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Taurine is an amino acid that has several physiological functions. Previously, we reported the apoptosis-inducing effect of taurine in human nasopharyngeal carcinoma (NPC) cells in vitro. However, the effect of taurine on NPC cell growth in vivo has not been elucidated. Autophagy plays an important role in cell metabolism and exhibits antitumor effects under certain conditions. In this study, we investigated the effects of taurine on apoptosis- and autophagy-related molecules in NPC cells in vitro and in vivo. In our in vitro study, NPC cells (HK1-EBV) were treated with taurine, and Western blot and immunocytochemical analyses revealed that taurine co-upregulated Beclin 1 and p53, with autophagy upregulation. In the in vivo study, we used a nude mouse model with subcutaneous xenografts of HK1-EBV cells. Once the tumors reached 2-3 mm in diameter, the mice were provided with distilled water (control group) or taurine dissolved in distilled water (taurine-treated group) ad libitum (day 1) and sacrificed on day 13. The volume and weight of the tumors were significantly lower in the taurine-treated group. Using immunohistochemistry (IHC), we confirmed that taurine treatment reduced the distinct cancer nest areas. IHC analyses also revealed that taurine promoted apoptosis, as evidenced by an increase in cleaved caspase-3, accompanied by upregulation of p53. Additionally, taurine increased LC3B and Beclin 1 expression, which are typical autophagy markers. The present study demonstrated taurine-mediated tumor growth suppression. Therefore, taurine may be a novel preventive strategy for NPC.

A regional epidemic of aseptic meningitis caused by echovirus 30 (E30) occurred in Hokkaido, Japan, during the period of August-December 2017. To investigate their phylogenetic relationship to other human enteroviruses, we determined the complete genomic nucleotide sequences of isolates from this outbreak. Phylogenetic analysis of the viral capsid protein 1 gene showed that the strains were most closely related to E30 strains detected in Germany, France, and Russia in 2013. In contrast, the region encoding the viral protease and the RNA-dependent RNA polymerase had a close phylogenetic relationship to non-E30 enteroviruses detected in the United Kingdom and Switzerland in 2015-2017, suggesting that a recombination event had occurred. Electronic supplementary material The online version of this article (10.1007/s00705-019-04484-7) contains supplementary material, which is available to authorized users.

Background: Echovirus 30 (E30) is one of the most common causative agents for aseptic meningitis. Objectives: In the autumn of 2017, there was an outbreak caused by E30 in Kushiro, Hokkaido, Japan. The aim of this study was to characterize this outbreak. Study design: Fifty-nine patients were admitted to the Department of Pediatrics, Kushiro Red Cross Hospital (KRCH) with clinical diagnosis of aseptic meningitis. Among those, 36 patients were finally diagnosed as E30-associated aseptic meningitis by the detection of viral RNA using reverse transcription-polymerase chain reaction (RT-PCR) and/or the evidence of more than four-fold rise in neutralizing antibody (NA) titers in the convalescent phase relative to those in the acute phase. We investigated these 36 confirmed cases. Results: The median age was 6 years (range: 6 months–14 years). The positive signs and symptoms were as follows: fever (100%), headache (94%), vomiting (92%), jolt accentuation (77%), neck stiffness (74%), Kernig sign (29%), and abdominal pain (28%). The median cerebrospinal fluid (CSF) white cell count, neutrophil count, and lymphocyte count were 222/μL (range: 3–1434/μL), 144/μL (range: 1–1269/μL), and 85/μL (range: 2–354/μL), respectively. Although the detected viral genes demonstrated same cluster, they were different from E30 strains observed in Japan between 2010 and 2014. Conclusion: We mainly showed clinical and virological features of the E30-associated aseptic meningitis outbreak that occurred in Kushiro. To prevent further spread of E30 infection, continuous surveillance of enterovirus (EV) circulation and standard precautions are considered essential.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening systemic thrombotic microangiopathy characterized by the presence of anti-ADAMTS13 antibodies (inhibitor). Here we report the case of a patient with refractory aTTP successfully treated with cyclosporine. A 69-year-old man presenting with hematuria and petechiae was referred to our hospital; he was disoriented and febrile. Laboratory results revealed Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. Undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies (inhibitor) confirmed the diagnosis of aTTP. Despite performing plasma exchange and administering prednisolone and rituximab (375 mg/m

