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A 27-year-old man was admitted to our hospital with right pleural effusion. He had suffered from right chest and back pain and a high fever for one week prior to the admission. He had been treated with clarithromycin without improvement. Since thoracoscopy under local anesthesia revealed purulent effusion, synechiae and fibrous septa in the thoracic cavity, synechiotomy was performed and we started antibiotic treatment with the diagnosis of acute bacterial empyema. At the same time, we also suspected parasitic infection because of massive eosinophilic infiltration in pleural effusion and his dietary history of eating raw frogs. During the course of the disease, he had an infiltration in the right lower lobe and pneumothorax. Finally, we diagnosed him with sparganosis mansoni because his serum as well as pleural effusion was positive for the binding to sparganosis mansoni plerocercoid antigen, without any positive findings in bacteriology. His pleural effusion and lung infiltration were resolved after the administration of a high-dose praziquantel. We report this rare parasitic empyema with findings by thoracoscopic examination., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mycobacterium shinjukuense lung disease was diagnosed in 3 men and 3 women [mean age: 77.0±12.2 (57-93) years]. On imaging, 3 patients with previous pulmonary tuberculosis exhibited a fibrocavitary pattern, while the other 3 patients showed nodular bronchiectasis. A test with a tuberculosis rRNA identification kit (TRC Rapid(®) M. TB) was falsely positive for M. tuberculosis due to DNA sequence similarity in 16SrRNA. M. shinjukuense was identified by the gene sequences of rpoB, 16S rRNA, and hsp65. The symptoms and imaging findings of most of the patients have improved with chemotherapy with low minimum inhibitory concentrations of anti-tuberculosis drugs.

Background: Hemoptysis frequently develops in patients with Mycobacterium avium complex (MAC) pulmonary disease. Bronchial artery embolization (BAE) has been established as one of the useful treatments of massive and persistent hemoptysis. We evaluated the efficacy and safety of BAE for controlling hemoptysis in MAC patients, and identified the risk factors of rebleeding after BAE., Methods: Among the 529 patients with MAC who were admitted to our institution from January 2007 to December 2012, we retrospectively reviewed the demographic data, imaging, sputum, and angiographic findings, and the clinical course of 43 patients who underwent BAE using coils, due to hemoptysis., Results: Among the 43 patients enrolled in the study, rebleeding developed in 13 cases (30.2%) with a mean follow-up period of 18 months. Median rebleeding-free time after BAE was 29.9 months and the cumulative hemoptysis control rates were 79.1%, 73.8%, and 63.3% in one, two, and three years, respectively. Rebleeding-free time significantly correlated with comorbid chronic pulmonary aspergillosis (CPA). When limited to 35 MAC patients without CPA, the rate increased to 88.6%, 82.1%, and 70.4%, respectively. Factors such as coexisting CPA, multiple embolized vessels at BAE, longer length of time from the diagnosis of MAC to BAE, and an administration of antibiotics for MAC at the time of hemoptysis, indicated statistically significant correlations with rebleeding. Major complications concerning BAE were not encountered., Conclusions: BAE using coils is an effective and safe method for controlling hemoptysis in patients with MAC pulmonary disease. However, it is important to carefully observe patients with risk factors for rebleeding after BAE., (Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: There have been scarce data evaluating the differences of clinical characteristics and prognosis of chronic pulmonary aspergillosis (CPA) depending on underlying pulmonary diseases. We tried to clarify them in CPA patients who had pulmonary emphysema or previous pulmonary tuberculosis., Methods: We reviewed and evaluated CPA patients diagnosed between 2007 and 2013 with pulmonary emphysema (PE group; n = 29), with previous pulmonary tuberculosis (PT group; n = 47) and with combination of these 2 underlying conditions (CTE group; n = 24)., Results: In CT findings, fungus balls were rare in PE group (7% in PE group and 36% in PT group; p = 0.006). Compared with PT group, PE group patients exhibited more frequent preceding antibiotics administration (45% vs 11%; p = 0.002) and fever (52% vs 17%; p = 0.002), less frequent hemosputum (24% vs 57%; p = 0.008), and more frequent consolidations in imaging (79% vs 38%; p = 0.001) and respiratory failure (34% vs 13%; p = 0.020), possibly suggesting more acute clinical manifestations of CPA in emphysematous patients. Trend of the differences between PT and PE group was not changed when patients with fungal balls were excluded. Multivariate Cox regression analysis of risks for all-cause mortality revealed age (HR, 1.079; p = 0.002) and emphysema (HR, 2.45; p = 0.040) as risk factors., Conclusions: Assessment of underlying lung diseases is needed when we estimate prognosis and consider treatment of CPA patients. Particularly, emphysematous patients can be presented as refractory pneumonia and show poor prognosis., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: We occasionally experience cases suspected of pulmonary Mycobacterium avium complex (MAC) disease without positive bacterial cultures., Objective: To evaluate features of pulmonary MAC cases diagnosed later in the follow-up after negative intensive investigation., Methods: We defined and compared three groups; the first study negative (FSN) group, the first study positive (FSP) group, and MAC negative group. The FSN group consisted of patients negative for MAC isolation by bronchial washing performed between 2007 and 2011, but positive later. Patients with positive MAC cultures in the first study were incorporated into the FSP group. MAC negative group consisted of MAC suspects without MAC isolation in the follow-up., Results: Twenty-four patients were classified as FSN group, 61 as MAC negative group and 265 as FSP group. FSN group exhibited more solitary nodule pattern (n = 7 in FSN, n = 6 in FSP; p < 0.001) and less nodular/bronchiectatic (NB) diseases (n = 17 in FSN, n = 245 in FSP; p < 0.001). When limited to NB type, the FSP group had more cavitations (6% in FSN, 32% in FSP; p = 0.028). Patients with more than three lung lobes involved were more frequent in the FSN group compared with FSP group with negative sputum cultures (65% vs 34%; p = 0.014) and with MAC negative group (65% vs 28%; p = 0.009)., Conclusions: Patients diagnosed as pulmonary MAC disease in the follow-up duration tend to show solitary nodular pattern or NB pattern without cavitation. In FSN patients with NB pattern, more lung lobes were involved in the first study, suggesting subsequent MAC infection onto the underlying ectatic bronchi., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This qualitative study investigated how resilience functions in the context of daily occupations for mothers of children with autism spectrum disorder (ASD). Fourteen mothers of children with ASD participated in two focus groups that were used to elicit stories of the mothers' resilience in daily occupations. A constant comparative method was used for data analysis. A model of resilience in daily occupations of mothers of children with ASD was developed consisting of four categories: (1) creating and re-creating accepting conditions, (2) finding solutions, (3) striving for balance among daily occupations, and (4) thinking about the child's future. Sources of resilience were found to reside in both the mothers themselves and their social environments. Occupational therapy practitioners can use these findings in developing supportive approaches aimed at mothers, family members, and other people in the lives of children with ASD., (Copyright © 2015 by the American Occupational Therapy Association, Inc.)

