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1.  A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration 
Case Reports in Endocrinology  2015;2015:416145.
Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.
PMCID: PMC4309302  PMID: 25664188
2.  Effects of xenon irradiation of the stellate ganglion region on fibromyalgia 
[Purpose] The aim of the study was to determine the effect of xenon irradiation of the stellate ganglion region on fibromyalgia. [Subjects] The study included 5 men and 22 women (age, 56.4 ± 16.3 years [range, 25–84 years]) who were diagnosed with fibromyalgia according to the modified 2010 criteria of the American College of Rheumatology between July and August 2013. [Methods] Bilateral xenon light irradiation (0.38–1.1 μm) around the stellate ganglion was performed in the supine position by physical therapists using a xenon phototherapy device. We evaluated pain before and after irradiation using the visual analogue scale. [Results] We did not observe a relationship between the change in the visual analogue scale score and duration of fibromyalgia. However, we observed a relationship between the change in the visual analogue scale score and the score for the Japanese version of the Fibromyalgia Impact Questionnaire using the Cochran-Armitage test for trend. [Conclusion] Xenon light irradiation of the stellate ganglion significantly decreased the visual analogue scale score in patients with fibromyalgia having a higher score in the Fibromyalgia Impact Questionnaire, suggesting that a stronger effect could be obtained in patients with more severe fibromyalgia.
PMCID: PMC4305564  PMID: 25642075
Fibromyalgia; Xenon light irradiation; Stellate ganglion
3.  Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system: a study using green fluorescent protein transgenic zebrafish 
Nitro-fatty acids are electrophilic fatty acids produced in vivo from nitrogen peroxide that have many physiological activities. We recently demonstrated that nitro-fatty acids activate the Keap1-Nrf2 system, which protects cells from damage owing to electrophilic or oxidative stresses via transactivating an array of cytoprotective genes, although the molecular mechanism how they activate Nrf2 is unclear. A number of chemical compounds with different structures have been reported to activate the Keap1-Nrf2 system, which can be categorized into at least six classes based on their sensing pathways. In this study, we showed that nitrooleic acid (OA-NO2), one of major nitro-fatty acids, activates Nrf2 in the same manner that of a cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) using transgenic zebrafish that expresses green fluorescent protein (GFP) in response to Nrf2 activators. In transgenic embryos, GFP was induced in the whole body by treatment with OA-NO2, 15d-PGJ2 or diethylmaleate (DEM), but not with hydrogen peroxide (H2O2), when exogenous Nrf2 and Keap1 were co-overexpressed. Induction by OA-NO2 or 15d-PGJ2 but not DEM was observed, even when a C151S mutation was introduced in Keap1. Our results support the contention that OA-NO2 and 15d-PGJ2 share an analogous cysteine code as electrophiles and also have similar anti-inflammatory roles.
PMCID: PMC4124525  PMID: 21143560
4.  Increase of nerve growth factor levels in the human herniated intervertebral disc: can annular rupture trigger discogenic back pain? 
Arthritis Research & Therapy  2014;16(4):R159.
Nerve growth factor (NGF) has an important role in the generation of discogenic pain. We hypothesized that annular rupture is a trigger for discogenic pain through the action of NGF. In this study, the protein levels of NGF in discs from patients with disc herniation were examined and compared with those from discs of patients with other lumbar degenerative disc diseases.
Patients (n = 55) with lumbar degenerative disc disease treated by surgery were included. Nucleus pulposus tissue (or herniated disc tissue) was surgically removed and homogenized; protein levels were quantified using an enzyme-linked immunosorbent assay (ELISA) for NGF. Levels of NGF in the discs were compared between 1) patients with herniated discs (herniated group) and those with other lumbar degenerative disc diseases (non-herniated group), and 2) low-grade and high-grade degenerated discs. Patient’s symptoms were assessed using a visual analog scale (VAS) and the Oswestry disability index (ODI); the influence of NGF levels on pre- and post-operative symptoms was examined.
Mean levels of NGF in discs of patients were significantly higher in herniated discs (83.4 pg/mg total protein) than those in non-herniated discs (68.4 pg/mg).
No significant differences in levels of NGF were found between low-grade and high-grade degenerated discs. Multivariate analysis, adjusted for age and sex, also showed significant correlation between the presence of disc herniation and NGF levels, though no significant correlation was found between disc degeneration and NGF levels. In both herniated and non-herniated groups, pre-operative symptoms were not related to NGF levels. In the herniated group, post-operative lower extremity pain and low back pain (LBP) in motion were greater in patients with low levels of NGF; no significant differences were found in the non-herniated group.