Strains of measles virus of genotypes D5, H1, D4, D8, and B3 were detected among epidemic, endemic, imported and import-associated cases in Hokkaido district, Japan, during 2006-2015. In the present study, their antigenic features were evaluated by determining the complete nucleotide sequences of their hemagglutinin proteins, which are a major target for neutralizing antibodies, and their amino acid sequences deduced. It was found that the hemagglutinin proteins of these strains had several novel amino acid changes in some functional regions. Although these strains have not caused further infections thus far, these antigenic changes should continue to be monitored to maintain their elimination status.

Background Infection with hepatitis E virus (HEV) genotypes 3 and 4 are usually asymptomatic but can occasionally result in life-threatening acute hepatitis. To date, only sporadic cases together with a few outbreaks have been documented. Seroprevalence studies with assays for the detection of HEV IgG antibodies, suggest that HEV is more prevalent than previously thought, even in non-endemic regions. Objectives The aim of this study was to characterize an outbreak of hepatitis E (HE) in a nursing home for aged people between February and March 2016. Study design After the identification of two cases living in the same nursing home, the presence of antibodies against HEV and HEV RNA were examined in serum samples collected from the other residents and staff members to identify any additional cases. An epidemiological investigation was also carried out. Results Only 4 patients showed mild symptoms such as anorexia, abdominal pain and fatigue. Among the 125 persons tested, 28 residents and one dietitian were confirmed positive for anti-HEV IgA or IgM antibodies, and/or HEV RNA. Eight samples had only IgG antibodies. Finally, 22 cases were notified with HE on the basis of the presence of IgA antibodies. All HEV isolates obtained were 99.8–100% identical and belonged to genotype 3. Conclusion HEV infections seem to be under-reported or underestimated possibly due to cases being generally asymptomatic. Testing for the presence of both anti-HEV antibodies and HEV RNA would be beneficial for both the comprehensive diagnosis of HE infections and the prevention of further infections.

Background An easy and reliable assay for detection of the rubella virus is required to strengthen rubella surveillance. Although a TaqMan RT-PCR assay for detection of the rubella virus has been established in Japan, its utility for diagnostic purposes has not been tested. Objectives To allow introduction of the TaqMan RT-PCR into the rubella surveillance system in Japan, the sensitivity of the assay was determined using representative strains for all genotypes and clinical specimens. Study design The detection limits of the method for individual genotypes were examined using viral RNA extracted from 13 representative strains. The assay was also tested at 10 prefectural laboratories in Japan, designated as local reference laboratories for measles and rubella, to allow nationwide application of the assay. Results The detection limits and amplification efficiencies of the assay were similar among all the representative strains of the 13 genotypes. The TaqMan RT-PCR could detect approximately 90% of throat swab and urine samples taken up to 5 days of illness. These samples were determined positive by a highly sensitive nested RT-PCR. Conclusions The TaqMan RT-PCR could detect at least 10 pfu of rubella virus. Although the sensitivity was somewhat lower than that of the conventional nested RT-PCR, the TaqMan RT-PCR could be more practical to routine tests for rubella laboratory diagnosis and detection in view of the rapid response and reducing risks of contamination.

Background The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic assay (ICA) kit, ALSONIC® Adeno (Alfresa Pharma Co., Osaka, Japan), for the detection of human adenovirus (HAdV) from throat swab samples based on the results of real-time PCR. The incubation time required for the novel assay kit (5 minutes) is shorter than that required for other ICA kits that are available in Japan. Methods Throat swab samples were taken from 151 patients aged 6 months to 15 years who were suspected of having respiratory tract infections caused by HAdV. Results The sensitivity and specificity of the ICA for detection of HAdV were 92.2% (83/90) and 95.1% (58/61), respectively, and the assay showed positive and negative predictive values of 96.5% (83/86) and 89.2% (58/65), respectively. Conclusions ALSONIC® Adeno is suitable as a diagnostic tool in the acute phase of HAdV infection.

