Studies on Acute Methionine Toxicity: I. Nucleolar Disaggregation in Guinea Pig Hepatic Cells with Methionine or Ethionine and Its Reversal with Adenine

The effects of methionine and ethionine on the fine structure of hepatic cell nucleoli of guinea pigs and rats were investigated. A single intraperitoneal injection of methionine into guinea pigs results in the disruption of nucleolonema as early as 2 hours after the injection. By 4 hours, nucleoli show complete fragmentation consisting of many small fragments and small remnants of nucleoli. Large aggregates of interchromatinic granules and condensation of chromatin appear in the nucleoplasm. These changes are remarkably similar to the lesions induced by ethionine in the liver of the rat or the guinea pig. The methionine-induced nuclear and nucleolar lesions persist up to 10 hours after the injection. The administration of adenine 4 hours after the methionine injection reverses the nucleolar lesions by 8 hours. The appearance of incompletely reconstructed nucleoli with twisted ropelike structures suggests a pattern of recovery very similar to the adenine-induced nucleolar reformation in ethionine-treated rats. Injecting methionine into rats induced no nucleolar abnormalities. It is suggested that the mechanism of nucleolar fragmentation induced by methionine or ethionine is related to the accumulation of S-adenosyl compounds with concomitant ATP deficiency in the liver.     

Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).     

Prevalence of chlamydia-pneumoniae-specific immunoglobulin M antibody and acute exacerbations of asthma in childhood]

BACKGROUND: Chlamydia pneumoniae is a frequent causative agent of acute respiratory disease and has been recently reported as a possible cause of asthma. We investigated the prevalence of C. pneumoniae infections in childhood patients with acute exacerbations of asthma. METHOD: One hundred twenty-six childhood patients with acute exacerbations of asthma, 77 with acute bronchitis and 22 Respiratory syncytial virus infections were studied. Serum samples were obtained and tested for C. pneumoniae-specific IgM antibody by Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: C. pneumoniae IgM-positive results were observed in 48.4% (Index value>or=1.60) and 23% (Index value>or=1.10) of patients with acute exacerbations of asthma. The prevalence of C. pneumoniae-specific IgM was significantly higher in asthma cases than in other subjects (p<0.05). CONCLUSION: Our data suggest that C. pneumoniae infection may trigger acute exacerbations of childhood asthma.     

Microinvasive ductal carcinoma (T1mic) of the breast. The clinicopathological profile and immunohistochemical features of 28 cases

Microinvasive ductal carcinoma of the breast, namely ductal carcinoma in situ with microinvasion (T1mic) as defined by the American Joint Committee on Cancer (AJCC) Staging Manual, is a rare disease, although it is increasing because of widespread use of mammography. The aim of the present study was to describe the clinicopathological and immunohistochemical features of this entity. Twenty-eight patients who were diagnosed as T1mic from January 1997 to August 2002 were studied by using 3-5 mm-thick serial sections with hematoxylin-eosin staining. Immunohistochemical staining for the estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and HER-2 were performed. All 28 patients were female, with a mean age of 48.8 years. Twenty-six patients (93%) revealed mammographic abnormalities on routine examination. All foci of the invasions were measured using an ocular micrometer. Invasive foci consisted of isolated cells or cell clusters, or appeared as a tongue-like projection of tumor through the basement membrane of the duct of ductal carcinoma in situ (DCIS). The mean number of invasive foci was 3, and the mean size was 0.6 mm. We found that high nuclear grade and predominant comedo subtype of DCIS components were 57.1% and 46.4%, respectively. Twenty-four cases (86%) demonstrated necrosis of DCIS components. Microinvasion was often associated with periductal stromal reaction (71.5%) and/or a lymphocytic infiltration (78.6%). All patients, excluding two, received axillary resection (the mean number of lymph nodes examined per case was 12), and none had lymph node metastasis. The positive expression of ER and PR strongly related to low grade nuclei and non-comedo subtype; however, the positive expression of HER-2 and P53 related to high grade nuclei and comedo subtype (P<0.01). Ki-67 expression was significantly higher in the high grade nuclei group than in the low grade group (P<0.01). Our study suggested that high nuclear grade and comedo DCIS were more aggressive and more common with microinvasion, and that microinvasion is more likely to be multifocal.     

