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// Yong Du 1, 2, # , Lili Liu 3, # , Chenliang Wang 1, 4, 5, # , Bohua Kuang 2, 6 , Shumei Yan 3 , Aijun Zhou 2 , Chuangyu Wen 1, 4, 5 , Junxiong Chen 1 , Yue Wu 1, 4, 5 , Xiangling Yang 1 , Guokai Feng 2 , Bin Liu 7 , Aikichi Iwamoto 8, 9 , Musheng Zeng 2 , Jianping Wang 1 , Xing Zhang 6 , Huanliang Liu 1, 4, 5 1 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Departments of Pathology and Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China 4 Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China 5 Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China 7 Department of Emergency, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China 8 Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 9 Current affiliation: Japan Agency for Medical Research and Development (AMED), Tokyo, Japan # These authors have contributed equally to this work Correspondence to: Huanliang Liu, email: liuhuanl@mail.sysu.edu.cn Xing Zhang, email: zhangxing@sysucc.org.cn Keywords: colorectal cancer, TACC3, proliferation, migration, invasion Received: November 10, 2015 Accepted: May 04, 2016 Published: May 26, 2016 ABSTRACT Colorectal carcinoma (CRC) is a malignant epithelial tumour with tremendous invasion and metastatic capacity. Transforming acidic coiled-coil protein-3 (TACC3), a frequently aberrantly expressed oncogene, is an important biomarker in various human cancers. Our study aimed to investigate the expression and function of TACC3 in human CRC. We found that TACC3 was over-expressed at both the mRNA and protein levels in CRC cells and in biopsies of CRC tissues compared with normal controls as determined by qRT-PCR, western blot and immunohistochemical (IHC) staining assays. IHC staining of samples from 161 patients with CRC also revealed that TACC3 expression was significantly correlated with clinical stage ( P = 0.045), T classification ( P = 0.029) and M classification ( P = 0.020). Multivariate analysis indicated that high TACC3 expression was an independent prognostic marker for CRC. Patients who had high TACC3 expression had significantly poorer overall survival (OS, P = 0.023) and disease-free survival (DFS, P = 0.019) compared to patients who had low TACC3 expression. Furthermore, TACC3 knockdown attenuated CRC cell proliferation, colony formation capability, migration and invasion capability, and tumourigenesis in nude mice; these properties were measured using a real-time cell analyser (RTCA), clonogenicity analysis, and transwell and xenograft assays, respectively. These data indicate that TACC3 promotes CRC progression and could be an independent prognostic factor and a potential therapeutic target for CRC.

Background Chronic kidney disease (CKD) has become one of the common comorbid conditions affecting the human immunodeficiency virus (HIV) population. Human immunodeficiency virus-infected individuals are at increased risk of developing CKD, and they are likely to experience faster progression of renal dysfunction compared with HIV-uninfected individuals. Albuminuria represents not only kidney damage but also manifests metabolic syndrome and vascular dysfunction. Methods We conducted a multicenter, cross-sectional study involving 2135 HIV-infected individuals in Japan to test the prevalence of CKD and proteinuria/albuminuria. Urine sample was analyzed by both dipstick test and albumin-to-creatinine ratio (ACR) assay. Chronic kidney disease was classified according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The diagnostic performance of dipstick test to detect albuminuria (ACR ≥30 mg/g) was evaluated. Results The prevalence of CKD, evaluated by K/DOQI and KDIGO guidelines, was 15.8% and 20.4%, respectively. Age, total cholesterol level, prevalence of hypertension, diabetes mellitus, and hepatitis C infection tended to increase, whereas levels of hemoglobin, serum albumin, and CD4 cell count tended to decrease as CKD risk grades progressed. Proteinuria and albuminuria were present in 8.9% and 14.5% of individuals, respectively. Dipstick test ≥1+ to detect albuminuria had an overall sensitivity of 44.9% and specificity of 97.2%. Conclusions The KDIGO guideline may enable physicians to capture HIV-infected patients at increased risk more effectively. The sensitivity of dipstick proteinuria to detect albuminuria is so poor that it may not serve as an alternative in HIV-infected individuals., This multicenter study demonstrated that the new CKD guideline that used albuminuria targeted more patients at high risk than the previous guideline that used dipstick proteinuria, and the sensitivity of dipstick proteinuria to detect albuminuria is poor among HIV-infected individuals.

GB virus type C (GBV-C) glycoprotein E2 protein disrupts HIV-1 assembly and release by inhibiting Gag plasma membrane targeting, however the mechanism by which the GBV-C E2 inhibits Gag trafficking remains unclear. In the present study, we identified ADP-ribosylation factor 1 (ARF1) contributed to the inhibitory effect of GBV-C E2 on HIV-1 Gag membrane targeting. Expression of GBV-C E2 decreased ARF1 expression in a proteasomal degradation-dependent manner. The restoration of ARF1 expression rescued the HIV-1 Gag processing and membrane targeting defect imposed by GBV-C E2. In addition, GBV-C E2 expression also altered Golgi morphology and suppressed protein traffic through the secretory pathway, which are all consistent with a phenotype of disrupting the function of ARF1 protein. Thus, our results indicate that GBV-C E2 inhibits HIV-1 assembly and release by decreasing ARF1, and may provide insights regarding GBV-C E2's potential for a new therapeutic approach for treating HIV-1.