In the 2011/2012 season, 18 patients were admitted to our hospital due to influenza virus A infection and the number had increased compared to the previous 3 years (average 5.3 patients/year). Therefore we evaluated the clinical characteristics, treatment, and prognosis of hospitalized cases. Although there were many reports on viral pneumonia caused by influenza (H1N1) 2009 among the young population in the 2009/ 2010 season, 16 out of 18 hospitalized patients were over 65 years-old in the 2011/2012 season. Major causes of admission were pneumonia in 8 cases, heart failure in 5 cases and bronchial asthma attack in 3 cases. The average age of 9 patients with pneumonia was higher significantly compared to 9 patients without pneumonia (average age 85.3 ± 10.2 : 71.4 ± 16.1, p < 0.05). Influenza vaccination was performed in 11 patients in total, and 6 out of 9 patients with pneumonia. The interval from illness onset to administration of neuraminidase inhibitors was 1.8 ± 1.1 days in cases with pneumonia and 2.1 ± 1.5 days in cases without pneumonia. Though 17 patients got well, one patient died from aspiration pneumonia after recovering from influenza A infection. In the 2011/2012 season, although many patients who had received vaccination needed to be hospitalized because of influenza A infection, the prognosis was fairly good.

To establish a highly efficient method of ex vivo expansion of hematopoietic cells (HCs), three-dimensional (3D) cocultures of HCs and stromal cell lines were performed using porous polymer scaffolds. Hematopoietic cells derived from mouse fetal livers were expanded by two successive cultures without the use of exogenous cytokines, namely, 3D cultures of stromal cells (DAS 104-8 cell line) to form stromal layers within the scaffolds, and, subsequently, by cocultures of the HCs on the stromal cell layers for 2 weeks. To expand the HCs more conveniently, in some experiments the stromal layers formed within the scaffolds were frozen (3D freezing) before the cocultures, then stored and applied to the cocultures after thawing. When the HCs were cocultured on the stromal layers of the DAS 104-8 cells, primitive HCs (c-kit(+) and CD34(+) cells) were expanded several fold during the cocultures. In contrast, the expansion of these primitive HCs was remarkably enhanced in the cocultures using the 3D frozen-thawed DAS 104-8 stromal layers (c-kit(+) cells > fifteenfold and CD34(+) cells > thirtyfold), and these expansions were significantly higher than those without the 3D freezing. The expansions enhanced by cocultures on the 3D frozen-thawed stromal layers were also observed in the cocultures with another stromal cell line (DAS 104-4). Because 3D frozen-thawed stromal cell lines are easy to handle, 3D coculture of HCs on frozen-thawed stromal cell lines may be an effective and convenient method for expanding primitive HCs., (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Objective: Cigarette smoking is a known risk factor for arteriosclerosis. In atheromatous plaques, vascular smooth muscle cells (VSMCs) display a phenotype that is different from the contractile type under normal conditions. Nicotine is the major pharmacological agent in cigarette smoke. However, any direct effect of nicotine on VSMCs remains uncertain. Because nicotine promotes VSMC migration, its phenotype may change due to nicotine., Approach and Results: We used human aorta primary smooth muscle cells (HuAoSMCs), differentiated with transforming growth factor-β, to investigate changes in the protein levels of differentiation markers and in the activity of mitogen-activated protein kinases (MAPKs) after exposure to 0.1 μM of nicotine for 48 h. After nicotine exposure, the protein levels of myosin II 10 (2.93-fold) and β-actin (1.66-fold), synthetic type markers, were increased. In contrast, the levels of the contractile type markers, myosin II 11 (0.63-fold), high-molecular-weight caldesmon (0.40-fold) and SM22 (0.66-fold), which concern differentiated VSMC, were decreased. Moreover, nicotine exposure induced enhanced activation of p38 MAPK (1.30-fold) and extracellular signal-regulated kinase (1.91-fold). These results indicated that the phenotype of HuAoSMCs had changed to a synthetic-like type because of nicotine exposure. Thus, nicotine is one factor that can alter protein expression of differentiation markers in VSMCs. Besides, the increase of intracellular Ca(2+) levels suggested that these effects of nicotine were mediated through nicotinic acetylcholine receptors., Conclusion: Nicotine has already been reported to promote VSMC migration from the tunica media to atheromatous plaques in the vascular intima. This phenomenon may occur because nicotine directly induces VSMC transformation from contractile type to synthetic-like type via nicotinic acetylcholine receptors and G protein-coupled receptors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A case of successful chemotherapy for a metachronous liver metastasis following resection for sigmoid colon cancer is presented. A 51-year-old man underwent sigmoidectomy, ileocecal resection, and descending colon colostomy for sigmoid colon cancer with ileum invasion. Six courses of FOLFOX4 were performed as adjuvant chemotherapy. One year after sigmoidectomy, a liver metastasis was detected on computed tomography (CT) examination. Chemotherapy with FOLFOX+bevacizumab was restarted. Three courses were administered, but hepatic dysfunction occurred after the second and third courses, and FOLFOX was discontinued. Subsequent chemotherapy was reinitiated with FOLFIRI+bevacizumab. After 9 courses, the carcinoembryonic antigen level was normalized and appeared to be decreased by imaging studies. Upon the patient's request, only oral S-1 was administered. After 2 courses, CT revealed that the diameter of the tumor had increased by 2 cm. Therefore, right lobectomy of the liver, colostomy closure, and anastomosis were performed. During these procedures, a nodule was found in the omentum and was removed. Rapid intra-operative diagnosis revealed peritoneal dissemination. The pathological diagnosis was liver metastasis of sigmoid colon cancer, with necrosis and fibrosis seen in approximately one-half of specimens. The surgical margins were negative. Neither metastatic cancer nor dissemination were found in the resected greater omentum.