This study reports that NGF increased in herniated discs, and may play an important role in the generation of discogenic pain. Analysis of patient symptoms revealed that pre-operative NGF levels were related to post-operative residual lower extremity pain and LBP in motion. The results suggest that NGF in the disc is related to pain generation, however, the impact of NGF on generation of LBP varies in individual patients.
Electronic supplementary material
The online version of this article (doi:10.1186/ar4674) contains supplementary material, which is available to authorized users.
PMCID: PMC4261264  PMID: 25069717
5.  Total-body low-dose irradiation of mice induces neither learning disability and memory impairment in Morris water maze test nor Alzheimer's disease-like pathogensis in the brain 
Journal of Radiation Research  2014;55(Suppl 1):i20-i21.
Purpose: Alzheimer's disease (AD) is the most common form of dementia, while its cause and progression are not well understood [ 1]. The possible cognitive and behavioral consequences induced by low-dose radiation are of great concern as humans are exposed to ionizing radiations from various sources including medical diagnosis [ 2]. A recent study in mice reported early transcriptional response in brain to low-dose X-rays (0.10 Gy) suggesting alterations of molecular networks and pathways associated with cognitive functions, advanced aging and AD. The present study is to investigate the late pathological, cognitive and behavioral consequences induced by low-dose radiation.
Materials and methods: C57BL/6J mice were total-body irradiated with an acute dose from X-rays (0.10 Gy) or carbon ions (0.05 or 0.10 Gy). The hippocampus was collected and the expression of 84 AD-related genes was analyzed. Morris water maze test was applied to the measurement of the learning ability and memory of the animals. Amyloid imaging with positron emission tomography were performed to detect the accumulation of fibrillary amyloid β peptide (Aβ), and characteristic pathologies of AD were examined with immunohistochemical staining of amyloid precursor protein (APP), Aβ, tau, and phosphorylated tau.
Results: For the transcriptional studies, results showed that a few genes out of 84 AD-related genes were significantly up-regulated at 4 h after irradiation and the other genes had no marked change; on the other hand, a few other genes showed a significant down-regulation, while the other genes had no marked change at 1 year after irradiation. For the behavioral studies, no significant difference on learning ability and memory was observed at 1 and 2 years after irradiation. Imaging and immunohistochemical staining showed no change in the accumulation of fibrillar amyloid and the expression of APP, Aβ, tau and phosphorylated tau were detectable in the animals 4 months and 2 years after irradiation.
Conclusion: These findings suggest that total-body irradiation at a dose of 0.10 Gy could hardly induce significant early or late transcriptional alterations in most of the AD-related genes in the hippocampus, learning disability and memory impairment, and AD-like pathological change in the brain in mice [ 3].
PMCID: PMC3941512
total-body irradiation; low dose; Alzheimer's disease; Morris water maze test; Alzheimer's disease-like pathogenesis; mice
6.  Enhanced diagnostic accuracy for quantitative bone scan using an artificial neural network system: a Japanese multi-center database project 
EJNMMI Research  2013;3:83.
Artificial neural network (ANN)-based bone scan index (BSI), a marker of the amount of bone metastasis, has been shown to enhance diagnostic accuracy and reproducibility but is potentially affected by training databases. The aims of this study were to revise the software using a large number of Japanese databases and to validate its diagnostic accuracy compared with the original Swedish training database.
The BSI was calculated with EXINIbone (EB; EXINI Diagnostics) using the Swedish training database (n = 789). The software using Japanese training databases from a single institution (BONENAVI version 1, BN1, n = 904) and the revised version from nine institutions (version 2, BN2, n = 1,532) were compared. The diagnostic accuracy was validated with another 503 multi-center bone scans including patients with prostate (n = 207), breast (n = 166), and other cancer types. The ANN value (probability of abnormality) and BSI were calculated. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) analyses were performed.