Background Distribution of HIV-1 subtypes, transmitted drug resistance (TDR)/drug resistance mutation (DRM), and their impact on response to combination antiretroviral therapy remain poorly understood in China. Methods We analyzed data from our multicenter cohort study with 444 antiretroviral-naive participants recruited between 2008 and 2010. HIV-1 subtype and tropism were determined by V3 sequencing, and TDR/DRM was determined by Pol sequencing. Virologic and immunologic responses were monitored over 96 weeks of follow-up. The initial combination antiretroviral therapy regimen for all patients was nevirapine + lamivudine + zidovudine or stavudine. Analysis 1 included patients who finished 96 weeks of follow-up (n = 379), and analysis 2 included all 444 patients. Results Subtype B/B' was associated with higher prevalence of TDR/DRM to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. Median time to HIV-1 suppression was 18 weeks in all 3 subtype groups. In Cox proportional models for viral suppression, neither viral tropism nor HIV-1 subtypes had any impact on viral suppression; however, subtypes CRF01_AE and C/CRF07_BC/CRF08_BC were associated with lower risk of virologic failure compared with subtype B/B', with adjusted hazard ratio of 0.11 (P = 0.032) and 0.06 (P = 0.036), respectively in analysis 1, 0.42 (P = 0.047) and 0.22 (P = 0.008), respectively in analysis 2. This association was attenuated by adding DRM profiles to multivariate regression models. Neither subtype nor HIV-1 tropism affected immunologic response. Conclusions HIV-1 subtype tended to be associated with virologic but not immunologic response; this effect could be ascribed to baseline DRM.

Akira Watanabe , Katsunori Yanagihara a, b, , Tetsuya Matsumoto , Shigeru Kohno a, , Nobuki Aoki a, , Toyoko Oguri , Junko Sato , Tetsuro Muratani , Morimasa Yagisawa , Kazuhiko Ogasawara , Naoto Koashi , Tsuneo Kozuki , Akira Komoto , Yoshisaburo Takahashi , Toshikatsu Tsuji , Michinori Terada , Kunio Nakanishi , Rikizo Hattori , Yukio Hirako , Akinori Maruo , Shinichi Minamitani , Kohei Morita , Tomotaro Wakamura , Keisuke Sunakawa , Hideaki Hanaki , Yoshinobu Ohsaki , Yasuhito Honda , Shoichi Sasaoka , Hiroaki Takeda , Hideki Ikeda , Atsuko Sugai , Makoto Miki , Susumu Nakanowatari , Hiroshi Takahashi , Mutsuko Utagawa , Nobuyuki Kobayashi , Jin Takasaki , Hisami Konosaki , Yasuko Aoki , Michi Shoji , Hajime Goto , Takeshi Saraya , Daisuke Kurai , Mitsuhiro Okazaki , Yoshio Kobayashi , Yasuhiro Katono , Akihiko Kawana , Katsu Saionji , Naoki Miyazawa , Yoshimi Sato , Yuji Watanuki , Makoto Kudo , Shigeru Ehara , Hiroki Tsukada , Yumiko Imai , Nobuei Watabe , Sakura Aso , Yasuo Honma , Hiroshige Mikamo , Yuka Yamagishi , Yoshio Takesue , Yasunao Wada , Tadahiro Nakamura , Noriko Mitsuno , Keiichi Mikasa , Kei Kasahara , Kenji Uno , Reiko Sano , Naoyuki Miyashita , Yukinori Kurokawa , Mariko Takaya , Masao Kuwabara , Yaeko Watanabe , Masao Doi , Satomi Shimizu , Kiyoshi Negayama , Junichi Kadota a, , Kazufumi Hiramatsu , Yoshitomo Morinaga , Junichi Honda , Masaki Fujita , Satoshi Iwata , Aikichi Iwamoto , Takayuki Ezaki , Shoichi Onodera , Shinya Kusachi , Kazuhiro Tateda , Michio Tanaka , Kyoichi Totsuka , Yoshihito Niki , Tetsuro Matsumoto a

Neisseria gonorrhoeae is one of the most important pathogens causing sexually transmitted infection, and strains that are resistant to several antimicrobials are increasing. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the first nationwide surveillance. The urethral discharge was collected from male patients with urethritis at 51 medical facilities from April 2009 to October 2010. Of the 156 specimens, 83 N. gonorrhoeae strains were tested for susceptibility to 18 antimicrobial agents. The prevalence of β-lactamase-producing strains and chromosomally mediated resistant strains were 7.2 % and 16.5 %, respectively. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) of ceftriaxone for 7 strains (8.4 %) was 0.125 μg/ml. One strain was resistant to cefixime (MIC 0.5 μg/ml). The MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin, and tosufloxacin, showed a bimodal distribution. The MIC of sitafloxacin was lower than those of the three fluoroquinolones listed here, and it was found that the antimicrobial activity of sitafloxacin was stronger than that of the fluoroquinolones. The MIC of azithromycin in 2 strains was 2 μg/ml, but no high-level resistance to macrolides was detected.