A 61-year-old man was diagnosed with rectal cancer with multiple liver metastases in December 2009, and low anterior resection of the rectum was performed. Postoperative adjuvant chemotherapy with 6 courses of oxaliplatin, Leucovorin, and 5-FU (FOLFOX4) and bevacizumab was initiated, followed by 5 courses of fluorouracil, Leucovorin, and irinotecan (FOLFIRI) and bevacizumab. Right posterior segment (S6, S7) hepatectomy with enucleation of S2, S3 and S5 was performed, and chemotherapy with FOLFOX4 (11 courses) was administered. New metastases in the S5 segment were observed in August 2011 and right hepatic lobectomy was performed. The patient then underwent 8 courses of adjuvant chemotherapy with FOLFOX4. However, left hepatic lobe lateral segment and caudate lobe metastases then appeared. Subsequent repeated chemotherapy with FOLFIRI plus cetuximab (3 courses) and irinotecan plus cetuximab was interrupted in August 2013 owing to adverse events resulting in rapid growth of hepatic metastases. The patient underwent hepatic left lateral segmentectomy and left caudate lobectomy. The postoperative course was uneventful and the patient has currently survived 4 years and 7 months after the initial surgery.

Stage IV gastric cancer has poor prognosis, and median survival time (MST) is reported to range from 6 to 13 months. We report a case of long-term survival in a Stage IV gastric cancer patient who was successfully treated with multi combination chemotherapy with S-1. A 73-year-old woman presenting with gastric cancer with pyloric stenosis and peritoneal dissemination at the sigmoid colon underwent distal gastrectomy with D2 lymphadenectomy and sigmoidectomy. She received adjuvant chemotherapy with S-1 and CDDP after surgery. During the twelfth administration of S-1 and CDDP, she developed an anaphylactic reaction against CDDP; therefore, only S-1 was administered for the next 6 courses. Thirty one months postgastrectomy, a left ovarian metastasis (about 4 cm) was detected by computed tomography. Two courses of S-1 and CPT-11 were administered; however, the ovarian metastasis grew to twice its initial size. She underwent hysterectomy and bilateral ovariectomy. The pathological diagnosis was metastatic tumors in the uterus and ovary(Krukenberg tumor). After the second surgery, S-1 and docetaxel therapy was initiated. A metastasis (S2, 5mm diameter) appeared in the right lung around 65 months after the gastrectomy. The patient received a total of 28 courses, up until 69 months post-gastrectomy. At present, she hopes to finish the chemotherapy and is consulting a palliative care facility. At 80 months post-gastrectomy, she has no symptoms because the lung metastasis exhibits slow growth (15 mm diameter), and is maintaining her quality of life (QOL).

