Primary Gingival Tuberculosis Diagnosed Based on Genetic Identification.

A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva.

Thyroid carcinomas found incidentally in the cervical lymph nodes: do they arise from heterotopic thyroid tissues?

PURPOSE: Thyroid carcinomas have been found incidentally in the cervical lymph nodes during surgery for head and neck squamous cell carcinoma (SCC). Such carcinomas have been considered a metastatic focus for malignant transformation of heterotopic thyroid tissue. We report on cases of so-called occult thyroid carcinoma in the cervical lymph nodes, and review the relevant literature. PATIENTS AND METHODS: We encountered 3 cases of incidental papillary carcinoma in the cervical lymph nodes of patients with oral SCC, and consequently reviewed 75 previously reported cases. RESULTS: Among 148 patients with oral SCC who had undergone cervical lymph node dissection, 3 were diagnosed with occult thyroid carcinoma. Papillary carcinomas were found in 3, 10, and 3 lymph nodes in cases 1, 2, and 3, respectively. Computed tomography showed 2 tumor-like shadows and 1 calcified mass in the thyroid gland in cases 2 and 3, respectively. These shadows did not enlarge during the 3 to 5 years of observation, and all patients are alive, without any events related to the neck and thyroid gland. Among the reviewed cases, approximately two fifths were histopathologically or clinically free from thyroid carcinoma. Progressive thyroid carcinoma was not detected in any patient. CONCLUSIONS: We propose the possibility that thyroid carcinoma in the cervical lymph nodes is not necessarily metastatic, but may occasionally arise from heterotopic thyroid tissue.

Full-length sequences of two hepatitis E virus isolates representing an Eastern China-indigenous subgroup of genotype 4.

Although the majority of hepatitis E virus (HEV) infections in Japan are 'domestic' due to the presence of indigenous strains, there are still 'imported' cases as well. Among 83 patients with non-A, non-B and non-C acute liver diseases admitted to Saitama Medical University Hospital, 7 (8.4%) were positive for serum HEV-RNA, of whom 2 had a recent history of traveling to China, one to Xian and another to Shanghai. We determined the full-genome sequences of HEV from these 2 patients (isolate names are JKO-ChiSai98c and JYI-ChiSai01c, genotype 4 in both) for phylogenetic analyses. Initially, when compared only to the 13 full-genome sequences of genotype 4 so far reported, our 2 isolates were thought to be novel strains because they showed a significant genetic difference from the sequences known to date. However, when we included a set of short sequences (150 nt) recently reported from China in the comparison, we found that our 2 isolates represent a subgroup of genotype 4, which seems to be restricted to eastern China. In conclusion, the 2 HEV isolates reported here could serve as full-genome prototypes for an eastern China-indigenous subgroup of the genotype 4 HEV.

Increased cytoprotective function in the liver of transgenic mice expressing osteopontin in hepatocytes.

Osteopontin is a crucial factor for initiation of Th1 immune reaction. Previously, we established transgenic mice expressing osteopontin in hepatocytes, in which lymphocyte infiltration occurred spontaneously at 12 weeks of age and liver necrosis at 24 weeks of age. This liver necrosis may develop through provocation by excessive Th1 immune reaction, but it is also possible that hepatocytes become fragile under abundant osteopontin in the cytoplasm. Thus, gene expression profiles in the liver were evaluated to seek such contributing factors in the transgenic mice. On DNA microarray analysis of 3774 mouse genes, 16 genes were selected as hepatic genes significantly up-regulated in the transgenic mice aged 8 weeks than in the negative littermate, which included mRNAs of cytoprotective metallothionein and glutathione S-transferase (GST). Hepatic up-regulations of both genes were also seen by Western blotting. Liver necrosis in the centrilobular areas developed after carbon tetrachloride treatment, but its histological extent and plasma ALT activities were significantly smaller in the transgenic mice aged 8 weeks than in the wild-type C57BL/6 control mice. We conclude that cytoprotective function of the liver is increased through up-regulated expressions of metallothionein and GST, and thereby susceptibility of hepatocytes to the stress may be less possible, if any, in the development of spontaneous liver necrosis in transgenic mice expressing osteopontin in hepatocytes.

Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes-A clue to advent of pathological state in various organs of chronic hepatitis C patients.

