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1.  Whole-genome sequencing of clarithromycin resistant Helicobacter pylori characterizes unidentified variants of multidrug resistant efflux pump genes 
Gut Pathogens  2014;6:27.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/1757-4749-6-27
PMCID: PMC4079918  PMID: 24995043
Whole-genome sequencing; Helicobacter pylori; Clarithromycin; Multidrug efflux; TolC homolog
2.  Enhancement of OVA-induced murine lung eosinophilia by co-exposure to contamination levels of LPS in Asian sand dust and heated dust 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1710-1492-10-30
PMCID: PMC4058696  PMID: 24982682
Lipopolysaccharide; Asian sand dust; Ovalbumin; Lung eosinophilia; Cytokine and chemokine; Asthma
3.  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.
doi:10.1128/AEM.01089-13
PMCID: PMC3811351  PMID: 23872576
4.  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.
doi:10.1038/srep04457
PMCID: PMC3964514  PMID: 24662725
5.  Leveraging public health nurses for disaster risk communication in Fukushima City: a qualitative analysis of nurses' written records of parenting counseling and peer discussions 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6963-14-129
PMCID: PMC3995308  PMID: 24642079
Public health nurses; Risk communication; Parenting; Radiation; Health communication; Fukushima nuclear accident; Japan
6.  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
7.  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
9.  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.
doi:10.1038/srep04051
PMCID: PMC3920275  PMID: 24514259
10.  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 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1710-1492-10-10
PMCID: PMC3918174  PMID: 24499133
Asian sand dust; Bjerkandera adusta; Fungus; Lung eosinophilia; Asthma
11.  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
13.  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
14.  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.
doi:10.3748/wjg.v19.i42.7426
PMCID: PMC3831225  PMID: 24259974
Great East Japan Earthquake Disaster; Hemorrhagic gastric; Duodenal ulcer; Helicobacter pylori infection; Stress
15.  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
16.  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
18.  Methotrexate-related Epstein-Barr virus-associated lymphoproliferative disorder occurring in the gingiva of a patient with rheumatoid arthritis 
It is well recognized that patients with immunodeficiency have a high risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with the occurrence of LPDs. Methotrexate (MTX) is one of the common cause of iatrogenic-associated LPD, and approximately 40-50% of MTX-related LPD cases occur in extranodal sites. However, the occurrence of MTX-related LPD in the gingiva is extremely rare. Herein, we report the fourth documented case of MTX-related EBV-associated LPD occurring in the gingiva of a patient with rheumatoid arthritis (RA). A 76-year-old Japanese female with a 10-year history of RA, who was treated with MTX and infliximab, presented with a tumorous lesion in the gingiva. Biopsy of the gingiva tumor revealed diffuse proliferation of large-sized lymphoid cells with cleaved nuclei containing conspicuous nucleoli. These lymphoid cells were CD20- and EBER-positive. Therefore, a diagnosis of MTX-related EBV-associated LPD showing features of diffuse large B-cell lymphoma (DLBCL) that occurred in the gingiva was made. Although the occurrence of LPD in the oral region, as seen in the present case, is rare, the prevalence of this disorder may be on the rise due to the increased number of patients undergoing immunosuppression therapy. Moreover, immunosenescence can also be a cause of EBV-associated LPD. Therefore, recognition of the occurrence of this disorder in the oral cavity and consideration of the clinical history can facilitate the correct diagnosis.
PMCID: PMC3796248  PMID: 24133604
Lymphoproliferative disorder; Epstein-Barr virus; methotrexate; gingiva
19.  Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol 
Deoxynivalenol (DON) is a natural toxin of fungi that cause Fusarium head blight disease of wheat and other small-grain cereals. DON accumulates in infected grains and promotes the spread of the infection on wheat, posing serious problems to grain production. The elucidation of DON-catabolic genes and enzymes in DON-degrading microbes will provide new approaches to decrease DON contamination. Here, we report a cytochrome P450 system capable of catabolizing DON in Sphingomonas sp. strain KSM1, a DON-utilizing bacterium newly isolated from lake water. The P450 gene ddnA was cloned through an activity-based screening of a KSM1 genomic library. The genes of its redox partner candidates (flavin adenine dinucleotide [FAD]-dependent ferredoxin reductase and mitochondrial-type [2Fe-2S] ferredoxin) were not found adjacent to ddnA; the redox partner candidates were further cloned separately based on conserved motifs. The DON-catabolic activity was reconstituted in vitro in an electron transfer chain comprising the three enzymes and NADH, with a catalytic efficiency (kcat/Km) of 6.4 mM−1 s−1. The reaction product was identified as 16-hydroxy-deoxynivalenol. A bioassay using wheat seedlings revealed that the hydroxylation dramatically reduced the toxicity of DON to wheat. The enzyme system showed similar catalytic efficiencies toward nivalenol and 3-acetyl deoxynivalenol, toxins that frequently cooccur with DON. These findings identify an enzyme system that catabolizes DON, leading to reduced phytotoxicity to wheat.