The ROC analysis based on the ANN value showed significant improvement from EB to BN1 and BN2. In men (n = 296), the area under the curve (AUC) was 0.877 for EB, 0.912 for BN1 (p = not significant (ns) vs. EB) and 0.934 for BN2 (p = 0.007 vs. EB). In women (n = 207), the AUC was 0.831 for EB, 0.910 for BN1 (p = 0.016 vs. EB), and 0.932 for BN2 (p < 0.0001 vs. EB). The optimum sensitivity and specificity based on BN2 was 90% and 84% for men and 93% and 85% for women. In patients with prostate cancer, the AUC was equally high with EB, BN1, and BN2 (0.939, 0.949, and 0.957, p = ns). In patients with breast cancer, the AUC was improved from EB (0.847) to BN1 (0.910, p = ns) and BN2 (0.924, p = 0.039). The NRI using ANN between EB and BN1 was 17.7% (p = 0.0042), and that between EB and BN2 was 29.6% (p < 0.0001). With respect to BSI, the NRI analysis showed downward reclassification with total NRI of 31.9% ( p < 0.0001).
In the software for calculating BSI, the multi-institutional database significantly improved identification of bone metastasis compared with the original database, indicating the importance of a sufficient number of training databases including various types of cancers.
PMCID: PMC3877947  PMID: 24369784
Bone scintigraphy; Bone scan index; Artificial neural network; Databases; Multi-center study
7.  Total body 100-mGy X-irradiation does not induce Alzheimer's disease-like pathogenesis or memory impairment in mice 
Journal of Radiation Research  2013;55(1):84-96.
The cause and progression of Alzheimer's disease (AD) are poorly understood. Possible cognitive and behavioral consequences induced by low-dose radiation are important because humans are exposed to ionizing radiation from various sources. Early transcriptional response in murine brain to low-dose X-rays (100 mGy) has been reported, suggesting alterations of molecular networks and pathways associated with cognitive functions, advanced aging and AD. To investigate acute and late transcriptional, pathological and cognitive consequences of low-dose radiation, we applied an acute dose of 100-mGy total body irradiation (TBI) with X-rays to C57BL/6J Jms mice. We collected hippocampi and analyzed expression of 84 AD-related genes. Mouse learning ability and memory were assessed with the Morris water maze test. We performed in vivo PET scans with 11C-PIB, a radiolabeled ligand for amyloid imaging, to detect fibrillary amyloid beta peptide (Aβ) accumulation, and examined characteristic AD pathologies with immunohistochemical staining of amyloid precursor protein (APP), Aβ, tau and phosphorylated tau (p-tau). mRNA studies showed significant downregulation of only two of 84 AD-related genes, Apbb1 and Lrp1, at 4 h after irradiation, and of only one gene, Il1α, at 1 year after irradiation. Spatial learning ability and memory were not significantly affected at 1 or 2 years after irradiation. No induction of amyloid fibrillogenesis or changes in APP, Aβ, tau, or p-tau expression was detected at 4 months or 2 years after irradiation. TBI induced early or late transcriptional alteration in only a few AD-related genes but did not significantly affect spatial learning, memory or AD-like pathological change in mice.
PMCID: PMC3885129  PMID: 23908553
total-body X-irradiation; low dose; Alzheimer's disease; Morris water maze test; Alzheimer's disease-like pathogenesis; mice
10.  Tissue-Restricted Expression of Nrf2 and Its Target Genes in Zebrafish with Gene-Specific Variations in the Induction Profiles 
PLoS ONE  2011;6(10):e26884.
The Keap1-Nrf2 system serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than one hundred cytoprotective proteins, including antioxidants and phase 2 detoxifying enzymes. Since induction profiles of Nrf2 target genes have been studied exclusively in cultured cells, and not in animal models, their tissue-specificity has not been well characterized. In this paper, we examined and compared the tissue-specific expression of several Nrf2 target genes in zebrafish larvae by whole-mount in situ hybridization (WISH). Seven zebrafish genes (gstp1, mgst3b, prdx1, frrs1c, fthl, gclc and hmox1a) suitable for WISH analysis were selected from candidates for Nrf2 targets identified by microarray analysis. Tissue-restricted induction was observed in the nose, gill, and/or liver for all seven genes in response to Nrf2-activating compounds, diethylmaleate (DEM) and sulforaphane. The Nrf2 gene itself was dominantly expressed in these three tissues, implying that tissue-restricted induction of Nrf2 target genes is defined by tissue-specific expression of Nrf2. Interestingly, the induction of frrs1c and gclc in liver and nose, respectively, was quite low and that of hmox1a was restricted in the liver. These results indicate the existence of gene-specific variations in the tissue specificity, which can be controlled by factors other than Nrf2.
