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1.  Cyanophage Infection in the Bloom-Forming Cyanobacteria Microcystis aeruginosa in Surface Freshwater 
Microbes and Environments  2012;27(4):350-355.
Host-like genes are often found in viral genomes. To date, multiple host-like genes involved in photosynthesis and the pentose phosphate pathway have been found in phages of marine cyanobacteria Synechococcus and Prochlorococcus. These gene products are predicted to redirect host metabolism to deoxynucleotide biosynthesis for phage replication while maintaining photosynthesis. A cyanophage, Ma-LMM01, infecting the toxic cyanobacterium Microcystis aeruginosa, was isolated from a eutrophic freshwater lake and assigned as a member of a new lineage of the Myoviridae family. The genome encodes a host-like NblA. Cyanobacterial NblA is known to be involved in the degradation of the major light harvesting complex, the phycobilisomes. Ma-LMM01 nblA gene showed an early expression pattern and was highly transcribed during phage infection. We speculate that the co-option of nblA into Microcystis phages provides a significant fitness advantage to phages by preventing photoinhibition during infection and possibly represents an important part of the co-evolutionary interactions between cyanobacteria and their phages.
PMCID: PMC4103541  PMID: 23047146
cyanobacteria; cyanophage; non-bleaching gene (nblA); phycobilisome; Microcystis
2.  Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study 
Environmental Health  2014;13(1):83.
The organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated.
The Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360°C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 μg and 5 μg), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.
Several kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 μg induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 μg increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 μg, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production.
These results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila.
PMCID: PMC4216376  PMID: 25326908
Tar; Polycyclic aromatic hydrocarbons; Asian sand dust; Ovalbumin; Lung eosinophilia; Cytokine and chemokine
3.  Autoimmune pancreatitis with colonic stenosis: an unusual complication and atypical pancreatographic finding 
BMC Gastroenterology  2014;14(1):173.
Type 1 autoimmune pancreatitis (AIP) often accompanies various systematic disorders such as sclerosing cholangitis, sialoadenitis, retroperitoneal fibrosis, interstitial pneumonitis and nephritis. Although rarely reported in acute pancreatitis, colonic stenosis is an uncommon complication in cases with AIP.
Case presentation
A 69-year-old Japanese man complained of abdominal pain and continuous diarrhea, resistant to intake of antimuscarinic and probiotic agents. A colonoscopy demonstrated a stenosis at the splenic flexure. Computed tomography revealed a focal enlargement of the pancreatic tail with a capsule-like rim, contacting with the descending colon. Endoscopic retrograde pancreatography (ERP) was unable to visualize the main pancreatic duct (MPD) at the pancreatic tail, despite a full contrast injection. A high serum IgG4 level (1060 mg/dL) and exclusion of pancreatic cancer by endoscopic ultrasound guided-fine needle aspiration suggested AIP, but did not fulfill the diagnostic criteria, and steroid therapy was initiated. One month after starting steroid intake, pancreatic swelling was minimized and the MPD was visualized by ERP, fulfilling the international consensus diagnostic criteria (ICDC) of AIP. Colonic stenosis was relieved and the patient’s symptoms disappeared.
The present case is the first report of AIP developing colonic stenosis by the inflammatory infiltration. In this case, steroid therapy was effective for the diagnosis and treatment of pancreatic mass involving the descending colon.