We evaluated the correlation between the conventional manual serological testing method for syphilis and a novel automated serological testing method and between six different reagents used in the automated method. Twenty-six serum samples, which were positive on non-treponemal manual serological testing, were obtained from 19 patients with early syphilis. The samples were manually analyzed using the non-treponemal serological test for syphilis kit and automatically analyzed using six different reagents approved by the Ministry of Health, Labor and Welfare in Japan. Statistically significant correlations were observed between most of the reagents used in the automated testing (r = 0.652-0.996, P < 0.001), except for one combination of the reagents. In the simple regression analysis, the slope of the simple regression line (range, 0.014-3.040) and some of the regression coefficients were not equal to 1.0. Therefore, it is recommended that when the automated serological testing method is used to test for syphilis, the same reagent should be consistently selected to evaluate the changes in antibody titers. Statistically significant correlations were also observed between the manual method and all the reagents used in the automated method (r = 0.682-0.811, P < 0.001). In this case, the regression coefficients ranged 0.375-6.270, and the simple regression line intercept ranged -71.926 to 4.184. The regression coefficient and the intercept between the manual method and some of the reagents used in the automated method were not similar to the values described in the documentation attached to the reagents used in this study.

A 47-year-old man with optimally controlled type-2 diabetes mellitus and chronic hepatitis B was admitted to a local hospital because of a 1-week history of cough and high-grade fever. He was diagnosed with Pneumocystis pneumonia (PCP) and Klebsiella pneumonia from a chest radiograph and sputum. Simultaneously, he was found to have HIV infection with a CD4 count of 76/μl. Despite alteration of treatment secondary to the development of allergic reaction to trimethoprim-sulfamethoxazole (TMP-SMX), the patient was able to complete a 3-week therapy for PCP after being switched to pentamidine isetionate. After the treatment of PCP, he was referred to our hospital for the initiation of anti-HIV therapy. He presented with recurrent high-grade fever of a few days' duration prior to his initial visit, which subsequently led to his admission. Chest computed tomography (CT) showed the enlargement of a previously identified infiltrate in the left upper lung field, and the sputum culture upon admission was positive for Gram-positive branching rods; the organism was later identified as Nocardia exalbida. Due to his allergy to sulfonamide, the patient was treated with imipenem (IMP) and amikacin (AMK) given intravenously for 17 days, followed by garenoxacin (GRNX) taken orally for 6 months, without any adverse effects. The chest infiltrate resolved completely, and he remains stable without relapse 8 months after the completion of the therapy. Pulmonary nocardiosis should be considered as a differential diagnosis of recurring pneumonia in immunocompromised patients, especially in HIV-infected individuals. Oral administration of GRNX following IMP and AMK can be used as an alternative to TMP-SMX therapy in cases of pulmonary nocardiosis caused by N. exalbida.

Objective Serum β-D-glucan has been demonstrated as a reliable, adjunct diagnostic marker for PCP, but its kinetics after PCP treatment are poorly understood. To evaluate the correlation between the levels of β-D-glucan and the clinical response, we investigated the individual transition of serum β-D-glucan levels after the initiation of PCP treatment. Methods Retrospective study Patients Seventeen PCP patients with AIDS who were admitted to our hospital were analyzed. Results All subjects showed the serum β-D-glucan levels above the cut-off value, and the median level was 224 pg/mL [IQR: 78-597] at the time of PCP diagnosis. There were no correlations between serum β-D-glucan levels and CRP, LDH, or AaDO2 at room air. Although there was a downward trend in serum β-D-glucan level as PCP treatment was initiated, a significant number of subjects showed a marked increase in the serum β-D-glucan levels despite their evident clinical improvement. Conclusion The serum β-D-glucan level does not reflect the severity and prognosis of PCP infection, and thus it may not be suitable for monitoring the response to treatment.

Drug-resistant virus infection has been a major hurdle in the management of human immunodeficiency virus type 1 (HIV-1) infection. Recently, three novel antiretrovirals [raltegravir (RAL), etravirine (ETR), and darunavir (DRV)] were introduced into the market almost simultaneously, and salvage regimens containing these three antiretrovirals have been reported to exhibit strong potency against drug-resistant HIV-1 infection. However, the sustainability of such regimens remains unclear, particularly for patients infected with multidrug-resistant viruses. Here we report a case of super-multidrug-resistant HIV-1 infection which has been successfully controlled by novel combination therapy including RAL, ETR, and DRV for over 2 years, indicating that the novel combination could become an ultimate weapon against drug-resistant HIV infection and could alter the landscape of HIV salvage therapy.

Three Japanese patients with lecithin: cholesterol acyltransferase (LCAT) deficiency, the offspring of a consanguineous marriage, are described. In addition to the Characteristic clinical and laboratory findings of the disease, our patients had hitherto unreported manifestations, namely unconjugated hyperbilirubinemia, peripheral neuropathy and marked hypocholesterolemia. Although the mechanism of the unconjugated hyperbilirubinemia is not clear, the rde of impaired hepatic bilirubin uridine-diphosphate-glucuronyl transferase activity combined with another unknown factor(s) was postulated. Non-random assortment was observed between LCAT deficiency and haptoglobin types, as previously reported. The discovery of Japanese patients with LCAT deficiency indicates that the distribution of this hereditary metabolic disorder is not confined to the Western hemisphere.

Post-malaria neurological syndrome (PMNS) is a rare complication after the treatment of falciparum malaria. We describe a case of a 56-year-old man who developed ataxia, tremor, and confusion 16 days after a successful treatment of falciparum malaria with artesunate followed by mefloquine. Magnetic resonance imaging of the brain revealed no abnormality, and he recovered spontaneously without any specific treatment including corticosteroids. Inflammatory changes were found in the cerebrospinal fluid, suggesting a localized inflammatory reaction as the cause of the syndrome.