Case History: A 3-month-old infant was found dead in his bed. A postmortem computed tomography (CT) scan suggested fatty attenuation in the liver parenchyma, but no other potentially fatal changes were found. To clarify the cause of death, a medicolegal autopsy was carried out., Autopsy Findings: Internal examination confirmed the presence of liver steatosis as well as hepatomegaly. There were no other significant findings including encephalitis or brain edema., Mass Spectrometry Analysis: To clarify the mechanism underlying lipid accumulation in the liver, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) analysis was conducted. This indicated a significant accumulation of C14:1 acylcarnitine in the liver of the deceased, suggesting very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency., Genetic Analysis: To find the cause of the VLCAD deficiency, genetic analysis of the responsible gene, acyl-CoA dehydrogenase, very long chain (ACADVL), was performed. This revealed two novel mutations that may have accounted for the disease., Conclusion: A combination of these data revealed that the liver steatosis in this case might have been caused by VLCAD deficiency based on genetic mutations of ACADVL. Thus, the deceased might have been vulnerable to energy crisis and sudden infant death. The present findings show that MALDI-IMS analysis as well as genetic analysis can be useful for elucidating the cause of death., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Neutralizing antibodies that target the hemagglutinin of influenza virus either inhibit binding of hemagglutinin to cellular receptors or prevent the low-pH-induced conformational change in hemagglutinin required for membrane fusion. In general, the former type of antibody binds to the globular head formed by HA1 and has narrow strain specificity, while the latter type binds to the stem mainly formed by HA2 and has broad strain specificity. In the present study, we analyzed the epitope and function of a broadly neutralizing human antibody against H3N2 viruses, F005-126. The crystal structure of F005-126 Fab in complex with hemagglutinin revealed that the antibody binds to the globular head, spans a cleft formed by two hemagglutinin monomers in a hemagglutinin trimer, and cross-links them. It recognizes two peptide portions (sites L and R) and a glycan linked to asparagine at residue 285 using three complementarity-determining regions and framework 3 in the heavy chain. Binding of the antibody to sites L (residues 171 to 173, 239, and 240) and R (residues 91, 92, 270 to 273, 284, and 285) is mediated mainly by van der Waals contacts with the main chains of the peptides in these sites and secondarily by hydrogen bonds with a few side chains of conserved sequences in HA1. Furthermore, the glycan recognized by F005-126 is conserved among H3N2 viruses. F005-126 has the ability to prevent low-pH-induced conformational changes in hemagglutinin. The newly identified conserved epitope, including the glycan, should be immunogenic in humans and may induce production of broadly neutralizing antibodies against H3 viruses., Importance: Antibodies play an important role in protection against influenza virus, and hemagglutinin is the major target for virus neutralizing antibodies. It has long been believed that all effective neutralizing antibodies bind to the surrounding regions of the sialic acid-binding pocket and inhibit the binding of hemagglutinin to the cellular receptor. Since mutations are readily introduced into such epitopes, this type of antibody shows narrow strain specificity. Recently, however, broadly neutralizing antibodies have been isolated. Most of these bind either to conserved sites in the stem region or to the sialic acid-binding pocket itself. In the present study, we identified a new neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against H3N2. This epitope may be useful for design of vaccines., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: To assess the prevalence and risk factors of recurrence of chronic pulmonary aspergillosis (CPA) after discontinuation of antifungal triazoles., Method: We reviewed the medical records of CPA patients who achieved resolution of clinical and radiographic manifestations and stopped taking antifungal triazoles between June 2006 and June 2012 at Tokyo National Hospital. We evaluated whether there was CPA recurrence within 1 year after treatment cessation and investigated risk factors for relapse. The association of anti-Aspergillus antibody conversion with CPA recurrence was also reviewed., Results: A total of 39 patients were included in this study and there was CPA recurrence in 14 patients. Compared with the Non-recurrence group, the Recurrence group exhibited 1) younger age (p = 0.017), 2) more than one lung lobe affected by CPA more frequently (p = 0.008), 3) longer duration needed to remit manifestations of chest radiograph (p = 0.031), 4) longer antifungal treatment duration (p = 0.042). The present study did not reveal an association between negative conversion of serum anti-Aspergillus antibody and recurrence risk. Multivariate logistic regression analysis revealed that patients with CPA with affected area of more than one lung lobe had increased risk (odds ratio, 10.20; 95% confidence interval, 1.49-69.77; p = 0.018)., Conclusion: CPA recurrence can be seen in about one-third of cases after discontinuing azole treatment. We should make decisions about treatment duration and follow up depending on the severity of each case, particularly on the expansion of CPA-affected area., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012-2013. Here we describe an antibody, F045-092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045-092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045-092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.

An observational study was conducted to determine immunogenicity before and after primary and secondary vaccinations with 23-valent pneumococcal polysaccharide vaccine in a cohort of 40 elderly patients with chronic lung diseases. Safety of this vaccine was also compared between primary and secondary vaccination. We analyzed serotype-specific immunoglobulin G (IgG) and the opsonization index (OI) for serotypes 6B, 14, 19F, and 23F and compared adverse local and systemic reactions. The levels of serotype-specific IgG and the OIs significantly increased 1 month after primary and secondary vaccinations. Peak levels of IgG after secondary vaccination were 5-20% lower than those after primary vaccination, while serotype-specific OIs after secondary vaccination were comparable with those after primary vaccination. The levels of serotype-specific IgG required for 50% killing significantly decreased 1 month after vaccination. These values for serotypes 14, 19F, and 23F were slightly elevated immediately before secondary vaccination, but those for serotype 6B did not change. After secondary vaccination, these values declined slightly for serotypes 14, 19F, and 23F and remained low for serotype 6B. Although self-limited local and systemic reactions were more frequent after secondary vaccination compared with primary vaccination, no serious systemic reaction was found after either vaccination. Our data suggest a sustained functional serotype-specific IgG after primary and secondary vaccination and confirmed the safety of secondary vaccination among elderly individuals with chronic lung disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Many people have a history of catching the flu several times during childhood but no additional flu in adulthood, even without vaccination. We analyzed the total repertoire of antibodies (Abs) against influenza A group 1 viruses induced in such a flu-resistant person after vaccination with 2009 H1N1 pandemic influenza virus. They were classified into two types, with no exceptions. The first type, the products of B cells newly induced through vaccination, binds near the sialic acid-binding pocket. The second type, the products of long-lived memory B cells established before vaccination, utilizes the 1-69 VH gene, binds to the stem of HA, and neutralizes both H1N1 and H5N1 viruses with few exceptions. These observations indicate that the sialic acid-binding pocket and its surrounding region are immunogenically very potent and majority of the B cells whose growth is newly induced by vaccination produce Abs that recognize these regions. However, they play a role in protection against influenza virus infection for a short period since variant viruses that have acquired resistance to these Abs become dominant. On the other hand, although the stem of HA is immunogenically not potent, the second type of B cells eventually becomes dominant. Thus, a selection system should function in forming the repertoire of long-lived memory B cells and the stability of the epitope would greatly affect the fate of the memory cells. Acquisition of the ability to produce Abs that bind to the stable epitope could be a major factor of flu resistance.

The glycerophosphodiester phosphodiesterases are evolutionarily conserved proteins that have been linked to several patho/physiological functions, comprising bacterial pathogenicity and mammalian cell proliferation or differentiation. The bacterial enzymes do not show preferential substrate selectivities among the glycerophosphodiesters, and they are mainly dedicated to glycerophosphodiester hydrolysis, producing glycerophosphate and alcohols as the building blocks that are required for bacterial biosynthetic pathways. In some cases, this enzymatic activity has been demonstrated to contribute to bacterial pathogenicity, such as with Hemophilus influenzae. Mammalian glyerophosphodiesterases have high substrate specificities, even if the number of potential physiological substrates is continuously increasing. Some of these mammalian enzymes have been directly linked to cell differentiation, such as GDE2, which triggers motor neuron differentiation, and GDE3, the enzymatic activity of which is necessary and sufficient to induce osteoblast differentiation. Instead, GDE5 has been shown to inhibit skeletal muscle development independent of its enzymatic activity., (© 2013 FEBS.)