PMCID: PMC4192343  PMID: 25280867
Autoimmune pancreatitis; Colonic stenosis; Differential diagnosis; Steroid therapy
4.  The Relationship between Clinicopathological Features and Expression of Epithelial and Mesenchymal Markers in Spontaneous Canine Mammary Gland Tumors 
It is known that epithelial mesenchymal transition (EMT) contributes to the acquisition of malignant property in human cancers. However, the role of EMT in canine tumors remains to be elucidated. To evaluate the correlation between expression levels of protein markers involved in EMT and clinicopathological characteristics in canine mammary gland tumors, immunohistochemistry using antibodies against ZO-1, E-cadherin, vimentin, N-cadherin and fibronectin was performed on 119 clinical tissue samples. Consequently, loss of ZO-1 and E-cadherin, and gain of vimentin and N-cadherin were more frequently observed in malignant tumors than in benign tumors. However, there was no correlation among expression of these molecules. Univariate and multivariate analysis identified that loss of E-cadherin independently had a low one-year survival rate (adjusted odds ratio: 2.3, P=0.02). These results suggested that EMT might relate to acquisition of malignancy, and additionally, E-cadherin was strongly correlated with malignant behavior in canine mammary gland tumors.
PMCID: PMC4221164  PMID: 24931646
canine mammary gland tumors; epithelial mesenchymal transition; immunohistochemistry; prognosis
5.  Molecular Characterization of a Novel N-Acetyltransferase from Chryseobacterium sp. 
N-Acetyltransferase from Chryseobacterium sp. strain 5-3B is an acetyl coenzyme A (acetyl-CoA)-dependent enzyme that catalyzes the enantioselective transfer of an acetyl group from acetyl-CoA to the amino group of l-2-phenylglycine to produce (2S)-2-acetylamino-2-phenylacetic acid. We purified the enzyme from strain 5-3B and deduced the N-terminal amino acid sequence. The gene, designated natA, was cloned with two other hypothetical protein genes; the three genes probably form a 2.5-kb operon. The deduced amino acid sequence of NatA showed high levels of identity to sequences of putative N-acetyltransferases of Chryseobacterium spp. but not to other known arylamine and arylalkylamine N-acetyltransferases. Phylogenetic analysis indicated that NatA forms a distinct lineage from known N-acetyltransferases. We heterologously expressed recombinant NatA (rNatA) in Escherichia coli and purified it. rNatA showed high activity for l-2-phenylglycine and its chloro- and hydroxyl-derivatives. The Km and Vmax values for l-2-phenylglycine were 0.145 ± 0.026 mM and 43.6 ± 2.39 μmol · min−1 · mg protein−1, respectively. The enzyme showed low activity for 5-aminosalicylic acid and 5-hydroxytryptamine, which are reported as good substrates of a known arylamine N-acetyltransferase and an arylalkylamine N-acetyltransferase. rNatA had a comparatively broad acyl donor specificity, transferring acyl groups to l-2-phenylglycine and producing the corresponding 2-acetylamino-2-phenylacetic acids (relative activity with acetyl donors acetyl-CoA, propanoyl-CoA, butanoyl-CoA, pentanoyl-CoA, and hexanoyl-CoA, 100:108:122:10:<1).
PMCID: PMC3957623  PMID: 24375143
6.  Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases 
PLoS ONE  2014;9(8):e104479.
The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.
PMCID: PMC4131904  PMID: 25119884
7.  Anatomical characterization of athetotic and spastic cerebral palsy using an atlas-based analysis 
To analyze diffusion tensor imaging (DTI) in two types of cerebral palsy (CP): the athetotic-type and the spastic-type, using an atlas-based anatomical analysis of the entire brain, and to investigate whether these images have unique anatomical characteristics that can support functional diagnoses.
We retrospectively analyzed the DTI of seven children with athetotic-type, 11 children with spastic-type, and 20 healthy control children, all age-matched. The severity of motor dysfunction was evaluated with the Gross Motor Function Classification System (GMFCS). The images were normalized using a linear transformation, followed by large deformation diffeomorphic metric mapping. For 205 parcellated brain areas, the volume, fractional anisotropy, and mean diffusivity were measured. Principal component analysis (PCA) was performed for the Z scores of these parameters.
The GMFCS scores in athetotic-type were significantly higher than those in spastic-type (p<0.001). PCA extracted anatomical components that comprised the two types of CP, as well as the severity of motor dysfunction. In the athetotic group, the abnormalities were more severe than in the spastic group. In the spastic group, significant changes were concentrated in the lateral ventricle and periventricular structures.