This report describes a case of hepatic phase Fasciola hepatica infection presenting huge and multilocular lesions. The unique radiological findings mimicked hydatid diseases and also cystic liver neoplasm. Fascioliasis should be included in the differential diagnosis for cystic liver diseases.

We report here a case of Pneumocystis jiroveci pneumonia (PCP) in an acquired immune deficiency syndrome (AIDS) patient with multiloculated cavitary lesions. Time-course analysis of chest computed tomography (CT) showed spontaneous ballooning of cavities and their disappearance after completion of PCP treatment. The characteristic radiological findings as well as histological features of a cavitary lesion suggested that check-valve phenomenon in small airways might explain the pathogenesis of cavities in this case.

Piperlongumine (PPLGM), an alkaloid isolated from the long pepper (Piper longum L.), can selectively trigger cancer cell death in colorectal cancer cells. The present study investigated whether the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in PPLGM-induced apoptosis in the human colorectal cancer HCT116 cell line. The results demonstrated that PPLGM reduced the cell viability and induced cell apoptosis in a time- and concentration-dependent manner, without a significant effect on cell cycle distribution. Meanwhile, treatment with 10 µM PPLGM resulted in JNK activation within 1 h, and a marked and sustained increase in c-Jun phosphorylation in the HCT116 cells. In addition, SP600125, a general inhibitor of JNK, inhibited PPLGM-induced apoptosis in the HCT116 cells by inhibiting PPLGM-induced c-Jun phosphorylation. Altogether, it can be concluded that the JNK signaling pathway, at least in part, is involved in PPLGM-mediated apoptosis in HCT116 cells.

In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15–20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.

Contains fulltext : 153627.pdf (Publisher’s version ) (Open Access) Perivascular epithelioid cell tumors of gastrointestinal tract (GI PEComas) are exceedingly rare, with only a limited number of published reports worldwide. Given the scarcity of GI PEComas and their relatively short follow-up periods, our current knowledge of their biologic behavior, molecular genetic alterations, diagnostic criteria, and prognostic factors continues to be very limited.We present 2 cases of GI PEComas, one of which showed an aggressive histologic behavior that underwent multiple combined chemotherapies. We also review the available English-language medical literature on GI PEComas-not otherwise specified (PEComas-NOS) and discuss their clinicopathological and molecular genetic features.Pathologic analyses including histomorphologic, immunohistochemical, and ultrastructural studies were performed to evaluate the clinicopathological features of GI PEComas, their diagnosis, and differential diagnosis. Immunohistochemistry, semiquantitative reverse transcriptase polymerase chain reaction, and DNA sequencing assays were carried out to detect the potential molecular genetic alterations in our cases. Microscopically, the tumors showed distinctive histologic features of PEComas-NOS, including fascicular or nested architecture, epithelioid or spindled cell type, and clear to eosinophilic cytoplasm. The tumor cells were immunohistochemically positive for melanocytic markers. Molecular pathological assays confirmed a PSF-TFE3 gene fusion in one of our cases. Furthermore, in this case microphthalmia-associated transcription factor and its downstream genes were found to exhibit elevated transcript levels.Knowledge about the molecular genetic alterations in GI PEComas is still limited and warrants further study.

Immune response enhanced by therapeutic HIV-1 vaccine may control viral proliferation after discontinuation of highly active antiretroviral therapy (HAART). Although which strategies for therapeutic vaccination are feasible remains controversial, application of dendritic cells (DCs) as a vaccine adjuvant represents a promising approach to improving deteriorated immune function in HIV-1-infected individuals. The safety and efficacy of DC-based vaccine loaded with HIV-1-derived cytotoxic T lymphocytes (CTL) peptides were thus investigated in this study. Autologous DCs loaded with seven CTL peptides with HLA-A*2402 restriction were immunized to four HIV-1-infected individuals under HAART. In terms of safety, peptide-loaded DCs were well tolerated, and only mild local and general symptoms were observed during vaccine administration. ELISPOT assays to detect IFN-gamma production in CD8(+) lymphocytes revealed a limited breadth of responses to immunized peptides in two of four participants, but no response in the remaining two participants. Differences in immunological response might be attributable to the fact that responders displayed higher nadir CD4 counts before starting HAART and were immunized with a larger number of DCs per reactive peptide than non-responders. Discontinuation of HAART after vaccination failed to lower viral set points compared to those before starting HAART. This early outcome warrants further exploration to elucidate the therapeutic value of vaccination with DCs in HIV-1 infection.

The outbreak of severe acute respiratory syndrome (SARS) has drawn enormous attention and caused fear worldwide since early 2003. The disease appears to be under control now; however, the possible return of SARS must be emphasized. Although many clinical experiments have been reported, the treatment of SARS is largely anecdotal, and so far no treatment consensus has been reached. We summarize 14 clinical reports and attempt to assess the effectiveness of various treatment regimens. A combination treatment of steroids and ribavirin was widely used empirically from the outset of the epidemic. In general, the use of steroids for SARS seemed beneficial, but the optimal timing, dosage, and duration of treatment have not yet been determined. On the other hand, ribavirin administration apparently reduced neither the rate of intratracheal intubation nor that of mortality. Moreover, significant toxicity, such as hemolytic anemia, has been attributed to ribavirin. A few preliminary trials and in vitro data suggest the possibility of treating SARS with interferon. Other agents, including the HIV protease inhibitor glycyrrhizin and convalescent plasma, remain to be evaluated.