A 35-year-old man with a six-month history of progressive exertional dyspnea was referred to our institution. He had been diagnosed with Mycobacterium intracellulare pulmonary infection with lung cavitation two years earlier, and was being followed up without any medications. After being referred to our hospital, he underwent computed tomographic pulmonary angiography, which indicated a pulmonary thrombus and lung cavitation. Furthermore, right heart catheterization confirmed pulmonary hypertension, and we made a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Following successful pulmonary endarterectomy, the patient's symptoms and hemodynamics were significantly improved, with the disappearance of lung cavitation. It is important to suspect CTEPH in patients with unaccountable infectious lung cavities.

This study's primary goal was to develop an effective ex vivo expansion method for haematopoietic cells. 3D culture of mouse bone marrow cells was performed in porous scaffolds using a sheet or cube shape. Bone marrow cells were cultured on bone marrow-derived stromal layers formed within the scaffolds and the effect of scaffold shape on the expansion of haematopoietic cells was examined. In some experiments, stromal layers within cubic scaffolds were frozen and then used to culture bone marrow cells after thawing. Results show that after comparison, total cell density and expansion of haematopoietic cells were greater in cultures using the cubic scaffold, suggesting that it was superior to the sheet-like scaffold for expanding haematopoietic cells. When cryopreserved stroma was used, it effectively supported the expansion of haematopoietic cells, and a greater expansion of haematopoietic cells [(erythroid and haematopoietic progenitor cells (HPCs)] was achieved than in cultures with stromal cells that had not been cryopreserved. Expansion of cells using cryopreserved stroma had several other advantages such as a shorter culture period than the conventional method, a stable supply of stromal cells, and ease of handling and scaling up. As a result, this is an attractive method for ex vivo expansion of haematopoietic stem cells (HSCs) and HPCs for clinical use., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background and Objective: The incidence and annual risk of infection of tuberculosis (TB) have decreased rapidly in Japan because of the development of anti-TB medicines and nutritional and hygienic improvements after World War II. The incidence of tuberculosis is currently high among elderly people, reflecting the fact that the prevalence rate of TB infection had been extremely high during their youth. This would suggest that most current cases of TB in the elderly are reactivation of infections acquired in their youth. TB reactivation in various organs have both common and unique aspects. We evaluated the frequency of endogenous reactivation of TB in various organs by examining the TB incidence rate over a 30-year period (1975-2005) in Japan., Methods: The incidence rate of TB in each organ was obtained for each 10-year birth cohort, using reports of newly registered TB patients in Japan in 1975, 1985, 1995, and 2005. Specifically, the incidence rates of pulmonary TB, lymph node TB, bone-joint TB, kidney TB, and meninges TB were analyzed., Results: Chronological changes in TB incidence rates in each organ were characterized by a rapidly declining phase followed by a stationary phase in every organ TB except pulmonary TB. Incidence rates among the already infected population in the stationary phase were 3.0 (lymph node TB), 1.2 (bone-joint TB), 0.5 (kidney TB), and 0.3 (meninges TB) per 100,000 cases, respectively., Conclusions: Once infected with TB, the incidence rate of TB in these organs does not decrease below the above-mentioned values.

The domain wall (DW) velocity above the Walker field drops abruptly with increasing magnetic field, because of the so-called Walker breakdown, where the DW moves with a precessional mode. On applying the higher field, the DW velocity again starts to increase gradually. We report the DW propagation around this local minimum regime in detail, investigated through the time-resolved electrical detection technique, with a magnetic tunnel junction. Just above the Walker field, we succeeded in detecting the precessional motion of the DW in a real-time regime, while a different mode appeared around the local minimum of the DW velocity.

Merkel cell carcinoma (MCC), an aggressive skin cancer with neuroendocrine features, has been found to be associated with a new type of human polyomavirus called Merkel cell polyomavirus (MCV). Patients diagnosed with MCC have a significantly increased risk of a second primary cancer. We report here the first case of two primary MCCs arising on the face at different times, associated with MCV infection. The tumour on the patient's right cheek was surgically removed, followed by chemoradiation. After a 10-year tumour-free period, a new tumour developed on the patient's left cheek. Histological and immunohistochemical findings were consistent with MCC. The tumours had high MCV copy numbers and expressed large T antigen, which may play a major role in MCV-mediated carcinogenesis. This case highlights the close links between MCC and MCV.

Serial changes in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and atrial natriuretic peptide (ANP) concentrations are unknown in dogs with myocardial injury. The time-course secretory responses between NT-proBNP and ANP or cardiac troponin-T (cTnT) related to myocardial infarction (MI) were investigated in this study. Six dogs were anaesthetised and the left anterior descending artery was ligated. A transient decrease in cardiac function was detected 1h after MI but returned to baseline levels within 7 days and remained so for 6 months. Echocardiographic examination revealed focal ventricular dyskinesis throughout the study. Six months following MI, the left atrium to aorta ratio increased significantly although the relative wall thickness decreased significantly from baseline. Significantly elevated plasma NT-proBNP and cTnT concentrations were detected 1 day after MI and these gradually decreased over 28 days to baseline levels without left ventricular pressure elevation. Plasma ANP was elevated significantly 6 months after MI. The NT-proBNP assay is a helpful diagnostic indicator for identifying asymptomatic acute and subacute myocardial injury whereas plasma ANP concentration mainly reflects atrial dilation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A 62-year-old woman, diagnosed as bronchial asthma 3 years previously, was admitted due to acute severe dyspnea. Physical examination revealed saddle nose, flare/swelling of the ear auricles, and stridor. Computed tomography demonstrated thickening of tracheal/bronchial walls and stenosis of the lumen that deteriorated on expiration, suggesting tracheobronchomalacia. Auricle biopsy indicated cartilage destruction. Based on these findings, the patient was diagnosed as relapsing polychondritis. As demonstrated in this case, relapsing polychondritis involving airways might be misdiagnosed as bronchial asthma due to stridor and transient corticosteroid-related improvement. Early diagnosis is necessary to prevent irreversible airway stenosis and progression to tracheobronchomalacia.