PMCID: PMC3201981  PMID: 22046393
11.  Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients 
Archives of Dermatological Research  2011;303(6):451-455.
Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome (MS). Psoriasis patients have a high prevalence of the MS. In this study, we investigated the statistics of circulating Th17-related cytokines and adipokines in psoriasis patients. Our study identified the significant elevation of serum IL-6, IL-21, IL-22, and resistin levels in psoriasis patients. Increased serum levels of IL-22 and adiponectin were positively correlated with Psoriasis Area and Severity Index (PASI). In contrast, serum high molecular weight adiponectin levels were decreased in psoriasis and negatively correlated with PASI.
PMCID: PMC3140918  PMID: 21681565
IL-6; IL-21; IL-22; Resistin; Adiponectin; HMW-adiponectin
12.  Expression of a transgene encoding mutant p193/CUL7 preserves cardiac function and limits infarct expansion after myocardial infarction 
Heart (British Cardiac Society)  2009;95(14):1159-1164.
Transgenic mice expressing the dominant interfering p193 protein in cardiomyocytes (MHC-1152stop mice) exhibit an induction of cell cycle activity and altered remodeling following experimental myocardial infarction (MI). We hypothesized that the altered remodeling would result in improved cardiac function in the MHC-1152stop mice following MI, as compared to non-transgenic mice.
MHC-1152stop mice and non-transgenic littermates were subjected to experimental MI via permanent occlusion of the coronary artery. Infarct size was determined at 24 hrs and at 4 weeks post-MI, and left ventricular pressure-volume measurements were performed at 4 weeks post-MI in infarcted and sham-operated animals.
Infarct size in MHC-1152stop mice and non-transgenic littermates was not statistically different at 24 hrs post-MI, as measured by tetrazolium staining. Morphometric analysis revealed that infarct scar expansion at 4 weeks post-MI was reduced by 10% in the MHC-1152stop mice (p<0.05). No differences in cardiac function were detected between sham-operated MHC-1152stop mice and their non-transgenic littermates. However, at 4 weeks post-MI ventricular isovolumic relaxation time constant (Tau) was decreased by 19% (p<0.05), and the slope of the dP/dtmax-EDV relationship was 99% increased (p<0.05), in infarcted MHC-1152stop mice as compared to infarcted non-transgenic littermates.
Expression of the dominant interfering p193 transgene resulted in a decrease in infarct scar expansion and preservation of myocardial function at 4 weeks post-MI. Antagonization of p193 activity may represent an important strategy for the treatment of MI.
PMCID: PMC3020667  PMID: 19435717
myocardial infarction; apoptosis; cardiac function; infarct size; heart regeneration
13.  Cardiomyocyte cell cycle activation ameliorates fibrosis in the atrium 
Circulation research  2005;98(1):141-148.
MHC-TGFcys33 ser transgenic mice have elevated levels of active Transforming Growth Factor (TGF)-beta1 in the myocardium. Previous studies have shown that these animals develop atrial, but not ventricular, fibrosis. Here we show that atrial fibrosis was accompanied with cardiomyocyte apoptosis. Although similar levels of cardiomyocyte apoptosis were present in the right and left atria of MHC-TGFcys33 ser hearts, the extent of fibrosis was more pronounced in the right atrium. Thus, additional factors influence the degree of atrial fibrosis in this model. Tritiated thymidine incorporation studies revealed cardiomyocyte cell cycle activity in left atrial cardiomyocytes, but not in right atrial cardiomyocytes. These observations suggested that cardiomyocyte cell cycle activation ameliorated the severity of atrial fibrosis. To directly test this hypothesis, MHC-TGFcys33 ser mice were crossed with MHC-cycD2 mice (which have constitutive cardiomyocyte cell cycle activity in the right atrium). Mice inheriting both transgenes exhibited right atrial cardiomyocyte cell cycle activity and a concomitant reduction in the severity of right atrial fibrosis, despite the presence of a similar level of cardiomyocyte apoptosis as was observed in mice inheriting the MHC-TGFcys33 ser transgene alone. These data support the notion that cardiomyocyte cell cycle induction can antagonize fibrosis in the myocardium.
PMCID: PMC2696639  PMID: 16306446
cardiomyocyte proliferation; cardiac myocyte apoptosis; heart regeneration
14.  The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation 
Molecular cell  2008;30(4):403-414.