Japan has been known as a low HIV-prevalence country with a concentrated epidemic among high-risk groups. However, it has not been determined whether Japan meets the 90-90-90 goals set by the Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO). Moreover, to date, the HIV care cascade has not been examined. We estimated the total number of diagnosed people living with HIV/AIDS (PLWHA) (n = 22,840) based on legal reports to the Ministry of Health, Labour and Welfare by subtracting the number of foreigners who left Japan (n = 2,273) and deaths (n = 2,321) from the cumulative diagnosis report (n = 27,434). The number of total undiagnosed PLWHA was estimated by age and sex specific HIV-positive rates observed among first-time blood donors between 2011–2015 in Japan. Our estimates show that 14.4% (n = 3,830) of all PLWHA (n = 26,670) were undiagnosed in Japan at the end of 2015. The number of patients retained in care (n = 20,615: 77.3% of PLWHA), the percentage of those on antiretroviral therapy (n = 18,921: 70.9% of PLWHA) and those with suppressed viral loads (

The Japanese Three Academic Societies Joint Antimicrobial Susceptibility Surveillance Committee has conducted a nationwide surveillance on antimicrobial susceptibility patterns and rates of isolation in 6 otolaryngological diseases. The surveillance program was conducted in the otorhinolaryngological departments of 29 universities, and their 26 affiliated hospitals. Patients suffering from acute otitis media, chronic otitis media, acute nasal sinusitis, chronic nasal sinusitis, acute tonsillitis, and peritonsillar abscess between January 2011 and June 2012 were investigated. The collected swab or incision samples were cultivated for microbial identification, and the drug susceptibility of detected bacteria was measured at the Kitasato University Research Center for Infections and Antimicrobials. The surveillance focused on three gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus), three gram-negative bacteria (Haemophilus influenzae, Moraxella Catarrhalis, and Pseudomonas aeruginosa), and three anaerobic bacteria (Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp.). Bacterial susceptibility to 39 antimicrobial drugs was investigated. We compared bacterial isolation ratio of each disease in this surveillance from those of past 4 times surveillance which we performed formerly, and we also compared percentage of main drug resistant strains from those of past 4 times surveillance. The age composition between this time and former surveillances was not statistically significant by student-t test. We were unable to completely resolve the rise in resistant bacteria, such as methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, penicillin-intermediate resistant S. pneumoniae, beta-lactamase non-producing ampicillin-resistant H. influenzae, beta-lactamase producing ampicillin-resistant H. influenzae, and beta-lactamase producing amoxicillin clavulanic acid-resistant H. influenzae. We suggest promoting the proper usage of antimicrobial drugs in order to avoid the spread of these bacteria.

With an ever increasing number of international travelers, physicians should be aware of the diseases that have rarely been encountered in their home countries. Cystic echinococcosis (CE) caused by Echinococcus granulosus is seldom seen in Japan despite frequent occurrence of the other type of echinococcosis, alveolar echinococcosis (AE) caused by E. multilocularis, in its northern parts. However, CE is prevalent in many parts of the world including the United Kingdom, Mediterranean basin, Middle East, South America, and Australia, and is supposed to be resurgent in several parts of the world. The disease is acquired by the oral ingestion of the eggs of E. granulosus passed into the feces of several definitive host animals carrying tapeworms, mostly dogs. These definitive hosts are infected by cannibalizing intermediate host animals including sheep and cattle whose livers and/or lungs are affected by cystic lesions that contain protoscoleces. In endemic areas the diagnosis of CE is not considered to be complicated; typical morphological features composed of cysts as revealed by ultrasonography and/or computerized tomography (CT) scan. The diagnosis is also aided by serological methods detecting serum antibodies. However, imaging procedures show a variety of features that could often lead to misdiagnosis as other diseases. Moreover, serological assays are sometimes difficult to interpret because of their incomplete sensitivities and specificities. Hence, a comprehensive understanding of a spectrum of imaging features and the application of serological methods with better sensitivities and specificities are indispensable. The mainstay of treatment of the disease is still surgical removal of cysts that has the potential to lead to a complete cure. Recently, the less invasive method PAIR (Puncture of cysts percutaneously, Aspiration of fluid, Introduction of protoscolicidal agent, and Reaspiration) was introduced with considerable success, and could be a promising alternative to surgery. Lastly, medical treatment with oral mebendazole or albendazole, especially the latter, can be beneficial not only as a adjunctive to surgery or PAIR, but as a sole treatment in cases in which invasive methods are not indicated. Here we report a Jordanian patient with CE whose diagnosis was substantiated by a novel immunoblot assay and who showed a rapid improvement during albendazole therapy.