Background: Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide., Methods: A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated., Results: Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by >80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting β(2) agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA., Conclusions: These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.

Influenza A viruses are classified into 16 subtypes according to the serotypes of hemagglutinin (HA). It is generally thought that neutralizing antibodies (Abs) are not broadly cross-reactive among HA subtypes. We examined the repertoire of neutralizing Abs against influenza viruses in humans. B lymphocytes were collected from donors by apheresis, and Ab libraries were constructed by using phage-display technology. Anti-HA clones were isolated by screening with H3N2 viruses. Their binding activity was examined, and four kinds of Abs showing broad strain specificity were identified from one donor. Two of the Abs, F045-092 and F026-427, were extensively analyzed. They neutralized not only H3N2 but also H1N1, H2N2, and H5N1 viruses, although the activities were largely varied. Flow cytometry suggested that they have the ability to bind to HA and HA1 artificially expressed on the cell surface. They show hemagglutination inhibition activity and do not compete with C179, an Ab thought to bind to the stalk region. F045-092 competes with Abs that recognize sites A and B for binding to HA. Furthermore, the serine at residue 136 in site A could be a part of the epitope. Thus, it is likely that F045-092 and F026-427 bind to a conserved epitope in the head region formed by HA1. Interestingly, while the V(H)1-69 gene can encode MAbs against the HA stem that are group 1 specific, F045-092 and its relatives that recognize the head region also use V(H)1-69. The possible epitope recognized by these clones is discussed.

Background: Patients with spinal cord injury and a chronic indwelling urinary catheter are known to have an increased risk of bladder malignancy. However, squamous cell carcinoma (SCC) of the epidermis around a suprapubic cystostomy is relatively rare. Here, we report a case of lower abdominal SCC arising from the suprapubic cystostomy tract., Case Presentation: A 58-year-old man with a complete spinal cord injury was referred to our hospital with a chief complaint of an abdominal mass. Abdominal enhanced computed tomography (CT) showed a 7-cm mass surrounding the suprapubic cystostomy and bilateral inguinal and para-aortic lymph nodes metastasis. Histopathological examination of percutaneous biopsy specimens was performed. The diagnosis was stage IV (cT4N1M1) epidermal SCC, which was treated with palliative external radiation therapy., Conclusion: The SCC in this case was thought to arise from mechanical stimulus of the suprapubic cystostomy. Physicians and patients should pay careful attention to any signs of neoplasms with long-term indwelling catheters, such as skin changes around the suprapubic cystostomy site. This case presentation is only the fourth report of SCC arising from the suprapubic cystostomy tract in the literature. In cases of unresectable tumors and contraindications to chemotherapy, palliative radiotherapy may lead to disease remission and symptom relief.

Current-induced magnetic domain wall (DW) displacement in a Co/Ni nano-wire with perpendicular magnetic anisotropy was investigated in real space by photoemission electron microscopy (PEEM) for the first time. DW velocity determined from the PEEM observation was 40 m s(-1) for the current density of 2.5 × 10(12) A m(-2), which was consistent with the result obtained by the electrical measurement used in our previous reports.

Objective: The purpose of this study was to evaluate tuberculosis treatment including levofloxacin (LVFX) and to investigate the effectiveness of changing drug regimens at our hospital., Subjects and Methods: A retrospective study was conducted on 331 patients with tuberculosis admitted to Tokyo National Hospital in 2005. Out of these 331 patients, LVFX was used in 48 (14.5%), 41 of which were initial-treatment cases. We studied why and how LVFX was used and compared bacteriological negative conversion rates between the initial-treatment cases in which the initial standard regimen was changed to regimens including LVFX, and those in which the initial standard regimen was either maintained throughout or modified with drugs other than LVFX. Sputum cultures were examined with Mycobacteria Growth Indicator Tube System (BACTEC MGIT 960)., Results: LVFX was used in 41 (13.6%) of 302 initial-treatment cases and in 7 (24.1%) of 29 retreatment cases. Out of the 269 initial-treatment cases starting with the standard regimen, LVFX was later used in 26 cases (9.7%). The reasons for using LVFX were adverse reaction to antituberculosis drugs in 23 cases (88.5%) and resistance to antituberculosis drugs in 3 cases (11.5%). We investigated the bacteriological conversion rate in 228 patients who could be followed up for more than five months. The conversion rates in 105 cases under the standard regimen including PZA (PZA+) were 92.4% in three months, 98.1% in four months, and 100% in five months. The rates in 56 cases under the standard regimen without PZA (PZA-) were 92.9 %, 98.2% and 100%,respectively. The rates of 22 cases under the initial regimen modified with LVFX (LVFX +) were 68.2 %, 95.5% and 100%, respectively. In 45 cases under the initial regimen modified with drugs other than LVFX (LVFX-), the rates were 80.0%, 97.8% and 100%, respectively., Conclusion: This study showed that LVFX was an effective drug in terms of the bacteriological conversion rate, without adverse reaction. LVFX is not approved as an antituberculosis drug in Japan, but it is often used in cases of MDR-TB or in situations in which the patients cannot continue treatment with the standard regimen. We hope that LVFX will be approved as an antituberculosis drug as soon as possible in Japan.