Recent genetic studies have documented a pivotal growth-regulatory role played by the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein. In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends onmammalian target of rapamycin and the p70 S6 kinase activities. Interestingly, while embryonic fibroblasts of Cul7−/− mice were found to accumulate IRS-1 and exhibit increased activation of IRS-1’s downstream Akt and MEK/ERK pathways, these null cells grew poorly and displayed phenotypes reminiscent of those associated with oncogene-induced senescence. Taken together, our findings demonstrate a key role for the CUL7 E3 in targeting IRS-1 for degradation, a process that may contribute to the regulation of cellular senescence.
PMCID: PMC2633441  PMID: 18498745
16.  Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition 
Gut  2008;57(11):1531-1538.
Background and aims:
The effect of adiponectin on colorectal carcinogenesis has been proposed but not fully investigated. We investigated the effect of adiponectin deficiency on the development of colorectal cancer.
We generated three types of gene-deficient mice (adiponectin-deficient, adiponectin receptor 1-deficient, and adiponectin receptor 2-deficient) and investigated chemical-induced colon polyp formation and cell proliferation in colon epithelium. Western blot analysis was performed to elucidate the mechanism which affected colorectal carcinogenesis by adiponectin deficiency.
The numbers of colon polyps were significantly increased in adiponectin-deficient mice compared with wild-type mice fed a high-fat diet. However, no difference was observed between wild-type and adiponectin-deficient mice fed a basal diet. A significant increase in cell proliferative activity was also observed in the colonic epithelium of the adiponectin-deficient mice when compared with wild-type mice fed a high-fat diet; however, no difference was observed between wild-type and adiponectin-deficient mice fed a basal diet. Similarly, an increase in epithelial cell proliferation was observed in adiponectin receptor 1-deficient mice, but not in adiponectin receptor 2-deficient mice. Western blot analysis revealed activation of mammalian target of rapamycin, p70 S6 kinase, S6 protein and inactivation of AMP-activated protein kinase in the colon epithelium of adiponectin-deficient mice fed with high-fat diet.
Adiponectin suppresses colonic epithelial proliferation via inhibition of the mammalian target of the rapamycin pathway under a high-fat diet, but not under a basal diet. These studies indicate a novel mechanism of suppression of colorectal carcinogenesis induced by a Western-style high-fat diet.
PMCID: PMC2582344  PMID: 18676419
17.  Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1 
Circulation research  2004;94(11):1458-1465.
Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.
PMCID: PMC2129102  PMID: 15117823
atrial fibrillation; fibrosis; growth factors
18.  Accumulation of Amino Acid Substitutions Promotes Irreversible Structural Changes in the Hemagglutinin of Human Influenza AH3 Virus during Evolution 
Journal of Virology  2005;79(10):6472-6477.
In order to clarify the effect of an accumulation of amino acid substitutions on the hemadsorption character of the influenza AH3 virus hemagglutinin (HA) protein, we introduced single-point amino acid changes into the HA1 domain of the HA proteins of influenza viruses isolated in 1968 (A/Aichi/2/68) and 1997 (A/Sydney/5/97) by using PCR-based random mutation or site-directed mutagenesis. These substitutions were classified as positive or negative according to their effects on the hemadsorption activity. The rate of positive substitutions was about 50% for both strains. Of 44 amino acid changes that were identical in the two strains with regard to both the substituted amino acids and their positions in the HA1 domain, 22% of the changes that were positive in A/Aichi/2/68 were negative in A/Sydney/5/97 and 27% of the changes that were negative in A/Aichi/2/68 were positive in A/Sydney/5/97. A similar discordance rate was also seen for the antigenic sites. These results suggest that the accumulation of amino acid substitutions in the HA protein during evolution promoted irreversible structural changes and therefore that antigenic changes in the H3HA protein may not be limited.