To determine the seroprevalence of human herpesvirus 8 (HHV8) among human immunodeficiency virus 1 (HIV-1)-positive (HIV-1+) and HIV-1-negative (HIV-1-) populations in Japan, 276 HIV-1+ patients and 1,000 HIV-1- blood donors were enrolled in this study. Antibodies against HHV8 latency-associated nuclear antigen (LANA) were examined through indirect immunofluorescent assay by using a B-cell line that was infected latently with HHV8 (body cavity-based lymphoma 1). An HHV8- and Epstein-Barr virus-negative B-cell line (Ramos) was used as a control. Thirty-two seropositive cases against LANA (anti-LANA+) were identified among the 276 HIV-1+ patients who were studied. Five cases were foreigners living in Japan. The risk factor of all 27 Japanese cases was unprotected sexual intercourse, and the great majority of these cases (23 in 27; 85%) reported homosexual/bisexual behavior. Anti-LANA+ status correlated with the presence of sexually transmitted diseases, such as amoeba and HBV infection, further suggesting male homosexual behavior as the main route of HHV8 transmission in Japan. Only two LANA+ cases were identified among 1,000 HIV- blood donors in Japan; thus, seroprevalence of HHV8 identified by LANA was estimated to be 0.2% among HIV-1- populations in this country.

A 40-year-old Japanese male stayed in Zimbabwe and developed a fever above 38 degrees C during which he noted a typical eschar in the lumbar region and also regional inguinal lymphadenopathy. Although not conspicuous, erythematous eruptions accompanied by itching were observed on the face, trunk and lower extremities. After returning to Japan and visiting our hospital, he was suspected of rickettsiosis and put on minocycline which gradually led to the improvement of the symptoms. Immunofluorescence antibody determinations disclosed rising titers against Rickettsia conorii (R. conorii) for both IgM and IgG classes. The second patient, a 34-year-old Japanese male, developed fever, generalized erythema and a typical eschar while staying in South Africa. The first blood sample showed positive IgM and IgG antibodies against R. conorii, and the second sample a decline in IgM but not in IgG class antibodies. Both cases were diagnosed as spotted fever group rickettsiosis based on their clinical manifestations including typical eschar and also the results of antibody determinations. Most of the previous cases of spotted fever group rickettsiosis in Africa have been regarded as Mediterranean spotted fever which is caused by R. conorii and transmitted by Rhipicephalus sanguineus. However, recently, the presence of another type of spotted fever group rickettsiosis, African tick-bite fever, caused by Rickettsia africae and transmitted by Amblyomma hebraeum has been proposed. Although clinical features of the two rickettsiosis are reported to be separable, apparent cross reaction between the two organisms hampers the use of conventional antibody determinations for their differentiation. For the two cases presented here identification of the causative rickettsia species was impossible, because they were not isolated. With ever increasing numbers of international travel, physicians should be alert to the possibility of spotted fever group rickettsiosis when encountering febrile patients returning from endemic countries. This is particularly important considering that beta-lactam antibiotics commonly used as an empiric therapy are not effective, and the disease has a potential to develop into severe forms.

ハンタウイルスとは,ブニヤウイルス科ハンタウイルス属に含まれる一群のウイルスを指す総称である.その名は1973年李たちによって分離されたハンターンウイルスに由来する.ヒトに腎症候性出血熱(HFRS)やハンタウイルス肺症候群(HPS)など劇症の感染症をおこすウイルスが含まれる.ハンタウイルスの自然宿主は齧歯類であり,感染個体由来の乾燥した排泄物のエアゾールを介してヒトにも感染する.

Background Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. Methods A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985–2012 were retrospectively reviewed. Clinical data were collected from patient medical records. Results Mean CD4 counts of patients were 77.0 cells/μL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/μL in naïve patients (ART (−) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (−) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (−) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (−) patients (1.5%; P = 0.026). Conclusions The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (−) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (−) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.

The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naive patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein–Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.

Hemophagocytic syndrome (HPS) is an unrecognized complication occurring in the acute stage of human immunodeficiency virus (HIV) infection that is seldom reported in the literature. We herein present a case of HPS that occurred during the seroconversion stage of HIV infection. In this case, pancytopenia and liver dysfunction related to HPS recovered after the initiation of antiretroviral therapy (ART). This report indicates the importance of early recognition of HPS and suggests that prompt initiation of ART has the potential to control HPS in the acute stage of HIV infection.

Despite the fact that approximately ten types of human papillomavirus (HPV) are associated with cervical carcinoma, the question of whether the HPV type present in cervical carcinoma is related to clinical behavior had yet to be answered when this study was conducted.The presence and type of HPV were determined by polymerase chain reaction (PCR)-based assay (LI-PCR) in 146 cervical carcinomas. Clinical features were compared among the following 4 groups: Group 18 (27 patients positive for HPV 18), Group 16 (55 patients positive for HPV 16), Group O (47 patients positive for the other HPV types), and Group N (17 HPV negative patients). Special focus was given to histologic type, patient's age at onset, and patient survival as indicators of the biologic properties of the carcinomas.Occurrence of adenocarcinoma or adenosquamous carcinoma was higher in Group 18 (48%) than in Group 16 (13%) or Group O (9%) (P0.0005). The mean age of the patients at onset was different among the 4 groups (Group 18, 46 years; Group 16, 55 years; Group O, 63 years; Group N, 58 years) (P0.005). The prevalence of HPV 18, HPV 16, and other forms of the virus was most frequent in ages40, 50-79, and60, respectively. Group 18 had a poorer prognosis than Group 16, O, or N. A statistical difference in the 5-year survival rate was found between Groups 18 and 16 (52% vs. 74%, P0.05).These data suggest that the HPV type present in cervical carcinoma is related to clinical behavior.