A 64-year-old man visited his physician complaining of bilateral gynecomastia and left shoulder pain. Chest X-ray showed multiple bilateral masses in the lung, and he was referred to our hospital. Radiographical findings, elevation of serum total hCG, and histological findings of the cervical lymph node revealed multiple pulmonary, nodal, and brain metastases of poorly differentiated carcinoma of an unknown primary site with choriocarcinoma components. He was administered a regimen of reduced bleomycin, cisplatin, etoposide combination(reduced BEP regimen)to reduce the risk of acute respiratory failure with intra-alveolar hemorrhage related to post-chemotherapy early tumor necrosis. After chemotherapy, the tumor marker hCG levels were almost restored to normal levels, and radiography showed he had achieved a clinical partial response.

A 23-year-old man from Mie Prefecture, Japan, with past and family history of hematuria was diagnosed with influenza A and admitted to our hospital on the following day because of hemoglobinuria. He was diagnosed with thrombotic microangiopathy and was suspected of having atypical hemolytic uremic syndrome (aHUS). C3 p.I1157T missense mutation, which we had previously reported in eight aHUS patients from six families in Mie Prefecture, was identified. The laboratory findings and symptoms of our patient promptly improved after administering eculizumab. Little information is available on abnormalities of the complement system in aHUS or on mutation-specific outcomes of eculizumab therapy. Eculizumab was effective for treating our aHUS patient with C3 p.I1157T missense mutation.

Measles is an acute and highly contagious disease caused by measles virus (MeV). The government of Japan, following the last epidemic in 2007 and 2008, which was caused by genotype D5 strains, introduced a catch-up-vaccination program for teenagers during Japan fiscal years 2008-2012 and a mandatory case-based reporting system for the nationwide elimination. Furthermore, laboratory confirmation of measles cases by genotyping of isolates has been performed to clarify the source of infection and support the interruption of measles cases. Owing to these preventive measures, the number of measles cases has been steadily decreasing after the last epidemic. In March 2015, Japan was internationally verified as having achieved measles elimination by the World Health Organization Regional Office for the Western Pacific. The continuous elimination of measles and high levels of vaccination coverage for MeV have been maintained nationally. However, imported or import-associated cases of measles have sporadically occurred during this time. After the last nationwide epidemic, 17 imported or import-associated measles cases (MeV strains identified as genotypes H1, D4, D8, and B3) were reported in Hokkaido, the northern islands of Japan. In this study, we present the occurrence of measles and surveillance activities in Hokkaido during 2006-2015.

Strains of measles virus of genotypes D5, H1, D4, D8, and B3 were detected among epidemic, endemic, imported and import-associated cases in Hokkaido district, Japan, during 2006-2015. In the present study, their antigenic features were evaluated by determining the complete nucleotide sequences of their hemagglutinin proteins, which are a major target for neutralizing antibodies, and their amino acid sequences deduced. It was found that the hemagglutinin proteins of these strains had several novel amino acid changes in some functional regions. Although these strains have not caused further infections thus far, these antigenic changes should continue to be monitored to maintain their elimination status.

Chronic myeloid leukemia (CML) typically causes leukocytosis rather than thrombocytosis. We encountered two women in their thirties with remarkable thrombocytosis, whose platelet counts were over 3,000×10

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for >7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication.