PMCID: PMC1091720  PMID: 15858030
19.  Multifocal intraportal invasion of breast carcinoma diagnosed by laparoscopy-assisted liver biopsy 
Hepar lobatum carcinomatosum (HLC) is defined as an acquired hepatic deformity consisting of an irregularly lobulated hepatic contour caused by intravascular infiltration of metastatic carcinoma. To date, only nine cases of HLC have been reported in the literature. We report a case of a 68-year-old woman showing hepatic metastasis of breast carcinoma in radiologically unidentified form. Initially, she received left partial mastectomy for breast cancer but solid hepatic metastases were identified in S2 and S6, 9 mo after surgery. Then, they responded to chemotherapy and radiologically disappeared. After radiological disappearance of the liver tumors, the patient's blood chemistry showed abnormal liver function. A CT scan demonstrated heterog-eneous enhancement effect in the liver in the late phase, suggesting uneven hepatic blood supply. Hepatic deformity was not obvious. Laparoscopy revealed a slightly deformed liver surface with multiple indentations and shallow linear depressions. Furthermore, a wide scar was observed on the surface of S2 possibly at the site where the metastatic tumor existed before chemotherapy. Liver biopsy from the wide scar lesion showed intraportal tumor thrombi with desmoplastic change. Because of its similarity to the histology of the original breast cancer, we concluded that the hepatic functional abnormalities and slightly deformed liver surface were derived from the circulatory disturbance caused by microscopic tumor thrombi. Besides, since the wide scar was located at the site of the pre-existing tumor, it is probable that chemotherapy was an important cause of fibrous scarring as a result of tumor regression. These morphologic findings are compatible with those of HLC. Laparoscopy-assisted liver biopsy was useful to make definite diagnosis, even though the hepatic deformity was radiologically undetectable.
PMCID: PMC4305828  PMID: 15818755
Metastatic breast cancer; Hepar lobatum carcinomatosum; Laparoscopy
20.  Restriction of Amino Acid Change in Influenza A Virus H3HA: Comparison of Amino Acid Changes Observed in Nature and In Vitro 
Journal of Virology  2003;77(18):10088-10098.
We introduced 248 single-point amino acid changes into hemagglutinin (HA) protein of the A/Aichi/2/68 (H3N2) strain by a PCR random mutation method. These changes were classified as positive or negative according to their effect on hemadsorption activity. We observed following results. (i) The percentage of surviving amino acid changes on the HA1 domain that did not abrogate hemadsorption activity was calculated to be ca. 44%. In nature, it is estimated to be ca. 39.6%. This difference in surviving amino acid changes on the HA protein between natural isolates and in vitro mutants might be due to the immune pressure against the former. (ii) A total of 26 amino acid changes in the in vitro mutants matched those at which mainstream amino acid changes had occurred in the H3HA1 polypeptide from 1968 to 2000. Of these, 25 were positive. We suggest that the majority of amino acid changes on the HA protein during evolution might be restricted to those that were positive on the HA of A/Aichi/2/68. (iii) We constructed two-point amino acid changes on the HA protein by using positive mutants. These two-point amino acid changes with a random combination did not inhibit hemadsorption activity. It is possible that an accumulation of amino acid change might occur without order. (iv) From the analysis of amino acids participating in mainstream amino acid change, each antigenic site could be further divided into smaller sites. The amino acid substitutions in the gaps between these smaller sites resulted in mostly hemadsorption-negative changes. These gap positions may play an important role in maintaining the function of the HA protein, and therefore amino acid changes are restricted at these locations.
PMCID: PMC224596  PMID: 12941919
21.  Outbreaks of Norwalk-like virus-associated gastroenteritis traced to shellfish: coexistence of two genotypes in one specimen. 
Epidemiology and Infection  1996;116(3):339-346.
We determined the nucleotide sequences of Norwalk-like viruses in 10 PCR products from stool or oyster specimens obtained from four outbreaks of gastroenteritis in which shellfish was suspected as the cause in Shizuoka prefecture in Japan between 1987-94. The sequences were determined from nucleotide positions 4561-4852 (292 bp) in the polymerase region. Two types of sequences were detected. One (genotype 1) had 87% sequence homology with the prototype Norwalk virus, and the other (genotype 2) had 59% sequence homology. The sequences from isolates belonging to the same genotype were almost the same regardless of the year of isolation. Because sequences of 2 genotypes were detected in 2 of the 4 outbreaks, nested PCR was performed with genotype-specific primers to detect the presence of 2 genotypes in the same specimen. In 5 of 10 specimens, PCR bands were detected with both genotype-specific primers, indicating the coexistence of 2 genotypes in 1 specimen. We also detected two genotypes of Norwalk-like virus in an oyster from a sample implicated in one of the outbreaks which may provide direct evidence of oysters as the cause of the gastroenteritis.