doi:10.1128/AEM.03227-12
PMCID: PMC3591976  PMID: 23275503
20.  Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections 
Neuron  2013;77(3):472-484.
Summary
Major outputs of the neocortex are conveyed by corticothalamic axons (CTA), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSA) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neurons identity and suggest that CTA and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTA away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate towards cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a “waiting signal” required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens novel perspectives on brain wiring.
doi:10.1016/j.neuron.2012.11.031
PMCID: PMC3756696  PMID: 23395374
corticothalamic; thalamocortical; axon guidance; reciprocal connections; waiting period; Sema3E; PlexinD1; handshake
21.  Binding of αvβ1 and αvβ6 integrins to tenascin-C induces epithelial–mesenchymal transition-like change of breast cancer cells 
Oncogenesis  2013;2(8):e65-.
Tenascin-C (TNC), a large hexameric extracellular glycoprotein, is a pleiotropic molecule with multiple domains binding to a variety of receptors mediating a wide range of cellular functions. We earlier reported that TNC induces epithelial–mesenchymal transition (EMT)-like change in breast cancer cells. In the present study, we clarified TNC receptor involvement in this process. Among integrins previously reported as TNC receptors, substantial expression of αv, α2, β1 and β6 subunits was detected by quantitative PCR and immunoblotting in MCF-7 cells. Integrin β6 mRNA was remarkably upregulated by transforming growth factor (TGF)-β1 treatment, and protein expression was prominently increased by additional exposure to TNC. Immunofluorescent labeling demonstrated integrin αvβ6 accumulation in focal adhesions after TNC treatment, especially in combination with TGF-β1. The α2 and β1 subunits were mainly localized at cell–cell contacts, αv being found near cell cluster surfaces. Immunoprecipitation showed increase in αvβ1 heterodimers, but not α2β1, after TNC treatment. Activated β1 subunits detected by an antibody against the Ca2+-dependent epitope colocalized with αv in focal adhesion complexes, associated with FAK phosphorylation at tyrosine 925. Neutralizing antibodies against αv and β1 blocked EMT-like change caused by TNC alone. In addition, anti-αv and combined treatment with anti-β1 and anti-αvβ6 inhibited TGF-β1/TNC-induced EMT, whereas either of these alone did not. Integrin subunits αv, β1 and β6, but not α2, bound to TNC immobilized on agarose beads in a divalent cation-dependent manner. Treatments with neutralizing antibodies against β1 and αvβ6 reduced αv subunit bound to the beads. Immunohistochemistry of these receptors in human breast cancer tissues demonstrated frequent expression of β6 subunits in cancer cells forming scattered nests localized in TNC-rich stroma. These findings provide direct evidence that binding of αvβ6 and αvβ1 integrins to TNC as their essential ligand induces EMT-like change in breast cancer cells.
doi:10.1038/oncsis.2013.27
PMCID: PMC3759126  PMID: 23958855
breast cancer cells; epithelial–mesenchymal transition; integrin αvβ1; integrin αvβ6; tenascin-c; transforming growth factor β
22.  Prominent gelatinous bone marrow transformation presenting prior to myelodysplastic syndrome: a case report with review of the literature 
Gelatinous bone marrow transformation (GMT) is a rare disorder characterized by the presence of fat cell atrophy, loss of hematopoietic cells, and deposition of extracellular gelatinous materials. GMT is not a specific disease, but is strongly associated with malnutrition and drugs. Albeit extremely rare, GMT has been reported in patients with myeloproliferative disorders. Herein, we report the second documented case of hypoplastic myelodysplastic syndrome (MDS) accompanying GMT. A 73-year-old Japanese male with excellent nutrition status and no history of alcohol or drug intake was detected with pancytopenia. The initial bone marrow aspirate specimen reveled hypocellular marrow without dysplastic signs in the myeloid cells. Bone marrow biopsy demonstrated hypocellular bone marrow with prominent GMT. He received blood transfusions, however, pancytopenia continued to progress. The second bone marrow aspirate specimen showed dysplastic changes, such as pseudo-Pelger-Huët cells, hypogranular or agranular granulocytes, and megakaryocytes with multiple small nuclei. Cytogenetic study demonstrated deletion of chromosome 7. Therefore, an ultimate diagnosis of hypoplastic MDS accompanying GMT was made. Only a limited number of cases of myeloproliferative disorders with GMT have been reported. Our analysis of these cases revealed that chromosome 7 abnormality is frequently observed in this condition. Moreover, findings from the current case suggested that myeloproliferative disorders including MDS must be included in the differential diagnostic considerations of GMT patients, who have no history of malnutrition or drugs, and careful examination of the bone marrow smear specimen and cytogenetic analysis are necessary for early detection of underlying myeloproliferative disorders.