Osteopontin is a cytokine essential for initiation of Th1 immune reaction. We established transgenic mice expressing osteopontin in hepatocyte, in which liver necrosis with lymphocyte infiltration developed gradually from 12 weeks of age with up-regulated osteopontin levels in the circulation, suggesting that extrahepatic manifestations might also occur as a result of excessive Th1 immune reaction. We examined histological and immunohistochemical features of various organs in these mice. Splenomegaly and enlargement of lymph nodes around the liver and intestine became apparent with marked infiltration of small lymphocytes in the transgenic mice later than 24 weeks of age. Immunostaining revealed that lymphocytes in the spleen and lymph nodes were positive for either CD3 or CD20, suggesting that the infiltrating lymphocytes were both B and T cells. Similar lymphocyte infiltration was found in the lung, kidney and submandibular gland. Alveolar septa became hypertrophic with lymphocyte infiltration, and the lung showed the appearance of interstitial pneumonia. These lesions are similar to extrahepatic manifestations in chronic hepatitis C patients, suggesting that augmented Th1 immune reaction to hepatitis C virus (HCV) proteins or the proteins with molecular mimicry of HCV may be a contributing factor for the formation of the pathological state not only in the liver but also in various organs under chronic infection of hepatitis C virus.

Administration of ANG II induces iron deposition and upregulation of TGF-beta1 mRNA in the rat liver.

We previously found that ANG II infusion into rats causes iron deposition in the kidney and heart, which may have a role in the regulation of profibrotic gene expression and tissue fibrosis. In the present study, we have investigated whether ANG II can also induce iron accumulation in the liver. Prussian blue staining detected frequent iron deposition in the interstitium of the liver of rats treated with pressor dose ANG II for 7 days, whereas iron deposition was absent in the livers of control rats. Immunohistochemical and histological analyses showed that some iron-positive nonparenchymal cells were positive for ferritin and heme oxygenase-1 (HO-1) protein and TGF-beta1 mRNA and were judged to be monocytes/macrophages. It was shown that ANG II infusion caused about a fourfold increase in ferritin and HO-1 protein expression by Western blot analysis and about a twofold increase in TGF-beta1 mRNA expression by Northern blot analysis, which were both suppressed by treating ANG II-infused rats with losartan and deferoxamine. In addition, mild interstitial fibrosis was observed in the liver of rats that had been treated with pressor dose ANG II for 7 days or with nonpressor dose ANG II for 30 days, the latter of which also caused loss of hepatocytes and intrahepatic hemorrhage in the liver. Taken together, our data suggest that ANG II infusion induces aberrant iron homeostasis in the liver, which may have a role in the ANG II-induced upregulation of profibrotic gene expression in the liver.

Plasma osteopontin levels in patients with fulminant hepatitis.

Fulminant hepatitis is characterized by massive or submassive liver necrosis. Massive liver necrosis can be induced by activated macrophages infiltrating into the liver. Osteopontin, an extracellular matrix, is a secretory glycoprotein as well essential for Th1 immune response, contributing to macrophage activation and infiltration. To know the significance of osteopontin in the development of fulminant hepatitis, plasma osteopontin levels were measured in patients with fulminant hepatitis. The levels were significantly greater in patients with fulminant hepatitis than in those with acute or chronic hepatitis as well as healthy adults. Among patients with fulminant hepatitis except one in whom bacterial infection was complicated, plasma osteopontin levels were elevated especially in the patients who developed hepatic encephalopathy of grade II or more within 10 days of the disease onset, a clinical type characteristic of massive liver necrosis. Immunohistochemical examination revealed that osteopontin was stained in macrophages positive for CD68, a marker for macrophages, in necrotic areas of the liver in a patient with fulminant hepatitis. In conclusion, plasma osteopontin levels were elevated in patients with fulminant hepatitis, probably reflecting production of osteopontin in Kupffer cells and hepatic macrophages, which might be involved in the development of massive liver necrosis in fulminant hepatitis.

Transgenic mice expressing osteopontin in hepatocytes as a model of autoimmune hepatitis.