Our results quantitatively delineated anatomical characteristics that reflected the functional findings in two types of CP.
PMCID: PMC3749241  PMID: 23737247
cerebral palsy; diffusion tensor imaging; atlas-based analysis; principal component analysis
8.  Ingested hyaluronan moisturizes dry skin 
Nutrition Journal  2014;13:70.
Hyaluronan (HA) is present in many tissues of the body and is essential to maintain moistness in the skin tissues, which contain approximately half the body’s HA mass. Due to its viscosity and moisturizing effect, HA is widely distributed as a medicine, cosmetic, food, and, recently marketed in Japan as a popular dietary supplement to promote skin moisture. In a randomized, double-blind, placebo-controlled clinical study it was found that ingested HA increased skin moisture and improved treatment outcomes for patients with dry skin. HA is also reported to be absorbed by the body distributed, in part, to the skin. Ingested HA contributes to the increased synthesis of HA and promotes cell proliferation in fibroblasts. These effects show that ingestion of HA moisturizes the skin and is expected to improve the quality of life for people who suffer from dry skin. This review examines the moisturizing effects of dry skin by ingested HA and summarizes the series of mechanisms from absorption to pharmacological action.
PMCID: PMC4110621  PMID: 25014997
Hyaluronan; Hyaluronic acid; Ingestion; Dry skin; Moisturizing
9.  Whole-genome sequencing of clarithromycin resistant Helicobacter pylori characterizes unidentified variants of multidrug resistant efflux pump genes 
Gut Pathogens  2014;6:27.
Clarithromycin (CLR) is the key drug in eradication therapy of Helicobacter pylori (H. pylori) infection, and widespread use of CLR has led to an increase in primary CLR-resistant H. pylori. The known mechanism of CLR resistance has been established in A2146G and A2147G mutations in the 23S rRNA gene, but evidence of the involvement of other genetic mechanisms is lacking. Using the MiSeq platform, whole-genome sequencing of the 19 clinical strains and the reference strain ATCC26695 was performed to identify single nucleotide variants (SNVs) of multi-drug resistant efflux pump genes in the CLR-resistant phenotype.
Based on sequencing data of ATCC26695, over one million sequencing reads with over 50-fold coverage were sufficient to detect SNVs, but not indels in the bacterial genome. Sequencing reads of the clinical isolates ranged from 1.82 to 10.8 million, and average coverage ranged from 90.9- to 686.3-fold, which were acceptable criteria for detecting SNVs. Utilizing the conventional approach of allele-specific PCR, point mutations in the 23S rRNA gene were detected in 12 clinical resistant isolates, but not in 7 clinical susceptible isolates. All sequencing reads of CLR-resistant strains had a G mutation in an identical position of the 23S rRNA gene. In addition, genetic variants of four gene clusters (hp0605-hp0607, hp0971-hp0969, hp1327-hp1329, and hp1489-hp1487) of TolC homologues, which have been implicated in multi-drug resistance, were examined. Specific SNVs were dominantly found in resistant strains.
Gene clusters of TolC homologues are involved in CLR susceptibility profiles in individual H. pylori strains. Whole-genome sequencing has yielded novel understanding of genotype-phenotype relationships.
PMCID: PMC4079918  PMID: 24995043
Whole-genome sequencing; Helicobacter pylori; Clarithromycin; Multidrug efflux; TolC homolog
10.  Enhancement of OVA-induced murine lung eosinophilia by co-exposure to contamination levels of LPS in Asian sand dust and heated dust 
A previous study has shown that the aggravation of Asian sand dust (ASD) on ovalbumin (OVA)-induced lung eosinphilia was more severe in lipopolysaccharide (LPS)-rich ASD than in SiO2-rich ASD. Therefore, the effects of different LPS contamination levels in ASD on the aggravation of OVA-induced lung eosinophilia were investigated in the present study.