Objective: The purpose of this study was to clarify the association of multiple genital human papillomavirus (HPV) types with vulvar neoplasias. Methods: We examined vulvar neoplasias by the polymerase chain reaction (PCR) method, which can detect almost all genital HPV types sensitively (L1-PCR). Results: Eight HPV types (types 6, 11, 16, 18, 52, 53, 56, and 68) were detected in 52 of 53 (98.1%) vulvar condylomas; 2 HPV types (types 16 and 18) were detected in all 6 Grade-3 vulvar intraepithelial neoplasias; and 5 HPV types (types 6, 16, 18, 51, and 56) were detected in 8 of 11 (72.7%) invasive vulvar carcinomas. Detection of HPV types 52, 53, 56, and 68 in vulvar condylomas and detection of HPV types 51 and 56 in vulvar carcinomas are the first examples ever reported. Conclusion: This study suggests that more HPV types are associated with the generation of vulvar neoplasias than was thought to be the case up to now.

Accuracy amplified Mycobacterium Tuberculosis Direct Test (MTD), Amplicor Mycobacteria kit (Amplicor) and PCR method routinely used in the University of Tokyo Hospital (J. Clin. Microbiol. 31: 446-450 1991) were evaluated and compared with the same samples. The detection limits of MTD, Amplicor and PCR method (University of Tokyo) were 0.01-0.1 CFU/tube, 0.625 CFU/tube and 0.2 CFU/tube respectively, which were almost the same. These were shown to be at least as sensitive as the conventional culture techniques. The Tokyo Univ. method using radioisotope, takes up to 3 days, on the other hand 2 kits take 4-5 hours. These kits become useful tools for the early and rapid detection of M. tuberculosis in uncultured clinical specimens. But the risk of laboratory contamination and false-positive results remain. These must be further improved.

Syphilis is one of the unrecognized etiologies of liver dysfunction. The incidence of syphilitic hepatitis is currently unknown. We conducted a retrospective study of causative agents of liver dysfunction at the time of diagnosis of early syphilis. Our study shows that 39 % (44/112) of early syphilis patients have liver enzyme abnormalities at the time of diagnosis and that 2.7 % (3/112) of patients are diagnosed with syphilitic hepatitis. Clinicians should include syphilitic hepatitis in the differential diagnosis for those patients with sexually transmitted diseases presenting with liver enzyme abnormalities.

Neutralizing antibody titers were determined before and after a single dose of pandemic (H1N1) 2009 influenza vaccine in HIV-1-positive Japanese adults in the first season of the pandemic and in those in the second season who had already received the vaccine in the first season. The antibody response rate at 2-month post-vaccination increased significantly from 49.0% (50/102, 95%CI: 39.0–59.1%) in the 2009/2010 season to 66.7% (42/63, 95%CI: 53.7–78.1%) in the 2010/2011 season. Geometric mean antibody titers (fold dilution) at baseline, at 2 months, and at 4 months also increased significantly from 4.4 (95%CI: 3.3–5.7), 19.0 (95%CI: 13.4–26.8) and 13.7 (95%CI: 9.3–20.2), respectively, in the 2009/2010 season to 8.3 (95%CI: 5.8–11.7), 47.0 (95%CI: 32.2–68.6) and 38.2 (95%CI: 23.8–61.4), respectively, in the 2010/2011 season. Although the vaccine response was low in the first season, it was improved in the second season.

We report the first known case of syphilis with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti- Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy.

An Indian woman with multiple and nodular cerebral lesions presenting epithelioid granulomas was diagnosed as suspected malignant tumours and the biopsy was carried at local hospital in Japan. The specimen was pathologically diagnosed as tuberculoma. However, due to her nationality, the authors suspected it to be neurocysticercosis (NCC) and carried out serology and applied mitochondrial DNA analysis of Taenia solium. These diagnostic tools revealed it as NCC radiologically and pathologically mimicking central nervous tuberculomas. Molecular confirmation of NCC cases is strongly recommended when we can get the biopsy specimens.

Pneumocystis pneumonia (PCP) remains the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). Familiarity with the clinical features of PCP is crucial for prompt diagnosis, even if the patient is unaware of their HIV serostatus. We describe herein the clinical features of 34 episodes in 32 patients with AIDS-associated PCP and review the existing literature. As for symptoms, the frequency of fever, cough, and dyspnea was 74%, 74%, and 65%, respectively, and the complete triad was present in only 14 of the 34 episodes on first examination. Median duration from onset of symptoms until diagnosis was 3 weeks, and AIDS-associated PCP tended to take an insidious clinical course. Although laboratory findings were generally nonspecific, measurement of beta-D-glucan levels in the serum or plasma was highly useful in the diagnosis of PCP. All but 1 of the patients showed beta-D-glucan levels higher than the cutoff value (median, 147 pg/ml; range, 5-6920 pg/ml). Typical radiographic features of PCP are bilateral, symmetrical ground-glass opacities, but a wide variety of radiographic findings were observed. In our patients, high-resolution computed tomography (HRCT) of the lung showed ground-glass opacities sparing the lung periphery (41% of episodes) or displaying a mosaic pattern (29%), or being nearly homogeneous (24%), ground-glass opacities associated with air-space consolidation (21%), associated with cystic formation (21%), associated with linear-reticular opacities (18%), patchily and irregularly distributed (15%), associated with solitary or multiple nodules (9%), and associated with parenchymal cavity lesions (6%).