Osteopontin, a crucial factor for Th1 immune response, is expressed in stellate cells and macrophages activated in injured liver. To clarify the role of osteopontin in inflammatory changes in the liver, we attempted to establish transgenic mice expressing osteopontin in hepatocytes. Mouse osteopontin cDNA, cloned from concanavalin-A-stimulated spleen cells in C57BL/6 mice, was constructed into the vector containing serum amyloid-P component promoter. This construction was microinjected into fertilized eggs of C57BL/6 mice, and 4 lines of the transgenic mice were obtained. Western blotting and immunohistochemistry revealed that osteopontin was expressed in hepatocytes, but not in non-parenchymal cells, in the transgenic mice. The mean osteopontin concentrations in the liver and plasma in the mice were 13 and 2.6 times higher than those in negative littermates. Antinuclear antibody was positive in the plasma in 50% of the transgenic mice. In the transgenic mice later than 12 weeks of age, mononuclear cell infiltration in the liver developed, and these cells were positive for CD8 and HLA-DR. Plasma ALT activity was increased with focal necrosis in hepatic lobules in the transgenic mice later than 24 weeks of age. The transgenic mice expressing osteopontin in hepatocytes may be useful as a model of autoimmune hepatitis.

Adenovirus-mediated overexpression of follistatin enlarges intact liver of adult rats.

Under normal physiologic conditions, liver size is under strict regulatory control. Activin, a member of the transforming growth factor beta (TGF-beta) superfamily, is expressed in the intact adult liver and is an inhibitor of hepatocyte growth. However, the exact role played by endogenous activin in maintaining the size of a normal adult liver has yet to be completely examined in vivo. Here, we report the development of an adenoviral vector (AdexCAFS288) that expressed human follistatin-288, which binds to activin and neutralizes its biologic activities. AdexCAGFP, a control virus, expressed green fluorescent protein. AdexCAFS288 effectively expressed follistatin-288, as measured both in HepG2 cell lysate and conditioned medium and blocked activin signaling and its biologic functions in vitro. Intraperitoneal injection of AdexCAFS288 in vivo resulted in significant liver growth (146% of control) in intact liver of adult male rats 12 days following treatment without significant dysfunctions. The increase in liver size was attributed to increased hepatocyte proliferation, as monitored by the mitotic index. Furthermore, there was a significant correlation between serum follistatin levels and liver weight. In conclusion, our results suggest that activin plays a critical role in maintaining optimal liver size and implicates the endogenous activin system as a therapeutic target in the treatment of liver disease.

Possible mechanisms of elevation of serum transaminase levels during interferon-beta therapy in chronic hepatitis C patients.

BACKGROUND: Serum transaminase levels are frequently elevated in patients with chronic hepatitis C who are receiving interferon (IFN)-beta therapy, despite hepatitis C virus (HCV)-RNA being eradicated from the serum. We examined liver histology to determine the reason for this elevation. METHODS: Patients with chronic hepatitis C, diagnosed by liver histology and positive serum HCV-RNA, were given intravenous injections of IFN-beta, at a daily dose of 6 MU, every day for periods of 6 to 12 weeks. When serum alanine transaminase (ALT) levels during the therapy were higher than three times the levels before the therapy, liver biopsy was performed. Histological findings on light microscopy were compared in liver biopsy specimens obtained before and during the therapy. RESULTS: An increase in serum ALT levels was found in 19 of the 102 patients who received the IFN-beta therapy. Autoimmune hepatitis was not contributory in any of these 19 patients, because serum antinuclear antigen was negative and IgG levels were not increased. Liver histology was examined in 10 of these 19 patients. The period between the start of IFN-beta therapy and the biopsy during the therapy ranged from 14 to 46 days. In 2 patients, the extent of mononuclear cell infiltration in the liver and hepatocyte necrosis was less than the extent before the therapy. In the remaining 8 patients, the grade of chronic hepatitis was unchanged during,the therapy, but vacuole formation and apoptotic nuclei in hepatocytes were found in 2 patients, and centrilobular necrotic areas in 1 patient. CONCLUSIONS: The elevation of serum ALT levels during IFN-beta therapy in chronic hepatitis C patients was not a result of increased hepatitis activity. Degenerative, apoptotic, and necrotic changes in hepatocytes, probably a result of the cytotoxic effects of IFN-beta, may have contributed to this elevation of ALT levels. However, such changes were absent in most of the patients, suggesting that decisions on the discontinuation of IFN-beta therapy must be made in accordance with liver histology findings.