Before beginning the in vivo experiment, we investigated whether the ultra-pure LPS would act only on TLR4 or not using bone marrow-derived macrophages (BMDMs) of wild–type, TLR2-/-, TLR4-/- and MyD88-/- BALB/c mice. ASD collected from the desert was heated to remove toxic organic substances (H-ASD). BALB/c mice were instilled intratracheally with 12 different testing samples prepared with LPS (1 ng and 10 ng), H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), the levels of inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.
The LPS exhibited no response to the production of TNF-α and IL-6 in BMDMs from TLR4-/-, but did from TLR2-/-. H-ASD aggravated the LPS-induced neutrophilic lung inflammation. In the presence of OVA, LPS increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 at the levels of 1 ng and 10 ng. In the presence of OVA and H-ASD, LPS induced severe eosinophil infiltration and proliferation of goblet cells in the airways as well as remarkable increases in Th2 cytokines IL-5 and IL-13 in BALF. The mixture containing LPS (1 ng) showed adjuvant activity on OVA-specific IgE and IgG1 production.
The results suggest that H-ASD with naturally-occurring levels of LPS enhances OVA-induced lung eosinophilia via increases in Th2-mediated cytokines and antigen-specific immunoglobulin. These results indicate that LPS is a strong candidate for being a major aggravating substance in ASD.
PMCID: PMC4058696  PMID: 24982682
Lipopolysaccharide; Asian sand dust; Ovalbumin; Lung eosinophilia; Cytokine and chemokine; Asthma
11.  Variation of the Virus-Related Elements within Syntenic Genomes of the Hyperthermophilic Archaeon Aeropyrum 
Applied and Environmental Microbiology  2013;79(19):5891-5898.
The increasing number of genome sequences of archaea and bacteria show their adaptation to different environmental conditions at the genomic level. Aeropyrum spp. are aerobic and hyperthermophilic archaea. Aeropyrum camini was isolated from a deep-sea hydrothermal vent, and Aeropyrum pernix was isolated from a coastal solfataric vent. To investigate the adaptation strategy in each habitat, we compared the genomes of the two species. Shared genome features were a small genome size, a high GC content, and a large portion of orthologous genes (86 to 88%). The genomes also showed high synteny. These shared features may have been derived from the small number of mobile genetic elements and the lack of a RecBCD system, a recombinational enzyme complex. In addition, the specialized physiology (aerobic and hyperthermophilic) of Aeropyrum spp. may also contribute to the entire-genome similarity. Despite having stable genomes, interference of synteny occurred with two proviruses, A. pernix spindle-shaped virus 1 (APSV1) and A. pernix ovoid virus 1 (APOV1), and clustered regularly interspaced short palindromic repeat (CRISPR) elements. Spacer sequences derived from the A. camini CRISPR showed significant matches with protospacers of the two proviruses infecting A. pernix, indicating that A. camini interacted with viruses closely related to APSV1 and APOV1. Furthermore, a significant fraction of the nonorthologous genes (41 to 45%) were proviral genes or ORFans probably originating from viruses. Although the genomes of A. camini and A. pernix were conserved, we observed nonsynteny that was attributed primarily to virus-related elements. Our findings indicated that the genomic diversification of Aeropyrum spp. is substantially caused by viruses.
PMCID: PMC3811351  PMID: 23872576
12.  A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering 
Scientific Reports  2014;4:4457.
Osteochondral injuries remain difficult to repair. We developed a novel photo-cross-linkable furfurylamine-conjugated gelatin (gelatin-FA). Gelatin-FA was rapidly cross-linked by visible light with Rose Bengal, a light sensitizer, and was kept gelled for 3 weeks submerged in saline at 37°C. When bone marrow-derived stromal cells (BMSCs) were suspended in gelatin-FA with 0.05% Rose Bengal, approximately 87% of the cells were viable in the hydrogel at 24 h after photo-cross-linking, and the chondrogenic differentiation of BMSCs was maintained for up to 3 weeks. BMP4 fusion protein with a collagen binding domain (CBD) was retained in the hydrogels at higher levels than unmodified BMP4. Gelatin-FA was subsequently employed as a scaffold for BMSCs and CBD-BMP4 in a rabbit osteochondral defect model. In both cases, the defect was repaired with articular cartilage-like tissue and regenerated subchondral bone. This novel, photo-cross-linkable gelatin appears to be a promising scaffold for the treatment of osteochondral injury.