Laboratory diagnoses for measles were performed in a total of 97 cases in Hokkaido, Japan, during 2011-2012. Two patients were confirmed to be positive for measles virus (MV), both of whom lived in the Iburi district of Hokkaido. Molecular analysis of the nucleotide sequences of the nucleoprotein (N) gene revealed that these 2 strains had high homology with each other and belonged to the genotype D8. The onset interval of these cases and epidemiological data suggested that MV transmission had occurred between them and then terminated. Phylogenetic analysis of the N gene revealed that the strains identified in Hokkaido were classified into a cluster that contained many genotype D8 strains that were detected within a large area of Japan. Eventually, 9 cases were officially reported as measles. However, other than the abovementioned 2 cases, no genetic information regarding MV was obtained. In future, further active surveillance combined with the genetic investigation should be required in all suspected measles cases to verify the elimination status.

Infectious mononucleosis (IM) is one of the representative, usually benign, acute diseases associated with primary Epstein-Barr virus (EBV) infection. IM is generally self-limiting and is characterized mostly by transient fever, lymphadenopathy and hepatosplenomegaly. However, very rarely primary EBV infection results in severe or fatal conditions such as hemophagocytic lymphohistiocytosis together with fulminant hepatitis designated as severe or fatal IM or EBV-associated hemophagocytic lymphohistiocytosis alone. In addition, chronic EBV-associated diseases include Burkitt’s lymphoma, undifferentiated nasopharyngeal carcinoma, Hodgkin lymphoma, T-cell lymphoproliferative disorder (LPD)/lymphoma, natural killer-cell LPD including leukemia or lymphoma, gastric carcinoma, pyothorax-associated lymphoma and senile B-cell LPD as well as chronic active EBV infection and LPD/lymphoma in patients with immunodeficiency. The number of chronic life-threatening diseases linked to the EBV infection is increasingly reported and many of these diseases have a poor prognosis. This review will focus on the historical, pathogenetic, diagnostic, therapeutic and prophylactic issues of EBV-associated life-threatening diseases.

Conventional reverse transcription-polymerase chain reaction (RT-PCR) to detect norovirus (NV) is a complex of multi-step procedure that requires gel electrophoresis as well as hybridization or sequencing to confirm the final diagnosis. A duplex TaqMan RT-PCR was developed to detect and classify genogroup (G) I and GII of NV. The primers and TaqMan probes for this assay were selected from the region of open reading frame (ORF) 1-ORF2 junction. A total of 796 stool specimens from 103 outbreaks of gastroenteritis, and a series of 46 stool specimens containing most NV genotypes was used for this study. For these specimens from 103 outbreaks, NV was detected and classified by the duplex TaqMan RT-PCR in 536 of the 541 specimens tested previously to be positive using the conventional RT-PCR. Two hundred fifty-one of the 255 specimens that were negative by the conventional RT-PCR were also negative by the TaqMan RT-PCR. No false positive result was observed for other enteric RNA viruses such as rotavirus and sapovirus. This is the first report on the development of a duplex TaqMan RT-PCR end-point assay for detection and differentiation of GI and GII of NV strains simultaneously followed by genotyping. These results suggest the practical application of this duplex TaqMan RT-PCR is useful for the detection of NV in clinical specimens.

A 14-year-old Japanese girl with a progressing combined immunodeficiency had developed non-Hodgkin's diffuse large B cell lymphoma. Her molecular analysis showed a compound heterozygote of novel mutations in the LIG4 gene, M249V substitution and a five nucleotides deletion from nucleotide position 1,270-1,274. She had also a set of characteristic clinical features of LIG4 syndrome. Mutations in the LIG4 gene, which plays a critical role in the repair of DNA double-strand breaks, imply a correlation with malignancies and several cases with leukemia or lymphoma have already been reported. We report here on a case of LIG4 syndrome complicated with distinct EBV-associated B-cell lymphoma.

