeted to IL-15 mRNA resulted in total inhibition of the IL-2Rβ and γc expression at mRNA and protein levels. Furthermore, inhibition of nuclear factor (NF)-κB abrogated the expression of IL-2Rβ and γc, and IL-2-induced-nuclear translocation of NF-κB was completely inhibited by the RNA interference in HGF. These results suggest that endogenous membrane-bound IL-15 sustains recruitment of IL-2Rβ and γc through activation of NF-κB in HGF.

Peptidoglycan recognition proteins (PGRPs), a novel family of pattern recognition molecules (PRMs) in innate immunity conserved from insects to mammals, recognize bacterial cell wall peptidoglycan (PGN) and are suggested to act as anti-bacterial factors. In humans, four kinds of PGRPs (PGRP-L, -Ialpha, -Ibeta and -S) have been cloned and all four human PGRPs bind PGN. In this study, we examined the possible regulation of the expression of PGRPs in oral epithelial cells upon stimulation with chemically synthesized pathogen-associated molecular patterns (PAMPs) in bacterial cell surface components: Escherichia coli-type tryacyl lipopeptide (Pam3CSSNA), E. coli-type lipid A (LA-15-PP), diaminopimelic acid containing desmuramyl peptide (gamma-D-glutamyl-meso-DAP; iE-DAP), and muramyldipeptide (MDP). These synthetic PAMPs markedly upregulated the mRNA expression of the four PGRPs and cell surface expression of PGRP-Ialpha and -Ibeta, but did not induce either mRNA expression or secretion of inflammatory cytokines, in oral epithelial cells. Suppression of the expression of Toll-like receptor (TLR)2, TLR4, nucleotide-binding oligomerization domain (NOD)1 and NOD2 by RNA interference specifically inhibited the upregulation of PGRP mRNA expression induced by Pam3CSSNA, LA-15-PP, iE-DAP and MDP respectively. These PAMPs definitely activated nuclear factor (NF)-kappaB in the epithelial cells, and suppression of NF-kappaB activation clearly prevented the induction of PGRP mRNA expression induced by these PAMPs in the cells. These findings suggested that bacterial PAMPs induced the expression of PGRPs, but not proinflammatory cytokines, in oral epithelial cells, and the PGRPs might be involved in host defence against bacterial invasion without accompanying inflammatory responses.

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

Anti-neutrophil cytoplasmic Abs targeting proteinase 3 (PR3) have been detected in relation to a wide range of inflammatory conditions such as periodontitis, and interaction of anti-PR3 Abs with endothelial and epithelial cells provokes cell activation, although the underlying mechanism has been unclear. The present study showed that human oral epithelial cells expressed PR3 mRNA after treatment with proinflammatory cytokines such as IL-1α, TNF-α, IFN-α, IFN-β, and IFN-γ. A 29-kDa PR3 was expressed on the cell surface and released into culture supernatants by the cells upon stimulation with these cytokines. The membrane and supernatant fractions of oral epithelial cells exhibited enzymatic activity, which was inhibited by serine proteinase inhibitors, but not by a cysteine proteinase inhibitor or secretory leukocyte protease inhibitor. Addition of anti-PR3 Abs to cytokine-primed oral epithelial cells in culture induced remarkable secretion of IL-8 and monocyte chemoattractant protein 1 and aggregation of PR3 on the cells. RNA interference targeted to protease-activated receptor-2 mRNA and intracellular Ca2+ mobilization assays revealed that anti-PR3 Abs activated the epithelial cells through protease-activated receptor-2, a family of G protein-coupled receptors. The anti-PR3 Ab-mediated cell activation was completely abolished by RNA interference targeted to PR3 mRNA and by inhibition of phospholipase C and NF-κB. Immunohistochemistry showed that inflamed oral epithelium actually expresses PR3 protein. These results suggest that oral epithelial cells express functional PR3 in the inflamed sites and respond to anti-PR3 Abs detected in diseased sera, and that these mechanisms may actively participate in the inflammatory process, including periodontitis.

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.