PMCID: PMC2271441  PMID: 8666079
22.  Analysis of influenza A virus reinfection in children in Japan during 1983-91. 
Epidemiology and Infection  1995;115(3):591-601.
The epidemiology of influenza A in Japan was studied during 1979-91 and viruses isolated from reinfections during 1983-91 were analysed. Of 2963 influenza viruses isolated from reinfections during 1983-91 were analysed. Of 2963 influenza viruses isolated during this period, 922 and 1006 were influenza A(H1N1) and A(H3N2) viruses respectively; the others were influenza B viruses. Influenza A(H1N1) and A(H3N2) caused 5 and 6 epidemics respectively, most accompanied by antigenic drift. Seventeen reinfections with H1N1 and 17 with H3N2 were detected during our study. The primary and reinfection strains isolated from 7 H1N1 and 10 H3N2 cases were studied by haemagglutination-inhibition, and amino acid and nucleotide sequences of the HA1 region of the haemagglutinin. Most of the primary and reinfection strains were antigenically and genetically similar to the epidemic viruses circulating at that time. However, in 4 out of 10 cases of reinfection with influenza H3N2 virus, reinfection strains were genetically different from the epidemic viruses.
PMCID: PMC2271582  PMID: 8557091
23.  Reinfection with influenza B virus in children: analysis of the reinfection influenza B viruses. 
Epidemiology and Infection  1994;113(1):103-112.
Influenza B virus reinfection in Japanese children was studied epidemiologically during 1979-91 and virologically during 1985-91. During this investigation, there were four epidemics caused by influenza B viruses, each of which accompanied antigenic drift. Between the epidemics in 1987/88 and 1989/90, the viruses changed drastically, both genetically and antigenically. The minimum rate of reinfection with influenza B virus during the whole period was 3-25% depending on the influenza seasons. The antigens of primary and reinfection strains of influenza B virus isolated from 18 children during 1985-90, which covered three epidemic periods, were studied by haemagglutination inhibition tests. The results showed that the viruses isolated in the 1984/85 and 1987/88 influenza seasons, which belonged to the same lineage, were antigenically close, and reinfection occurred with these viruses. The results of amino-acid analysis of the HA1 polypeptide of these viruses corresponded with those of antigenic analysis. There were no specific amino-acid changes shared by the primary infection and reinfection influenza B viruses; the patients were infected with the viruses epidemic at that time.
PMCID: PMC2271217  PMID: 8062866
24.  Comparison of the HA genes of type B influenza viruses in herald waves and later epidemic seasons. 
Epidemiology and Infection  1992;109(3):559-568.
From January 1985 to May 1991, herald strains of influenza B virus were isolated in 1987 and 1989 in Japan. In both cases, influenza epidemics caused by the same type followed in the next winter season. The HA gene sequences of the influenza B viruses isolated in Japan from 1987-91, which covers two herald waves of influenza B viruses, were analysed and located on the phylogenetic tree for influenza B viruses after the B/Singapore/64 strain. Co-circulation of at least two evolutionary lineages of the HA genes existed for influenza B viruses in Japan during the period of this study. The herald viruses in one wave (1987) were genetically close to the winter isolates and were considered to be the parental viruses for the following influenza season, while in the other wave (1989) winter isolates belonged to another lineage on which one of the herald viruses was located, but they were genetically and antigenically different from the herald viruses.
PMCID: PMC2271949  PMID: 1468537
25.  Genetic relationship between the HA genes of type A influenza viruses isolated in off-seasons and later epidemic seasons. 
Epidemiology and Infection  1991;106(2):383-395.
From January 1985 to March 1989, off-season viruses of H1N1 and H3N2 subtypes of influenza A viruses were isolated on five occasions in Japan. The HA gene sequences of the influenza A(H1N1) and A(H3N2) viruses isolated in Japan from 1985-9 were analysed and the phylogenetic tree for each subtype virus was constructed to determine any genetic relationship between viruses isolated in off-seasons and the epidemic viruses of the following influenza seasons. In one instance with H1N1 viruses in 1986 and in two instances with H3N2 viruses in 1985 and 1987, the spring isolates were genetically close to some of the winter isolates and were considered to be the parental viruses of the following influenza seasons. However, even in these cases, influenza viruses of the same subtype with different lineages co-circulated in Japan.
PMCID: PMC2272002  PMID: 2019304

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