PMCID: PMC3964514  PMID: 24662725
13.  Leveraging public health nurses for disaster risk communication in Fukushima City: a qualitative analysis of nurses' written records of parenting counseling and peer discussions 
Local public health nurses (PHNs) have been recognized as the main health service providers in communities in Japan. The Fukushima nuclear disaster in 2011 has, however, created a major challenge for them in responding to mothers’ concerns. This was in part due to difficulties in assessing, understanding and communicating health risks on low-dose radiation exposure. In order to guide the development of risk communication plans, this study sought to investigate mothers’ primary concerns and possible solutions perceived by a core healthcare profession like the PHNs.
A total of 150 records from parenting counseling sessions conducted between PHNs and mothers who have attended mandatory 18-month health checkups for their children at the Fukushima City Health and Welfare Center in 2010, 2011 (year of disaster) and 2012 were examined. Discussion notes of three peer discussions among PHNs organized in response to the nuclear disaster in 2012 and 2013 were also analyzed. All transcribed data were first subjected to text mining to list the words according to their frequencies and inter-relationships. The Steps Coding and Theorization method was then undertaken as a framework for qualitative analysis.
PHNs noted mothers to have considerable needs for information on radiation risks as they impact on decisions related to relocations, concerns for child safety, and experiences with interpersonal conflicts within the family owing to differing risk perceptions. PHNs identified themselves as the information channels in the community, recommended the building of their risk communication capacities to support residents in making well-informed decisions, and advocated for self-measurement of radiation levels to increase residents’ sense of control. PHNs also suggested a more standardized form of information dissemination and an expansion of community-based counseling services.
Inadequate risk communication on radiation in the Fukushima nuclear incident has resulted in multiple repercussions for mothers in the community. Empowerment of local residents to assume more active roles in the understanding of their environment, increasing PHNs’ capacity in communication, and an expansion of health services such as counseling will together better address risk communication challenges in post-disaster recovery efforts.
PMCID: PMC3995308  PMID: 24642079
Public health nurses; Risk communication; Parenting; Radiation; Health communication; Fukushima nuclear accident; Japan
14.  Primary cutaneous anaplastic large cell lymphoma occurring in an atopic dermatitis patient: a case report with review of the literature with emphasis on their association 
Although the risk of malignant lymphoma in patients with atopic dermatitis (AD) remains controversial, an increased risk of malignant T-cell lymphoma in patients with AD has been reported. Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a relatively common distinct clinicopathological entity. However, occurrence of C-ALCL in patients with AD has been rarely reported. Herein, we describe the 5th reported case of C-ALCL occurring in a patient with AD and review the clinicopathological features. A 30-year-old Japanese male with a long-standing history of AD presented with a gradually enlarged nodular lesion in the right abdominal wall, which had spontaneously regressed without therapy. Two years later, multiple nodular lesions appeared in his trunk, and swelling of multiple lymph nodes was also detected. Histopathological studies demonstrated diffuse proliferation of large-sized lymphocytes with large convoluted nuclei containing conspicuous nucleoli and relatively rich cytoplasm in the skin and lymph node. Immunohistochemically, these lymphocytes were positive for CD30, CD8, and MUM1, and negative for CD3, CD4, and ALK1. Accordingly, a diagnosis of primary C-ALCL was made. The patient died of disease after various courses of chemotherapy. Our clinicopathological review revealed that the prognosis of C-ALCL occurring in patients with AD is poor because two of 5 patients died of disease. Therefore, albeit extremely rare, AD patients with C-ALCL should be monitored closely, and additional clinicopathological studies are needed to clarify the pathogenesis of C-ALCL occurring in patients with AD.