A 55-year-old woman was admitted to our hospital because of chest pain, fever, and right pleural effusion that was exudative and lymphocyte-dominant with a high level of adenosine deaminase (ADA). Since her blood QuantiFERON-TB 3G test (QFT) was positive, she was diagnosed with tuberculous pleurisy. After initiation of anti-tuberculosis chemotherapy with isoniazid, rifampicin, ethambutol, and pyrazinamide, her symptoms improved. Later, liquid culture of the pleural effusion turned positive for Mycobacterium tuberculosis. On the 18th day of treatment, her chest X-ray and computed tomography exhibited pleural effusion in a moderate amount in the left thorax, with subsiding pleural effusion in the right thorax. Thoracocentesis demonstrated that the left thorax effusion was also exudative and lymphocyte-dominant, with elevated QFT response and high ADA concentration, suggesting tuberculous pleurisy. Mycobacterium tuberculosis was detected in the culture of a left pleural biopsy specimen obtained by thoracoscopy. We assumed that the left pleural effusion was due to paradoxical worsening because (1) on admission no effusion or lung parenchymal lesion was detected in the left hemithorax, (2) on the 14th day of treatment she was afebrile without pleural effusion on both sides, and (3) the bacilli were sensitive to the drugs she had been taking regularly. We performed drainage of the left effusion and continued the same anti-tuberculosis drugs, which led to the elimination of all her symptoms and of the pleural effusion on both sides. In conclusion, paradoxical worsening should be included in the differential diagnosis when contralateral pleural effusion is detected during the treatment of tuberculosis.

The first case in Japan of 2009 pandemic influenza A (H1N1) was reported in May, with pediatric hospitalization exceeding that of adults. We evaluated six adults hospitalized for 2009 H1N1 respiratory complications and compared the pandemic to seasonal influenza. Hospitalization was due to aggravated asthma in four of the six, two of whom had simultaneous pneumonia probably virus-caused, and two cases of bacterial pneumonia. Among the three seasons examined, the number of adults increased slightly but the hospitalization rate was low in 2009-2010. Respiratory complications such as viral pneumonia were not seen outside of 2009-2010. Attention should therefore be paid to respiratory complications in adults with pandemic 2009 influenza A (H1N1) virus.

Through extensive isolation of neutralizing mAbs against H3N2 influenza viruses representing the in vivo repertoire in a human donor, we examined the relationships between antigenic drift of influenza virus and protective antibodies generated in an infected individual. The majority of mAbs isolated from a donor born in 1960 were divided into three major groups with distinct strain specificity: 1968-1973, 1977-1993 and 1997-2003. In the present study, we developed a new method that allowed us to comprehensively determine the location of epitopes recognized by many mAbs. Original haemagglutinins (HAs) of several strains and chimaeric variants, in which one of the seven sites (A, B1, B2, C1, C2, D or E) was replaced by some other strain-derived sequence, were artificially expressed on the cell surface. The binding activity of mAbs to the HAs was examined by flow cytometry. By using this method, we determined the location of epitopes recognized by 98 different mAbs. Clones that neutralize the 1968-1973 strains bind to site B2/D, A or A/B1. While sites C, E and B were recognized by clones that neutralized the 1977-1993 strains, the majority of these clones bind to site C. Clones that neutralize the 1997-2003 strains bind to site B, A/B1, A/B2 or E/C2.

To establish an ex vivo expansion method of haematopoietic progenitor cells (HPCs) and erythroid cells, three-dimensional (3D) cultures of mouse bone marrow cells were performed, employing a porous polyvinyl formal (PVF) resin as a scaffold. In these cultures, the effects of oxygen concentration and co-cultures with stromal cells on the expansion of HPCs and erythroid cells were investigated. When bone marrow cells were cultured under 3D conditions, HPCs and erythroid cells expanded without supplementation of exogenous cytokines, irrespective of the presence of stromal cells. On the contrary, slight expansion of HPCs or erythroid cells was observed in monolayer cultures as controls, indicating that the 3D cultures using the PVF scaffold were far better in expanding HPCs and erythroid cells than the monolayer cultures. Under hypoxic conditions, bone marrow stromal cells allowed for a 3D culture of erythroid cells and HPCs at higher cell densities compared to cultures without stromal cells, and the duration of the expansion of HPCs and erythroid cells after initiating the 3D co-cultures was prolonged. The number of these cells increased throughout the culture period up to 3 weeks under hypoxic conditions, although the number decreased after 2 weeks under normoxic conditions. In conclusion, the 3D co-culture method of haematopoietic cells with stromal cells under hypoxic conditions was confirmed to be effective in expanding HPCs and erythroid cells, and this method seemed to be useful for developing an ex vivo expansion method for haematopoietic cells., (Copyright © 2010 John Wiley & Sons, Ltd.)

The assisted reproductive techniques (ARTs) such as in vitro fertilization, embryo transfer, and cryopreservation of gametes have contributed considerably to the development of biomedical sciences in addition to improving infertility treatments in humans as well as the breeding of domestic animals. However, ARTs used in canine species have strictly limited utility when compared with other mammalian species, including humans. Although successful somatic cell cloning has been reported, artificial insemination by frozen semen to date is only available for the improved breeding and reproduction for companion and working dogs as well as guide dogs for the blind. We describe here the successful cryopreservation of embryos and subsequent embryo transfer in dogs. Canine embryos were collected from excised reproductive organs after artificial insemination and subsequently cryopreserved by a vitrification method. When the 4-cell to morula stage of cryopreserved embryos were nonsurgically transferred into the uteri of nine recipient bitches using a cystoscope, five recipients became pregnant and four of them delivered a total of seven pups. The cryopreservation of embryos in canine species will facilitate the transportation and storage of genetic materials and will aid in the elimination of vertically transmitted diseases in dogs. In addition, this technique will contribute to the improved breeding of companion and working dogs such as guide dogs, drug-detecting dogs, and quarantine dogs.