Chronic active Epstein-Barr virus infection (CAEBV) is characterized mainly by prolonged or intermittent fever, lymphadenopathy and hepatosplenomegaly without definite underlying diseases at the diagnosis. Patients with CAEBV also may have various life-threatening conditions including hematological, neurological, pulmonary, cardiac, digestive tract, ocular and/or dermal disorders. Additionally, during the course of illness, they often develop hematological malignancies such as T cell, NK cell or B cell lymphoproliferative disorder (LPD) and/or lymphoma. No causative pathogenetic mechanisms have been sufficiently clarified, and additionally no promising efficacious treatment was demonstrated except for the hematopoietic stem cell transplantation (HSCT) in cases who develop T cell or NK cell LPD or lymphoma. This minireview outlines the recent development for the comprehensive viewpoints of CAEBV mainly regarding to virological, immunological, pathological and therapeutical progresses.

orrigendum to “Evaluation of sensitivity of TaqMan RT-PCR for ubella virus detection in clinical specimens” J. Clin. Virol. 80 (2016) 98–101] iyoko Okamotoa, Yoshio Moria,∗, Rika Komagomeb, Hideki Naganob, Masahiro Miyoshib, otohiko Okanob, Yoko Aokic, Atsushi Ogurad, Chiemi Hottad, Tomoko Ogawad, iwako Saikusae, Hiroe Kodamaf, Yoshihiro Yasuig, Hiroko Minagawag, Takako Kuratah, aiki Kanbayashih, Tetsuo Kaseh, Sachiko Murata i, Komei Shirabe i, Mitsuhiro Hamasaki j, akashi Katok, Noriyuki Otsukia, Masafumi Sakataa, Katsuhiro Komasea, Makoto Takedaa

Epstein-Barr virus (EBV) is one of eight known human herpesviruses (HHVs). A primary EBV infection is generally subclinical in immunocompetent individuals, but often causes infectious mononucleosis (IM) in adolescents and adults, which is generally a benign and self-limiting disease. Therefore, in immunocompetent individuals only symptomatic treatment is recommended, although fatal or malignant diseases such as fatal IM, Burkitt's lymphoma (BL) and nasopharyngeal carcinoma (NPC) may develop without obvious preceding immunodeficiency. However, in certain circumstances such as in patients with hereditary immunodeficiencies, in recipients receiving a potent immunosuppressant or in patients with acquired immunodeficiency syndrome (AIDS), this virus strongly links to the development of lethal lymphoproliferative diseases (LPD). These LPD range from IM-like illness associated with polyclonal proliferation to malignant lymphoma in monoclonal fashion. To date, no specific therapy has been available for latent EBV infection itself, but understanding the underlying pathogenetic mechanisms in each condition provides the possible treatment including anti-viral agents, immune modulators and chemotherapeutic drugs. Furthermore, severe combined immunodeficiency (SCID) mouse engrafted with human peripheral blood mononuclear cells is a suitable model for EBV-associated LPD which occur in human beings. Using this, several therapeutic trials have been investigated, and some are possibly beneficial. This concise review focuses on recent understanding of the pathogenetic mechanisms in various EBV-associated diseases in immunocompetent and immunocompromised individuals, and discusses potent therapeutic approaches in each condition.

Objectives. Interstitial lung disease (ILD) is a rare complication of juvenile dermatomyositis (JDM). The aim of this study was to clarify the clinical features of JDM-associated ILD and to evaluate the efficacy of cyclosporin A (CSA). Methods. We reviewed clinical records of 10 cases of JDM that were admitted to Hokkaido University Hospital between April 1990 and March 2001. Results. Five cases were complicated with ILD, three with interstitial pneumonia and two with bronchiolitis obliterans organizing pneumonia. ILD was associated with active JDM and progressed despite corticosteroid therapy. Testing for anti-Jo-1 antibody was negative in all cases. Respiratory symptoms were initially noticed in only one case. In the other cases, ILD was first detected by routine examination of chest X-ray. All the cases received CSA (3‐5 mgukguday) in combination with prednisolone. One patient died of respiratory failure, but the others responded well to treatment with CSA. Conclusion. ILD should be evaluated carefully in all cases of JDM regardless of respiratory symptoms. CSA is a choice for steroid-resistant cases of JDM-associated ILD.