PMCID: PMC4014256  PMID: 24817972
Primary cutaneous anaplastic large cell lymphoma; atopic dermatitis; lymph node
15.  Occurrence of Epstein-Barr virus-associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature 
It is well established that patients with immunosuppression have a higher risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with development of LPDs. Aplastic anemia (AA) is an immune-mediated hematological disorder, and immunosuppression therapy (IST), such as antithymocyte globulin (ATG), is widely used for treatment of AA. However, occurrence of LPD without bone marrow transplantation has been extremely rarely documented in patients with IST for AA. Herein, we report the 6th documented case of EBV-associated LPD after IST for AA and review the clinicopathological features of this extremely rare complication. A 46-year-old Japanese female was admitted for evaluation of progressive pancytopenia. Bone marrow biopsy revealed fatty marrow with marked decrease of trilineage cells, and bone marrow aspiration demonstrated no dysplastic changes. IST with rabbit ATG was administered, after which, she developed high fever. Bone marrow aspiration showed increase of atypical plasma cells with mildly enlarged nuclei and irregular nuclear contour. These atypical plasma cells were EBER-positive. Accordingly, a diagnosis of EBV-positive plasmacytic LPD was made. Most cases of LPDs are B-cell origin, and plasmacytic LPD is a rare subtype. The current report is the second case of plasmacytic LPD in patients with IST for AA. Therefore, detailed histopathological and immunohistochemical analyses are needed for correct diagnosis and treatment, and additional studies are needed to clarify the clinicopathological features of EBV-LPD after IST for AA.
PMCID: PMC4014258  PMID: 24817974
Epstein-Barr virus-associated lymphoproliferative disorder; antithymocyte globulin therapy; aplastic anemia
17.  Tenascin C protects aorta from acute dissection in mice 
Scientific Reports  2014;4:4051.
Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl2 caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.
PMCID: PMC3920275  PMID: 24514259
18.  Lung inflammation by fungus, Bjerkandera adusta isolated from Asian sand dust (ASD) aerosol and enhancement of ovalbumin-induced lung eosinophilia by ASD and the fungus in mice 
Bjerkandera adusta (B. adusta) is one of the most important etiological fungi associated with chronic cough. However, precise details of the inflammatory response to exposure are not well understood yet. B. adusta was recently identified in Asian sand dust (ASD) aerosol. Therefore, in the present study the exacerbating effects of ASD on B. adusta-induced lung inflammation and B. adusta + ASD on ovalbumin (OVA)-induced murine lung eosinophilia were investigated using experimental mice.
In order to prepare testing samples, B. adusta obtained from ASD aerosol was inactivated by formalin and ASD collected from the atmosphere was heated to remove toxic organic substances (H-ASD). CD-1 mice were instilled intratracheally with 12 different samples prepared with various combinations of B. adusta, H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in bronchoalveolar lavage fluid (BALF), and the levels of inflammatory cytokines/chemokines in BALF were investigated.
H-ASD aggravated the lung eosinophilia induced by B. adusta alone, which also aggravated the lung eosinophilia induced by OVA. The mixture of OVA, H-ASD, and B. adusta caused serious fibrous thickening of the subepithelial layer, eosinophil infiltration, and proliferation of goblet cells in the airways along with remarkable increases of IL-13, eotaxin, IL-5, and MCP-3 in BALF.
The results of the present study demonstrated that B. adusta isolated from ASD aerosol induces allergic lung diseases. H-ASD enhanced allergic reactions caused by OVA or B. adusta. A mixture of B. adusta, H-ASD, and OVA caused the most remarkable exacerbation to the allergic airway inflammation via remarkable increases of pro-inflammatory mediators.