PMCID: PMC3726986  PMID: 23923088
Gelatinous bone marrow transformation; myelodysplastic syndrome; bone marrow
23.  Spontaneous spinal epidural hematoma with hemiparesis mimicking acute cerebral infarction: Two case reports 
Context
Acute hemiparesis is a common initial presentation of ischemic stroke. Although hemiparesis due to spontaneous spinal epidural hematoma (SSEH) is an uncommon symptom, a few cases have been reported and misdiagnosed as cerebral infarction.
Design
Case reports of SSEH with acute hemiparesis.
Findings
In these two cases, acute stroke was suspected initially and administration of intravenous alteplase therapy was considered. In one case, the presentation was neck pain and in the other case, it was Lhermitte's sign; brain magnetic resonance imaging (MRI) and magnetic resonance angiography were negative for signs of ischemic infarction, hemorrhage, or arterial dissection. Cervical MRI was performed and demonstrated SSEH.
Conclusion
Clinicians who perform intravenous thrombolytic treatment with alteplase need to be aware of this possible contraindication.
doi:10.1179/2045772312Y.0000000014
PMCID: PMC3425883  PMID: 22925753
Spontaneous spinal epidural hematoma; Hemiparesis; Tetraparesis; Lhermitte's sign; Cerebral infarction; Intravenous thrombolytic treatment; Magnetic resonance imaging; Computerized tomography; Alteplase
24.  Three-dimensional image-based high-dose-rate interstitial brachytherapy for mobile tongue cancer 
Journal of Radiation Research  2013;55(1):154-161.
To investigate the influence of a 3D image-based treatment-planning method for high-dose-rate interstitial brachytherapy (HDR-ISBT) for mobile tongue cancer, we analyzed dose–volume histogram results for the clinical target volume (CTV) and the mandible. Between October 2010 and November 2011, one and four patients having T2 and T3 tumors, respectively, were treated with HDR-ISBT. Multiplane implantation using 9–15 treatment applicators was performed. Lugol's iodine staining, metal markers, ultrasonography, and magnetic resonance imaging were used to identify the contours of the gross tumor volume (defined as the CTV). The results of the image-based treatment plan were compared with those of the conventional simulated plan on the basis of a reference point 5 mm from the applicator position. The mean D90(CTV) and V100(CTV) were 112% of the prescribed dose (PD) and 98.1%PD, respectively, for the image-based plan, and 113%PD and 97.2%PD, respectively, for the conventional plan. The median CTVref/Vref was 0.23 for the image-based plan and 0.16 for the conventional plan (P = 0.01). The mean D0.1 cm3 (mandible), D1 cm3 (mandible), and D2 cm3 (mandible) were 80.1%PD, 62.5%PD, and 55.7%PD, respectively, for the image-based plan, and 109.1%PD (P = 0.02), 82.4%PD (P = 0.005), and 74%PD (P = 0.004), respectively, for the conventional plan). Image-based treatment planning may achieve high-conformity radiotherapy for the CTV and decrease irradiated doses to the mandible.
doi:10.1093/jrr/rrt079
PMCID: PMC3885112  PMID: 23732769
high-dose-rate interstitial brachytherapy; mobile tongue cancer; image-based plan; dose–volume histogram
25.  Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4 
Purpose
Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein.
Methods
BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen–sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model.
Results
In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen–sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4-treated mice than in all other groups, including BMP4-treated mice. Finally, CBD-BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold.
Conclusion
Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation.
doi:10.2147/IJN.S44124
PMCID: PMC3626372  PMID: 23630418
BMP4; bone repair; bone tissue engineering; osteogenesis

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