Lichen planus is a chronic inflammatory disease of the skin and oral mucosa in which the cell-mediated cytotoxicity is regarded as a major mechanism of pathogenesis. To understand its pathophysiology further, the present study examined the in situ expression of chemokines and chemokine receptors in oral lichen planus. Immunohistochemical analysis of 15 cases has consistently revealed that infiltrating CD4+ and CD8+ T cells in the submucosa predominantly expressed CCR5 and CXCR3. Furthermore, infiltrating T cells, particularly CD8+ T cells, were positive for RANTES/CCL5 and IP-10/CXCL10, the ligands of CCR5 and CXCR3, respectively. By immunoelectron microscopy, these chemokines were localized in the cytolytic granules of CD8+ T cells. Lesional keratinocytes also overexpressed the ligands of CXCR3, namely, MIG/CXCL9, CXCL10, and I-TAC/CXCL11. Our data suggest that the chemokines signaling via CCR5 and CXCR3, which are known to be selectively expressed by type 1 T cells, are predominantly involved in T-cell infiltration of oral lichen planus. Furthermore, the presence of CCL5 and CXCL10 in the cytolytic granules of tissue-infiltrating CD8+ T cells expressing CCR5 and CXCR3 reveals a potential self-recruiting mechanism involving activated effector cytotoxic T cells.

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.

The purpose of this paper is to clarify how and why the conservation of Kurazukuri buildings increased the number of tourists and re-vitalized a shopping street in Kawagoe City, Saitama Prefecture.Kawagoe City is located about 30 Kilometers from the central part of Tokyo with a population in 1998 of 324, 879. Ichibangai Street was planned as an area for craftsmen and merchants about 300 years ago. Since then, Ichibangai Street continued to be the center of commerce in Kawagoe City. However, the center of commerce in Kawagoe moved to the south of the city in the early 1960s. This is mainly because Japanese National Railways and three private railways built terminals there, and supermarkets and department stores moved to or were newly-opened nearby. As a consequence, commercial activities in Ichibangai Street declined.Fortunately, a lot of Kurazukuri style warehouses, houses, and stores with their invaluable historical heritage remained as the original buildings. These buildings were constructed to make them fire-proof structures after the great fire of 1893. Following the advice of external architects, the local administration and the inhabitants have become deeply committed to the conservation of these buildings.The local administration took the following steps: 1) providing a subsidy for the restoration of buildings; 2) enforcing landscape regulations; 3) constructing small parks along the street; 4) laying a more attractive pavement; and 5) burying the electric power lines.Inhabitants of Ichibangai Street organized the Kura-No-Kai (Association of Kurazukuri buildings) for the re-vitalization of commerce and conservation of Kurazukuri buildings. One more important action by the inhabitants was to design the Machinami Kihan (Standards for House Conservation) which is applied in the case of house restoration.Today, many tourists visit Ichibangai Street with the number of people visiting Kawagoe amounting to 3.5 million persons per year. Visitors to the Kurazukuri Museum, for example, increased 3.6 times between 1982 and 1997. Tourists make up nearly 100per cent of the customers at shops in Kashiya Yokocho Street and tourists make up at least half of the customers at almost 40per cent of the shops in Ichibangai and Kanetsuki streets. Between 1975 and 1997, almost 60per cent of the shops changed their function, with restaurants and coffee shops for tourists especially increasing in number.A large increase in consumption by tourists has resulted and shops and bustling streets have been re-vitalized. It follows that the inhabitants gained in confidence to conserve the Kurazukuri buildings and to maintain a landscape featuring a row of well-conserved buildings.

A 52-year-old woman had a primary neuroendocrine tumor, Grade 2(NET G2)with multiple liver metastases and a mesenteric tumor. Since no drugs were approved for NET at that time in Japan, we treated her with sunitinib after approval by the Ethics Committee of Mie University Hospital and obtaining informed consent. Sunitinib was administered at a daily dose of 37.5mg/day, but the dose was reduced to 12.5mg/day because of thrombocytopenia(G3)and neutropenia(G3). CT revealed stable disease after 3 months of treatment, but disease progression was observed after 11 months. The non-hematological toxicity was hypertension(G3), which was controlled with antihypertensive agents. Although there are no previous reports of the treatment of well-differentiated NET with sunitinib in Japan, sunitinib may be effective against this disease.