PMCID: PMC3918174  PMID: 24499133
Asian sand dust; Bjerkandera adusta; Fungus; Lung eosinophilia; Asthma
19.  Concomitant occurrence of IgG4-related pleuritis and periaortitis: a case report with review of the literature 
IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Some recent reports have demonstrated that this disease can occur in the respiratory system including the pleura. Herein, we describe the first documented case of concomitant occurrence of IgG4-related pleuritis and periaortitis. A 71-year-old Japanese female with a history of essential thrombocythemia presented with persistent cough and difficulty in breathing. Computed tomography demonstrated thickening of the right parietal pleura, pericardium, and periaortic tissue and pleural and cardiac effusions. Histopathological study of the surgical biopsy specimen of the parietal pleura revealed marked fibrous thickening with lymphoplasmacytic infiltration. Phlebitis was noted, however, only a few eosinophils had infiltrated. Immunohistochemical study revealed abundant IgG4-positive plasma cell infiltration and high ratio of IgG4-/IgG-positive plasma cells (84%). Therefore, a diagnosis of IgG4-related pleuritis was made with consideration of the elevated serum IgG4 level (684 mg/dL). Recently, the spectrum of IgG4-related sclerosing disease has expanded, and this disease can occur in the pleura, pericardium, and periaortic tissue. Although histopathological analysis of the pericardium and periaortic tissue was not performed in the present case, it was suspected that thickening of the pericardium and periaortic tissue was clinically due to IgG4-related sclerosing disease. Our clinicopathological analyses of IgG4-related pleuritis and pericarditis reveal that this disease can present as dyspnea and pleural and pericardial effusion as seen in the present case, therefore, it is important to recognize that IgG4-related sclerosing disease can occur in these organs for accurate diagnosis and treatment.
PMCID: PMC3925932  PMID: 24551308
IgG4-related sclerosing disease; pleuritis; periaortitis
21.  Epstein-Barr virus-related post-transplant lymphoproliferative disorder occurring after bone marrow transplantation for aplastic anemia in Down’s syndrome 
It is well established that Down’s syndrome exhibits a predisposition to development of leukemia, however, association between aplastic anemia and Down’s syndrome is exceptional. Herein, we describe a case of aplastic anemia occurring in Down’s syndrome following post-transplant lymphoproliferative disorder (PTLD) after bone marrow transplantation (BMT). A 27-year-old Japanese male with Down’s syndrome presented with a headache. Laboratory tests revealed severe pancytopenia, and bone marrow biopsy demonstrated hypocellular bone marrow with decrease of trilineage cells, which led to a diagnosis of aplastic anemia. One year after diagnosis, he was incidentally found to have an anterior mediastinal tumor, which was histopathologically diagnosed as seminoma. Subsequently, he received BMT from a female donor, and engraftment was observed. Three months after transplantation, he experienced cough and high fever. Biopsy specimen from the lung revealed diffuse proliferation of large-sized lymphoid cells expressing CD20 and EBER. These lymphoid cells had XY chromosomes. Thus, a diagnosis of EBV-associated PTLD was made. This is the seventh documented case of aplastic anemia occurring in Down’s syndrome. Association between aplastic anemia and Down’s syndrome has not been established, therefore, additional clinicopathological studies are needed. Moreover, this is the first case to undergo BMT for aplastic anemia in Down’s syndrome. Although engraftment was observed, he developed EBV-positive PTLD. The neoplastic cells of the present case were considered to be of recipient origin, although the majority of PTLD cases with BMT are of donor origin.
PMCID: PMC3885503  PMID: 24427369
Aplastic anemia; Down’s syndrome; bone marrow transplantation; Epstein-Barr virus; post-transplant lymphoproliferative disorder
22.  Hemorrhagic gastric and duodenal ulcers after the Great East Japan Earthquake Disaster 
AIM: To elucidate the characteristics of hemorrhagic gastric/duodenal ulcers in a post-earthquake period within one medical district.