Different effects of the liver mitogens triiodo-thyronine and ciprofibrate on the development of rat hepatocellular carcinoma

Previous work has shown that treatment with thyroid hormone (T3) decreased the incidence of rat hepatocellular carcinoma (HCC). The present study was designed to determine whether the inhibitory effect of T3 on HCC development was limited to early steps of the carcinogenetic process or, whether a similar effect could also be exerted by starting T3 treatment at later stages. Hepatic nodules were induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3 groups: group 1 was maintained on basal diet: group 2 was fed a diet containing 4 mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA administration: group 3 was exposed to cycles of T3 starting 8 months after initiation. Results demonstrate that inhibition of HCC development was essentially similar in rats exposed to T3 starting either 9 weeks or 8 months after initiation (50% inhibition compared to control rats). We have previously shown that T3-induced nodule regression and HCC inhibition occurred in spite of its mitogenic effect. Therefore, we next wished to determine whether a similar antitumoral effect could be exerted by other liver mitogens, such as peroxisome proliferators. Rats exposed to the initiation-promotion protocol described previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented diet, each cycle consisting of 7 days/month: the incidence of HCC and lung metastases was determined 13.5 months after initiation. Results showed that although treatment with T3 strongly inhibited HCC development (only 31% of T3+ rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same number of HCC as T3-untreated rats. In conclusion, the results of this study showed that the anticarcinogenic effect of T3 is maintained also when treatment begins late in the process, and its antitumoral property appears to be specific and may not be shared by other liver mitogens.     

The communicating branch of the 4th cervical nerve to the brachial plexus: the double constitution, anterior and posterior, of its fibers

Twenty-four adult cadavers (48 sides) were used to investigate the incidence of a branch arising from the ventral ramus of the fourth cervical nerve (C4) with the phrenic nerve and subsequently joining the brachial plexus. Six brachial plexuses with spinal cords and phrenic nerves were dissected under a surgical microscope to investigate localization of fibers contained in the C4 branch to the brachial plexus. The incidence of the C4 branch was 23% (11/48 sides). Branches from C4 to the brachial plexus divided into anterior and posterior divisions on four sides (4/6 sides). On two sides, the branch did not divide but consisted entirely of an anterior division (2/6 sides). In the brachial plexus, anterior division fibers of the C4 branch were intertwined with fibers from the anterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve and the anterior division of the superior trunk (6/6 sides). On the other hand, posterior division fibers of the C4 branch were intertwined with fibers from the posterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve (2/6 sides) and the posterior division of the superior trunk (4/6 sides). The anterior division of the C4 branch received fibers from the ventral rootlets of the entire fourth cervical segment, whereas the posterior division received fibers from the ventral rootlets of the caudal half of the fourth cervical segment only. The fact that the suprascapular nerve received fibers from both the anterior and posterior divisions of the C4 branch was considered to support our claim that the human suprascapular nerve belongs to both the anterior and posterior divisions of the brachial plexus.     

Lowered effectiveness of immunotherapy for cypress pollinosis by using Japanese cedar pollen extract]

BACKGROUND: Japanese cedar and cypress pollen share a common antigen. The cedar pollen season is followed by the cypress pollen season. However, both the clinical significance and involvement of cypress pollinosis in the treatment of the cedar pollinosis have not yet been clarified. METHODS: The clinical efficacy of sublingual immunotherapy with cedar pollen extract for cedar pollinosis was evaluated during the cypress pollen dispersal season in Japan. In addition, the change in cypress pollen specific IgE antibodies of the patients with cedar pollinosis was examined before and after the pollen season. RESULTS: Sublingual immunotherapy with cedar pollen extract did not improve the clinical symptoms of the cedar pollinosis patients combined with cypress pollinosis in the cypress pollen season. The cypress pollen specific IgE antibodies were found to demonstrate significant seasonal changes. CONCLUSION: The presence of cypress pollinosis should therefore be taken into consideration when planning the optimal treatment for cedar pollinosis. Sublingual immunotherapy with cedar pollen extract may not be effective for cypress pollinosis.     

MALLORY BODY-LIKE STRUCTURES IN THE LUNG

Mallory body-like structures (MBLs), which resemble Mallory body (MB) in the liver, were observed in lungs of 4 cases showing interstitial pneumonitis. MBLs were found in the cytoplasm of especially swollen alveolar epithelial cells. MBLs and MBs had almost similar characteristics morphologically and tinctorially under the light microscopy. MBLs were composed of intermediate type fine fibrils which were positive for anti-keratin antibody. These findings suggested that MBLs were a kind of pathological keratinization of alveolar epithelial cells. Although the origin of MBL containing cells could not be clarified, they were closely related to type 2 alveolar epithelial cells.     

Effects of Bordetella bronchiseptica dermonecrotic toxin on the structure and function of osteoblastic clone MC3T3-e1 cells.

The effects of Bordetella bronchiseptica dermonecrotic toxin on the structure and function of a clonal osteoblastic cell line, MC3T3-E1, were investigated. The toxin induced a morphological change in the cells from a spindle shape to a spherical form with many blebs. The toxin-treated cells were viable and grew to form confluent cell layers composed of irregularly shaped cells and multinuclear cells. The toxin inhibited elevation of alkaline phosphatase activity in the cells in a dose-dependent manner at concentrations from 10 pg to 10 ng/ml. The accumulation of type I collagen in the cells was also reduced by the toxin. Since high alkaline phosphatase activity and accumulation of collagen are closely linked to differentiation of the cells into osteoblasts, it is considered likely that B. bronchiseptica dermonecrotic toxin impairs the ability of the cells to differentiate.