Increasing syphilis incidence among men who have sex with men (MSM) has been reported. The index case was a human immunodeficiency virus type 1 (HIV-1)-positive MSM who presented coincidentally with the secondary syphilis and a rebound of plasma viral load after complete suppression of HIV-1 (below 50 copies/ml) for 13 months with potent antiretroviral therapy (PART), suggesting a possibility of HIV-1 superinfection. We analyzed HIV-1 sequences before and after syphilis in four HIV-1-positive patients including the index case to explore drug resistance mutations (DRMs) and a possibility of HIV-1 superinfection. There were patients who obtained DRMs around syphilis infection but no evidence of HIV-1 superinfection was obtained. Our results underline the importance of strict adherence to PART.

Recent introduction of highly active antiretroviral therapy (HAART) is reported to have reduced the incidence of lymphoma among HIV-infected individuals. A clinicopathological study was performed on 86 AIDS-related lymphoma patients who were treated in Tokyo area from 1987 to 2005. The incidence of lymphoma detected by autopsy was 27% (53 cases/198 autopsies). Diffuse large B cell lymphoma was the most predominant histological subtype throughout the period (78%). Burkitt's lymphoma (BL) increased from 2% in the pre-HAART era (before end-1997) to 13% in the HAART era, whereas incidence of BL did not vary between HAART users and non-users. Epstein-Barr virus (EBV)-positive lymphoma decreased from 88% in the pre-HAART era to 58% in the HAART era, but did not differ significantly between HAART users (73%) and non-users (74%). Nodal involvement of lymphoma increased from 14% in the pre-HAART era to 50% in the HAART era; however, central nervous system involvement decreased from 62 to 38%. Kaposi's sarcoma-associated herpesvirus infection was rare (4%) among all cases. These data suggest that HAART might play a partial role in these changes, and the alteration in immunological backgrounds, such as EBV prevalence, is suggested as another leading cause of these changes in Japanese AIDS-related lymphoma.

The neuroradiological findings are helpful for the diagnosis of toxoplasmic encephalitis. The T1 hypersignal intensity foci on brain magnetic resonance (MR) images without contrast enhancement are presented and can be a pathognomonic sign of this disease.

Imported malaria remains an important problem in Japan. We have reviewed the medical records of 170 cases of malaria in our hospital, which corresponds to 14.9% of the total cases in Japan. The predominant malarial species was Plasmodium falciparum (52.3%), and the most frequent area of acquisition was Africa (54.2%), followed by Asia (20.9%) and Oceania (19.6%). The most common reason for travel among Japanese patients was business. A significant proportion (22.2%) of vivax malaria cases experienced relapse despite standard primaquine therapy. Most primaquine failures were from Oceania. We also found that a substantial number of Japanese patients contracted malaria without chemoprophylaxis and consulted medical facilities with an unfavorably long delay from initial symptoms (median: 3.0 days). Direct education of travelers and travel companies, in addition to health care providers, is likely necessary to improve outcomes of imported malaria.

We experienced a case of trichinellosis that had traveled in Kenya. The initial symptoms of the patient were myalgia and fever which started 2 weeks after she came back from Kenya, and blood examination showed marked eosinophilia (14,300/mm3) and elevated creatinine kinase (826IU/L). When we made serological diagnosis of trichinellosis 3 weeks after onset, symptoms started to resolve spontaneously and we observed the patient without any medication. As of 2 months after onset, symptoms and abnormal findings in laboratory data almost disappeared. The patient was speculated to be infected with trichinella spp. by incompletely cooked wild animal meats including alligator, zebra, pig, and ostrich during travel in Kenya. Since high incidence of trichinella infection in both wild and domestic animals has been reported in some areas of developing countries, travelers must be aware that raw or incompletely cooked animal meats can be source of trichinella spp.

In human immunodeficiency virus infected individuals, human cytomegalovirus (CMV) remains a significant pathogen. The adrenal gland is a preferential site of CMV disease in acquired immunodeficiency syndrome (AIDS) patients. However, glucocorticoid replacement is often not selected because of the risk of exacerbating underlying infection. To evaluate the need for glucocorticoid replacement in these patients, we performed a prospective study to investigate the adrenal function in 60 advanced AIDS patients. Their adrenal function including rapid ACTH test (RAT), basal plasma ACTH level, and daily urinary free cortisol level was evaluated. Approximately 25% of the patients turned out to be abnormal in this evaluation. Almost 60% of the patients could be followed up for one year or until their death. Using the follow-up data, we calculated sensitivity, specificity, positive predictive value and negative predictive value. Excretion of urinary free cortisol with normal RAT was comparable to normal controls, whereas patients with abnormal RAT excreted significantly lower urinary free cortisol. During hospitalization, 14 patients with normal RAT had febrile episode. During the febrile period the concentration of the urinary free cortisol level increased by 2.2 times. This study suggests that glucocorticoid replacement is necessary for AIDS patients suspected as clinically adrenal insufficiency, and that the dose of glucocorticoid replacement might be increased during sick days in AIDS patients with abnormal adrenal function.