METHODS: Hemorrhagic gastric/duodenal ulcers in the Iwate Prefectural Kamaishi Hospital during the 6-mo period after the Great East Japan Earthquake Disaster were reviewed retrospectively. The subjects were 27 patients who visited our hospital with a chief complaint of hematemesis or hemorrhagic stool and were diagnosed as having hemorrhagic gastric/duodenal ulcers by upper gastrointestinal endoscopy during a 6-mo period starting on March 11, 2011. This period was divided into two phases: the acute stress phase, comprising the first month after the earthquake disaster, and the chronic stress phase, from the second through the sixth month. The following items were analyzed according to these phases: age, sex, sites and number of ulcers, peptic ulcer history, status of Helicobacter pylori (H. pylori) infection, intake of non-steroidal anti-inflammatory drugs, and degree of impact of the earthquake disaster.
RESULTS: In the acute stress phase from 10 d to 1 mo after the disaster, the number of patients increased rapidly, with a nearly equal male-to-female ratio, and the rate of multiple ulcers was significantly higher than in the previous year (88.9% vs 25%, P < 0.005). In the chronic stress phase starting 1 mo after the earthquake disaster, the number of patients decreased to a level similar to that of the previous year. There were more male patients during this period, and many patients tended to have a solitary ulcer. All patients with duodenal ulcers found in the acute stress phase were negative for serum H. pylori antibodies, and this was significantly different from the previous year’s positive rate of 75% (P < 0.05).
CONCLUSION: Severe stress caused by an earthquake disaster may have affected the characteristics of hemorrhagic gastric/duodenal ulcers.
PMCID: PMC3831225  PMID: 24259974
Great East Japan Earthquake Disaster; Hemorrhagic gastric; Duodenal ulcer; Helicobacter pylori infection; Stress
23.  Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma 
IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.
PMCID: PMC3816828  PMID: 24228121
IgG4-related sclerosing disease; cholecystitis; malignant lymphoma; anaplastic large cell lymphoma
24.  Anaplastic lymphoma kinase-positive large B-cell lymphoma: a case report with emphasis on the cytological features of the pleural effusion 
Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (ALK-positive LBCL) is an extremely rare distinct clinicopathological subtype of LBCL, characterized by the presence of ALK-positive monomorphic large immunoblast-like neoplastic B cells. Herein, we describe the first cytological report on ALK-positive LBCL in the pleural effusion. A 69-year-old Japanese male with a past history of malignant lymphoma of the cecum presented with progressive dyspnea and pleural effusion. Removal of the pleural effusion and aspiration of bone marrow were performed. May-Grünwald-Giemsa stain of the pleural fluid revealed abundant single or small aggregates of large-sized round cells. These cells had centrally-located large round to oval nuclei. The peculiar finding was the presence of pseudopodial cytoplasmic projections, and some neoplastic cells had eosinophilic pseudopodial cytoplasmic projections, which resembled “flaming plasma cells”. Histopathological and immunohistochemical studies of the bone marrow demonstrated CD138+, ALK1+, CD20-, CD79a-, CD30-, and IgA+ large-sized neoplastic cells. Therefore, a diagnosis of ALK-positive LBCL was made. The peculiar finding of the present case was that most of the neoplastic cells had pseudopodial cytoplasmic projections, and some of them had eosinophilic pseudopodial cytoplasmic projections that resembled “flaming plasma cells”, which has been recognized as the characteristic finding of IgA myeloma. Therefore, tumor cells that resembled “flaming plasma cells” in the pleural effusion may have had IgA in the cytoplasm. Albeit extremely rare, ALK-positive LBCL shows aggressive clinical course, thus, recognition of the cytomorphological features of this type of malignant lymphoma is important for early and correct diagnosis.
PMCID: PMC3816839  PMID: 24228132
ALK-positive large B-cell lymphoma; pleural effusion; pseudopodial cytoplasmic projection

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