A chronic undefined illness characterized by infectious mononucleosis (IM)-like symptoms and signs, possibly associated with Epstein-Barr virus (EBV) infection, designated as so-called chronic active EBV infection (CAEBV), is focused and discussed in this mini-review. Patients with CAEBV often develop T cell lymphoproliferative disorder (LPD)/lymphoma or NK cell LPD/lymphoma. Unique manifestations with generally poor prognosis of the disease prompt us to understand in particular the entity, diagnosis and treatment.

We report the epidemiology and laboratory diagnostic results of rubella cases from 2011 to 2013 in Hokkaido district, Japan. A total of 150 cases were officially reported as rubella; 102 (68%) involved males and 48 (32%) involved females. The highest proportion of cases were notified in 40-49-year-old age group among males and the 20-29-years-old age group among females. Forty-six cases (25 males and 21 females) had not been vaccinated, and 17 had been vaccinated, whereas 87 had the unknown vaccination status. Eighty-three cases (55.3%) showed the 3 typical principal rubella symptoms (fever, rash, and lymphadenopathy). Seven, 11, 92, and 40 cases were identified in the northern, eastern, central, and southern areas of Hokkaido district, respectively. In the central and southern areas of Hokkaido district, endemic rubella transmissions were indicated by both the epidemiological survey and molecular analyses. However, these outbreaks terminated spontaneously and did not expand to other areas of Hokkaido district. Fortunately, no congenital rubella syndrome (CRS) cases were reported during this observation period. However, to control virus transmission, prevent CRS, and maintain the routine vaccination program, the immediate introduction of an immunization strategy is required for susceptible individuals, particularly young adults.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication.

The Epstein-Barr virus (EBV), one of eight known human herpesviruses, causes a wide spectrum of diseases under certain conditions. In particular, in the setting of immunodeficiency, which includes primary or secondary/acquired immunodeficiencies, they have been increasingly reported. The major clinical phenotype is the EBV genome-positive lymphoproliferative disorder, which ranges from benign lymphoproliferation to malignant lymphoma with cytogenetic alterations. Severe or fatal infectious mononucleosis may develop in some patients with immunodeficiencies such as X-linked lymphoproliferative disease.

We report on an 11-year-old Japanese girl with combined immunodeficiency and chromosomal instability. She had postnatal growth deficiency and microcephaly, preaxial polydactyly of the left hand, and susceptibility to infections. Immunological studies showed marked lymphocytopenia (around 500/ll), reduced lymphocyte response to various mitogens, and reduced or absent serum IgA, IgG, and IgM. Cell biological studies of her primary skin fibroblasts demonstrated spontaneous chromosome aberrations and radiation hypersensitivity. The combination of immunodeficiency, chromosomal instability, and radiation hypersensitivity as seen in the girl is present in both ataxia–telangiectasia and Nijmegen breakage syndrome. Ataxia-telangiectasia was excluded because of differences in clinical features and laboratory data. Likewise, Nijmegen breakage syndrome is unlikely to be the case because the characteristic face, hyperpigmented spots, and mental retardation present in the syndrome were missing in the girl. Sequence analysis of a Nijmegen breakage syndrome responsible gene, NBS1, revealed no mutations. A normal NBS1 product was also demonstrated by immunoblot analysis using an anti-NBS1 antibody. We propose that the disorder in the girl represents a new combination of combined immunodeficiency and chromosomal instability. © 2001 Wiley-Liss. Inc.

Epstein-Barr virus (EBV), one of 8 known human herpesviruses, infects the vast majority of mankind and infections are generally subclinical. However, EBV infection has been associated with a spectrum of diseases, lymphoproliferative diseases (EBV-LPD) in particular, including malignant lymphoma. EBV-LPD are frequently observed in patients with primary or secondary immunodeficiencies. The incidence of EBV-LPD is on the rise, partly because of increasing numbers and success of hematopoietic stem cell and solid organ transplants and partly because many patients with immunodeficiencies, both primary and secondary, including AIDS, live longer, with improvements in supportive care. Herein, a spectrum of EBV-associated diseases in patients with immunodeficiency are summarized and discussed mainly focusing on their pathogenetic mechanism(s).