The novel glycosphingolipid, β-D-GalNAcp(1-->4)[α-D-Fucp(1-->3)]-β-D-GlcNAcp(1-->)Cer (A), isolated from the marine sponge Aplysinella rhax has a unique structure, with D-fucose and N-acetyl-D-galactosamine moieties attached to a reducing-end N-acetyl-D-glucosamine through an α1-->3 and β1-->4 linkage, respectively. We synthesized glycolipid 1 and some non-natural di- and trisaccharide analogues 2-6 containing a D-fucose residue. Among these compounds, the natural type showed the most potent nitric oxide (NO) production inhibitory activity against LPS-induced J774.1 cells. Our results indicate that both the presence of a D-Fucα1-3GlcNAc-linkage and the ceramide aglycon portion are crucial for optimal NO inhibition.

Objectives: Pulmonary sarcoidosis which predominantly affects the lower lung fields is relatively rare. We performed this study to clarify the clinical manifestations of this type of sarcoidosis., Subjects and Methods: Over a period of 13 years, we diagnosed pulmonary sarcoidosis in 119 patients. Among these, we reviewed the clinical characteristics of 9 patients (3 men, 6 women, mean age 62 years) with pulmonary lesions predominantly affecting the lower lung fields., Results: Four patients had a history of dust inhalation and 6 had symptoms of dyspnea. All patients had ocular lesions and 5 had cutaneous lesions. Serum KL-6 levels were elevated in all patients, whereas angiotensin-converting-enzyme (ACE) levels were elevated in 3. Pulmonary function tests revealed stenosis in 4 patients, and decreased diffusion capacity in 7. Chest CT findings in the lower lung fields revealed bronchovascular thickening, micronodular opacities in the vessels and chest wall, and interlobular septal thickening in 8 patients; ground-glass opacities in 5; curvilinear shadows in 4; and patchy shadows, traction bronchiectasis, and pleural effusion in 3. Histopathologic findings of lung biopsy specimens featured granulomas in all patients, and pulmonary interstitium fibrosis and small round-cell infiltration in the alveoli of most patients., Conclusion: Patients with sarcoidosis affecting the lower lung fields often had symptoms of dyspnea, extrapulmonary lesions in the eye and/or on the skin, and elevated serum KL-6 levels but not ACE. Chest CT showed findings typical of sarcoidosis, such as lymphatic distribution, but also showed unusual findings such as ground-glass opacities, curvilinear shadows, patchy shadows, traction bronchiectasis and pleural effusion. We speculated that 1 patient with ground-glass opacities and traction bronchiectasis without lymphatic distribution on CT, and fibroblastic foci with active alveolitis histopathologically, had complications of a different type of interstitial pneumonia.

We reported a case of peritoneal disseminated recurrence after total gastrectomy for perforated gastric malignant lymphoma. A 73-year-old man underwent total gastrectomy for perforated gastric diffuse large B cell lymphoma on day 5 of RCHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) chemotherapy. He has rejected chemotherapy and received no additional treatment after gastrectomy. Computer tomography 13 months after surgery revealed peritoneal dissemination and abdominal lymph node metastasis. R-CHOP chemotherapy was performed, and after 4 courses of chemotherapy, peritoneal dissemination and metastatic abdominal lymph nodes disappeared. Chemotherapy was discontinued for a time, however, the tumors relapsed 2 months after stopping chemotherapy. He underwent chemotherapy with etoposide, but died of tumor progression 21 months after gastrectomy.

A 70-year-old female with severe tricuspid regurgitation and stenosis was admitted to our institution because of watery diarrhea and peripheral edema. The urinary 5-hydroxyindoleacetic acid (5-HIAA) level was 292.9 mg/l (normal, 0.5-5.0 mg/l). Abdominal computed tomography showed enhanced multiple nodules in the liver. The liver biopsy revealed metastatic carcinoid disease, which was thought as an etiology in severe tricuspid regurgitation and stenosis. We administered long acting somatostatin analog, octreotide to control carcinoid symptoms. After improvement of general condition, she successfully underwent bioprosthetic valve replacement with concomitant octreotide administration. Postoperative course was uneventful. She had been followed up with administration of octreotide at outpatient clinic. Cardiac surgery for carcinoid heart disease is complicated by hemodynamic instability secondary to carcinoid crises which can be provoked pharmacologically by administration of vasoactive medications. Octreotide is an effective tool to manage manifestation of carcinoid activity. We could performed surgical treatment of carcinoid heart disease safely in the perioperative presence of octreotide.

Mammalian glycerophosphodiester phosphodiesterases (GP-PDEs) have been identified recently and shown to be implicated in several physiological functions. This study isolated a novel GP-PDE, GDE5, and showed that GDE5 selectively hydrolyzes glycerophosphocholine (GroPCho) and controls skeletal muscle development. We show that GDE5 expression was reduced in atrophied skeletal muscles in mice and that decreasing GDE5 abundance promoted myoblastic differentiation, suggesting that decreased GDE5 expression has a counter-regulatory effect on the progression of skeletal muscle atrophy. Forced expression of full-length GDE5 in cultured myoblasts suppressed myogenic differentiation. Unexpectedly, a truncated GDE5 construct (GDE5DeltaC471), which contained a GP-PDE sequence identified in other GP-PDEs but lacked GroPCho phosphodiesterase activity, showed a similar inhibitory effect. Furthermore, transgenic mice specifically expressing GDE5DeltaC471 in skeletal muscle showed less skeletal muscle mass, especially type II fiber-rich muscle. These results indicate that GDE5 negatively regulates skeletal muscle development even without GroPCho phosphodiesterase activity, providing novel insight into the biological significance of mammalian GP-PDE function in a non-enzymatic mechanism.