SummaryThe detection of serum 1,3-β-d-glucan (BDG) has been reported to be useful for the diagnosis and therapeutic monitoring of various invasive fungal infections. Although Trichosporon fungemia is increasingly recognized as a fatal mycosis in immunocompromised patients, the utility of this assay for Trichosporon fungemia is still unknown. In our experience (28 cases), the level of BDG rose in about half of the patients with hematologic disorders who developed Trichosporon fungemia. Among them, early death from this infection was more frequently seen in BDG-negative patients than in BDG-positive patients. In addition, overall survival was also significantly worse in BDG-negative patients than in BDG-positive patients. There were no significant differences between these two patient groups in terms of clinical background. Unlike for other invasive fungal infections, elevation of BDG level may indicate a paradoxical sign for Trichosporon fungemia in patients with hematologic disorders.

This study aimed to assess the clinical utility of PCR for the analysis of bacteria and fungi from blood for the management of febrile neutropenic patients with hematologic malignancies. Using a PCR system able to detect a broad range of bacteria and fungi, we conducted a prospective pilot study of periodic analyses of blood from patients following intensive chemotherapy. When fever occurred, it was treated with empirical antibiotic therapy, basically without knowledge of the PCR results. In 23 febrile episodes during the neutropenic period, bacteria were detected by PCR in 11 cases, while the same species were identified by blood culture in 3 cases. In 10 out of 11 PCR-positive cases, fever could be managed by empirical therapy. In the empirical-therapy-resistant case, the identification of Stenotrophomonas maltophilia by PCR led to improvement of fever. No fungi were detected by PCR in febrile cases, while Aspergillus fumigatus was detected in one afebrile patient, several days before a clinical diagnosis was made. In subsequent sporadic PCR analyses in 15 cases of febrile neutropenia, bacteria were detected by both PCR and blood culture in 7 cases and by PCR alone in 6. Fungi were not detected. While fever was improved by empirical therapy in 12 out of the 13 PCR-positive cases, the identification of Pseudomonas aeruginosa by PCR in one therapy-resistant case contributed to the successful treatment of persistent fever. Our results indicate that PCR analysis of bacteria from blood provides essential information for managing empirical-therapy-resistant febrile neutropenia.

Objective Invasive Trichosporon infection has been increasingly recognized in patients with hematologic malignancies. Our study aims to clarify the clinical characteristics of this disease and factors influencing patient prognosis. Patients and methods We retrospectively analyzed 33 cases of Trichosporon fungemia (TF) in patients with hematologic malignancies treated at our collaborating five hospitals in Japan between 1992 and 2007. Results The majority of these patients had acute leukemia (82%), neutropenia (85%), and a history of intensive chemotherapy (91%). TF occurred as a breakthrough infection during antifungal therapy in 30 patients (91%), 18 of whom were receiving micafungin. The surveillance cultures of most patients were negative for Trichosporon. Only a few patients exhibited elevated levels of 1,3-beta-d-glucan before positive blood culture. Twenty-five patients (76%) died of this infection. The resolution of infection was associated with neutrophil recovery (P = 0.0001), absence of hyperglycemia (P = 0.023), and azole inclusive therapy (P = 0.031). Survival was significantly longer in patients receiving antifungal therapies containing azole than in those who did not receive azole (P = 0.0034). Conclusions At present, the diagnosis of invasive trichosporonosis depends on blood culture studies, and the mortality of this disease is high; however, azole therapy and control of blood glucose level, together with hematopoietic recovery could help in improving the clinical outcome. When we use antifungals lacking anti-Trichosporon activity, sufficient care should be taken to prevent the development of breakthrough trichosporonosis.