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology. It is quite difficult to diagnose CD without typical localized signs or symptoms. We present a 5-year-old boy with unicentric plasma cell CD in the mesentery, which was too small to be detected by any conventional imaging. (18)F-fluorodeoxyglucose positron emission tomography image and a serum cytokine profile prompted us to perform a curative surgical excision, confirming his diagnosis. Our case also supported an important role of interleukin-6 in the pathophysiology of plasma cell CD.

Background & Aims: We have previously reported a 75-kilodalton autoantigen specific to X-linked autoimmune enteropathy (AIE) associated with tubulonephropathy. The aim of this study was to identify the autoantigen. Methods: Complementary DNA (cDNA) clones were isolated by immunoscreening a human duodenal cDNA-expression library with serum from a patient with AIE. Results: cDNA encoding the 75-kilodalton antigen (AIE-75) was identified. The composite nucleotide sequence of the cDNA for AIE-75 was 2214 base pairs long and encoded 552 amino acids. The genomic sequence of AIE-75 was found in Sequence DataBank, which consisted of 21 exons and was located on the chromosome 11p14.3. Recombinant AIE-75 specifically reacted with sera from 3 of 4 unrelated patients with AIE but not with 58 control sera. AIE-75 was predominantly distributed in the epithelial cells of the luminal surface and the upper half of the crypts of the intestine and in the proximal renal tubulus. Similarity searches revealed that the AIE-75 cDNA sequence was an authentic form of several colon cancer–related cDNAs of unknown function. The deduced amino acid sequence contained 3 conserved PSD-95/Dlg/ZO-1 (PDZ) domains. Conclusions: AIE-75 is a PDZ domain–containing protein expressed in the differentiated epithelial cells of the intestine and kidney and may be involved in protein-protein interaction. The identification of the autoantigen may prove useful in the approach to the pathogenesis of this poorly understood disease. GASTROENTEROLOGY 1999;117:823-830

Human lymphotropic viruses interacting with human immune systems may cause a wide spectrum of human diseases. Kawasaki disease has been thought to be related to events associated with infection, although a direct causative role has not been clearly demonstrated. In this concise review, the reported relationship between human lymphotropic viruses and Kawasaki disease is briefly described.

Ten patients with adenosine deaminase deficiency (ADA−) have been enrolled in gene therapy clinical trials since the first patient was treated in September 1990. We describe a Japanese ADA− severe combined immune deficiency (SCID) patient who has received periodic infusions of genetically modified autologous T lymphocytes transduced with the human ADA cDNA containing retroviral vector LASN. The percentage of peripheral blood lymphocytes carrying the transduced ADA gene has remained stable at 10% to 20% during the 12 months since the fourth infusion. ADA enzyme activity in the patient's circulating T cells, which was only marginally detected before gene transfer, increased to levels comparable to those of a heterozygous carrier individual and was associated with increased T-lymphocyte counts and improvement of the patient's immune function. The results obtained in this trial are in agreement with previously published observations and support the usefulness of T lymphocyte-directed gene transfer in the treatment of ADA−SCID.

Sjögren syndrome (SS) is a common disorder in adults and involves both glandular and extraglandular systems. We report here four cases of childhood SS complicated by chronic thyroiditis, interstitial nephritis or sweat gland inflammation. Additionally, in one of these cases, the central nervous system was involved. All of these complications are common in adult cases.Childhood SS is a systemic "ductilitis" or "exocrinopathy" with complications which are commonly observed in adult cases.

Virus-associated hemophagocytic syndrome (VAHS) has been thought to be a distinct clinical entity, characterized by intermittent fever, enlarged liver and spleen, and the appearance of hemophagocytosis. Hemopoietic cells are actively ingested by monocytes/macrophages in various organs, including lymph nodes, bone marrow, liver, and spleen. Epstein-Barr virus (EBV) is now thought to be one of the major causes for the development of this unique syndrome. Additionally, VAHS is often associated with fatal infectious mononucleosis (IM). The relationship between EBV-associated VAHS and fatal IM is discussed in this concise review.