This study was designed to assess the functional role of interleukin-18 (IL-18) in periodontal tissues. IL-18 transgenic (IL-18Tg) mice and wild-type (WT) mice were inoculated intraorally with Porphyromonas gingivalis. Alveolar bone loss, gingival cytokine levels, and gingival gene expression were assessed using morphometric analysis, enzyme-linked immunosorbent assay (ELISA), and semiquantitative reverse transcription polymerase chain reaction, respectively. P. gingivalis-infection induced periodontal bone loss in IL-18Tg mice, whereas bone loss did not occur in WT mice. Interferon gamma was downregulated only in IL-18Tg mice by P. gingivalis-infection. P. gingivalis-infection upregulated the expression of receptor activator of nuclear factor kappa B ligand (RANKL) in IL-18Tg mice vs. WT-type mice.These results suggest that IL-18Tg mice are highly susceptible to bone loss induced by the periodontal pathogen P. gingivalis, which may be mediated via RANKL-dependent pathway.

Oral lichen planus is a refractory and chronic inflammatory disease with bilateral white reticular lesions on oral mucosa. Identification of Candida species including non-Candida albicans from buccal mucosa, tongue surfaces, and tooth surfaces of oral lichen planus patients by molecular biological method was performed in the present study. The Candida isolates were identified at species level by polymerase chain reaction (PCR) for genes of 18S, 5.8S, and 25/28S ribosomal RNAs and the sequence analyses of these PCR products. The isolation frequency of Candida species was higher from oral lichen planus than from healthy subjects. Non-C. albicans species (Candida glabrata, Candida fukuyamaensis, and Candida parapsilosis) were isolated only from oral lichen planus patients. In addition, Candida fukuyamaensis and Candida parapsilosis were genetically close to C. albicans, while C. glabrata was genetically distinguished from these species. These results support that Candida species are related with oral lichen planus, and suggest that C. glabrata may have a unique pathogenicity to oral lichen planus.

Interleukin (IL)-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in inflammatory and autoimmune disorders. In the present study, immunohistochemical examination showed that the expression of IL-18 was detected in acinar and ductal epithelial cells in the salivary glands of patients with Sjogren’s syndrome (SS) but not in those of healthy subjects. Human salivary gland human parotid gland cell lines (HSY) cells constitutively expressed mRNA of IL-18 and caspase-1. Receptors for IL-18 and IL-17 were expressed on the cell surface. IL-18 induced the secretion of IL-6 and IL-8 in the presence of low amount of IL-17, a T cell-derived proinflammatory cytokine. These results suggest that IL-18 expressed in salivary gland cells is associated with pathogenesis of SS in microenvironment of salivary glands in synergy with IL-17.

This study was designed to determine if sympathetic nerve fibers exist in dentinal tubules in rat normal dental pulp, and if they sprout into the tubules in the inflamed condition. Sympathetic nerve fibers in rat molar dental pulp were labeled using an anterograde axonal transport technique involving injection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into the superior cervical ganglion. In the normal dental pulp, scattered WGA-HRP reaction products were observed in unmyelinated nerve endings in odontoblast layer and subodontoblastic region, mostly close to odontoblast cell bodies. More reaction products were detected in the above areas in the inflamed dental pulp than that in the normal pulp. However, no labeled nerve fibers were observed in dentinal tubules in either normal or inflamed dental pulp. These results indicate that although sympathetic nerve fibers do indeed sprout in inflamed dental pulp, they do not penetrate into the dentinal tubules.

Interleukin (IL)-18 is one of the inflammatory cytokine which is expressed not only in activated macrophages but also in non-immune cells, such as keratinocytes and epithelial cells. It is unclear which type of cell is the major source of serum IL-18. We showed that serum levels of IL-18 were increased in mice treated with Propionibacterium acnes and lipopolysaccharide (LPS), whereas, administration of clodronate-liposomes (Clo-lip) to induce depletion of macrophages showed no obvious effect on IL-18 levels. IL-18 levels were marginal in the liver, lung and spleen. Treatment with P. acnes alone induced IL-18 in each organ, and P. acnes and LPS induced increase in IL-18 levels in the liver and spleen, but decrease in the intestines. The administration of Clo-lip in mice showed only a marginal effect on the IL-18 levels in the organs. These results suggest that IL-18 expressed in keratinocytes/epithelial cells contributes to serum IL-18 levels.

Oral epithelium is endowed with innate immune receptors for bacterial components, which play important roles in host defense against bacterial infection. We examined the expression of various Toll-like receptors (TLRs), NOD1 and NOD2 in oral epithelial cells, and the production of β-defensin 2 and peptidoglycan recognition proteins (PGRPs) upon stimulation with their respective chemically synthesized ligands. We found a clear expression of TLR4 as well as TLR2, and a strong expression of NOD1 and NOD2 in normal oral epithelial tissues by immunohistochemical analysis. In the inflamed oral epithelium, cell-surface localizations of TLR2 and TLR4 were more clearly observed than in the healthy tissue. We also showed that oral epithelial cells in culture constitutively expressed TLR3 and TLR7 in addition to TLR2, TLR4, NOD1, and NOD2, and stimulation with synthetic ligands for these receptors (TLR2 agonistic lipopeptide, TLR3 agonistic poly I:C, TLR4 agonistic lipid A, TLR7 agonistic single-stranded RNA, NOD1 agonistic iE-DAP and NOD2 agonistic muramyldipeptide) markedly up-regulated the expression of antibacterial factors, such as β-defensin 2 and PGRPs, but not the proinflammatory cytokines. These findings indicate that these molecules in oral epithelial cells are functional receptors that induce antibacterial responses without excessive inflammatory responses.

Sjogren’s syndrome (SS) is a chronic autoimmune disease of the exocrine glands with infiltration of lymphocytes and destruction of glandular cells. We previously reported that interleukin (IL)-18, an inflammatory cytokine that is involved in autoimmune diseases, is produced in salivary gland (SG) of SS patients. In this study, histological changes and lymphocytes subpopulations in SG of keratin 5 (K5)/IL-18 transgenic (Tg) mice overexpressing mature IL-18 using human K5 promoter were examined. Histological analysis revealed severe infiltration of lymphocytes and atrophy of glandular duct cells in SG. Flow cytometric analyses showed that T, B, NK cells and Macrophages are infiltrated in SG of the mice. These results indicated that overexpression of IL-18 with K5 promoter induced SS-like feature.

A 66year-old man with sustained fever was diagnosed as having acute myeloid leukemia with multilineage dysplasia. Induction therapy with etoposide and AraC was initiated, but was ineffective. Although fever had persisted for more than a few days, there was no evidence of any infection on radiological examination or culture studies. The patient was disorientated and demonstrated personality change. After a severe convulsive seizure, the patient died. Autopsy findings showed that the leukemic cells had permeated the Virchow Robin space, but without a mass lesion in the cerebral parenchyma. He was diagnosed as having had central nervous system leukemia (CNSL) that provoked sustained fever, consciousness disturbance and convulsive seizure. These findings suggested that the Virchow Robin space plays a particular role in the development of CNSL. Even with repeated cerebrospinal fluid examinations and radiological tests, we were unable to correctly diagnose CNSL before death, which may indicate the intractability of diagnosing CNSL spread along the Virchow Robin space. This case provides useful information about the pathophysiology and diagnosis of CNSL.

Primary effusion lymphoma (PEL) is a unique clinicopathological entity usually associated with human herpesvirus-8 (HHV-8) infection. It occurs almost exclusively in human immunodeficiency virus (HIV) -infected individuals. We presented a rare case of HIV-negative PEL in an elderly HHV-8-negative patient who developed cardiac tamponade due to pericardial effusion. The patient was treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). This disease generally has a poor prognosis; however, this patient achieved complete remission and remains without signs of disease 30 months after the last treatment. Because most HIV-negative and HHV-8- negative PEL cases show pan-B-cell markers, there is considerable usage of rituximab, though its optimal usage for PEL is unclear. To the best of our knowledge, there have been five reported cases where rituximab treatment has been used against HIV-negative and HHV-8-negative PEL. The clinical courses of these cases were relatively good without specific adverse effects. HIV-negative and HHV-8-negative PEL appears to be a reasonably new clinicopathological entity. While further investigation will of course be needed, the use of rituximab is worth considering for treatment of such patients.