The X-linked lymphoproliferative disease (XLP), one of six described X-linked immunodeficiencies, stems from a mutation at Xq25 which renders males impotent to mount an effective immune response to the ubiquitous EBV. Purtilo, who first observed this disease in 1969, established a Registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. Since Purtilo's death in late 1992, the Registry and research unit have not only continued to function as a worldwide consultative service, but have contributed the following. First, the number of affected boys has continued to grow; some 272 among 80 kindreds have been identified. Second, some boys (10%) who inherit the mutated XLP gene are immunologically abnormal even before evidence of EBV exposure. Third, the search for the XLP gene has been narrowed to a small region on Xq25. Its identification is near at hand; once cloned, this gene may well illustrate how the body orchestrates the complex immune response to EBV. Therein lies the justification for the quest for this gene, not only for the benefit of the few surviving boys and those to be born to female carriers, but also for defining its role in defending the body against a ubiquitous DNA virus.

Peripheral blood mononuclear cells (PBMC) from four Japanese patients with Epstein-Barr virus (EBV) genome-positive Burkitt's lymphoma (BL) during remission were exposed to the B95-8 strain of EBV. Maximum concentrations of the EBV-determined nuclear antigen (EBNA) before cellular DNA synthesis were similar to those of healthy counterparts. Subsequently, EBV-immortalised cell lines were established. These immortalised lymphoblastoid cells were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and superinfected with the P3HR-1 strain of EBV. EBV early antigens (EA) and viral capsid antigen (VCA) were expressed in approximately 3-10 fold higher concentrations by these lymphoblastoid cells than by those from patients with other types of malignant neoplasia including EBV genome-negative BL and from healthy counterparts. Moderate to extremely high IgG antibody titres to EBV VCA as well as IgG antibodies to EA were demonstrated in these patients during the study. These results suggest that defective underlying cellular mechanisms for regulating the replication of EBV may be present in patients with EBV genome-positive BL.

We determined four complete nucleotide sequences of echovirus 6 (E6) isolated from an epidemic of aseptic meningitis (AM) in Hokkaido, Japan, in 2011. Phylogenetic analysis of the genes encoding viral capsid protein 1 revealed that the strains were closely related to E6 strains isolated in China in recent years, but they were distantly related to E6 strains isolated from patients with AM in Osaka Prefecture, Japan, in 2011. The genes encoding the viral protease and RNA-dependent RNA polymerase (3CD) were closely related to those of several non-E6 strains of the species Human enterovirus B isolated in China, South Korea, and Australia from 1999 to 2010, resulting in a novel cluster in the phylogenetic tree. These results suggest that the incidence of AM in Japan in 2011 was caused by at least two lineages of E6 strains, and a lineage of the 3CD gene was interspersed among different serotypic strains isolated in Western Pacific countries.

The rapid determination system of viral genome sequences (the RDV method) consists of detecting and determining the nucleotide sequences of viral genomes without using specific primers. To evaluate the usefulness of the RDV method, the detection of human norovirus (NV) genomes in stool specimens was investigated. In addition, the effect of nuclease treatment of the process was examined. A total of 23 human stool specimens were used, all of which were collected from patients with acute viral gastroenteritis, and were shown to contain NV genomes and also determined the cDNA copy numbers by the real-time reverse transcriptase-polymerase chain reaction. NV genomes were detected by the RDV method with nuclease treatment in nine specimens containing cDNA copies ranging between 6.2×10(9) and 9.8×10(11)/g stool. In contrast, NV genome was found by the method in 15 specimens without nuclease treatment and the number of NV cDNA copies ranged between 1.2×10(6) and 9.8×10(11)/g stool. These results suggest that the RDV method has potential for detecting viral genomes in stool specimens. The procedure without a step of nuclease treatment appears to be sensitive.