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An approach to derive the below-bandgap absorption in GaSb/GaAs self-assembled quantum dot devices using room-temperature external quantum efficiency measurement results is presented. Devices with five layers of delta-doped quantum dots placed in the intrinsic, n- and p-regions of a GaAs solar cell are studied. The importance of incorporating an extended Urbach tail absorption in analyzing the absorption strength of quantum dots and the transition states is demonstrated. The theoretically integrated absorbance via quantum dot ground states is calculated as 1.04 × 1015 cm−1s−1, which is in reasonable agreement with the experimentally derived value 8.1 × 1015 cm−1s−1. The wetting layer and quantum dot absorption contributions are separated from the tail absorption and their transition energies are calculated. Using these transition energies and the GaAs energy gap of 1.42 eV, the heavy hole confinement energies for the quantum dots (320 meV) and for the wetting layer (120 meV) are estimated.

Abstract Background Sarcoidosis affects multiple organs and exhibits diverse clinical manifestations. Although tubulointerstitial nephritis is a known feature of renal involvement, necrotizing vasculitis is rare. Furthermore, prostate involvement with urinary retention is unusual in patients with sarcoidosis. Here, we report a case of systemic sarcoidosis with a rare combination of manifestations and different acute kidney injuries. Case presentation A 66-year-old man developed sudden urinary retention and fever. He was diagnosed with prostatitis and admitted to our hospital. An indwelling urethral catheter was inserted, and antimicrobial therapy was initiated; however, the prostatitis was refractory. Computed tomography revealed enlarged mediastinal lymph nodes. Analysis of transbronchoscopic lymph node and prostate biopsies showed epithelioid cell granulomas, suggesting systemic sarcoidosis. During the clinical course, the serum creatinine level rapidly increased to 2.36 mg/dL without oliguria. A kidney biopsy revealed tubulointerstitial injury with moderate lymphohistiocytic infiltration and small-vessel vasculitis in the interstitium. Following oral administration of 60 mg/day prednisolone, the patient’s renal function immediately improved, and urinary retention did not recur. Conclusions To the best of our knowledge, this is the first reported case of sarcoidosis with two unusual complications. Given its clinical course and pathology, this case is clinically valuable.

To elucidate the epidemiology of murine typhus, which is infrequently reported in Japan, we conducted a cross-sectional study involving 2,382 residents of rickettsiosis-endemic areas in Honshu Island during August–November 2020. Rickettsia typhi seroprevalence rate was higher than that of Orientia tsutsugamushi, indicating that murine typhus is a neglected disease.

Objectives: We examined the frequency of cross-reactions to Rickettsia typhi in patients with Japanese spotted fever (JSF) and evaluated the differences between two rickettsiae using antibody endpoint titers. Methods: Patients’ immunoglobulin (Ig)M and IgG titers against Rickettsia japonica and Rickettsia typhi in two phases were measured using an indirect immunoperoxidase assay at two reference centers for rickettsiosis in Japan. Cross-reaction was defined as a higher titer against R. typhi in convalescent sera than in acute sera among patients fulfilling the criteria for JSF diagnosis. The frequencies of IgM and IgG were also evaluated. Results: Approximately 20% of cases showed positive cross-reactions. A comparison of antibody titers revealed the difficulty in identifying some positive cases. Conclusion: Cross-reactions of 20% in serodiagnosis may lead to the misclassification of rickettsial diseases. However, with the exception of some cases, we were able to successfully differentiate JSF from murine typhus using each endpoint titer.

Abstract Background Tenosynovial giant cell tumor (TSGCT) is a benign fibrohistiocytic tumor that affects the synovium of joints, bursa, and tendon sheaths and is categorized into localized TSGCT (LTSGCT) and diffuse TSGCT (DTSGCT). LTSGCT and DTSGCT are characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and its translocation partner collagen type VI alpha 3 chain. The fusion gene induces intratumoral overexpression of CSF1 mRNA and CSF1 protein. CSF1 expression is a characteristic finding of TSGCT and detection of CSF1 mRNA and CSF1 protein may be useful for the pathological diagnosis. Although there have been no effective anti-CSF1 antibodies to date, in situ hybridization (ISH) for CSF1 mRNA has been performed to detect CSF1 expression in TSGCT. We performed CSF1 immunohistochemistry (IHC) using anti-CSF1 antibody (clone 2D10) in cases of TSGCT, giant cell-rich tumor (GCRT), and GCRT-like lesion and verified its utility for the pathological diagnosis of TSGCT. Methods We performed CSF1 IHC in 110 cases including 44 LTSGCTs, 20 DTSGCTs, 1 malignant TSGCT (MTSGCT), 10 giant cell tumors of bone, 2 giant cell reparative granulomas, 3 aneurysmal bone cysts, 10 undifferentiated pleomorphic sarcomas, 10 leiomyosarcomas, and 10 myxofibrosarcomas. We performed fluorescence ISH (FISH) for CSF1 rearrangement to confirm CSF1 expression on IHC in TSGCTs. We considered the specimens to have CSF1 rearrangement if a split signal was observed in greater than 2% of the tumor cells. Results Overall, 50 of 65 TSGCT cases, including 35 of the 44 LTSGCTs and 15 of the 20 DTSGCTs, showed distinct scattered expression of CSF1 in the majority of mononuclear tumor cells. MTSGCT showed no CSF1 expression. Non-TSGCT cases were negative for CSF1. FISH revealed CSF1 rearrangement in 6 of 7 CSF1-positive cases on IHC. On the other hand, FISH detected no CSF1 rearrangement in all CSF1-negative cases on IHC. Thus, the results of IHC corresponded to those of FISH. Conclusion We revealed characteristic CSF1 expression on IHC in cases of TSGCT, whereas the cases of non-TSGCT exhibited no CSF1 expression. CSF1 IHC may be useful for differentiating TSGCTs from histologically mimicking GCRTs and GCRT-like lesions.

In retrospective analyses, we report 3 febrile patients in Japan who had seroconversion to antibodies against Ehrlichia chaffeensis antigens detected by using an immunofluorescence and Western blot. Our results provide evidence of autochthonous human ehrlichiosis cases and indicate ehrlichiosis should be considered a potential cause of febrile illness in Japan.

Fukuoka et al. investigate the possible role of miR-199-3p during aging, which significantly decreases in the blood of aged mice compared to young mice. They also show that miR-199-3p enhance muscle regeneration, and administering miR-199 mimics to mdx mice, a dystrophy animal model, markedly improves muscle strength of the mice, highlighting its therapeutic potential.

Abstract Ehrlichia species are obligatory intracellular bacteria transmitted by arthropods, and some of these species cause febrile diseases in humans and livestock. Genome sequencing has only been performed with cultured Ehrlichia species, and the taxonomic status of such ehrlichiae has been estimated by core genome-based phylogenetic analysis. However, many uncultured ehrlichiae exist in nature throughout the world, including Japan. This study aimed to conduct a molecular-based taxonomic and ecological characterization of uncultured Ehrlichia species or genotypes from ticks in Japan. We first surveyed 616 Haemaphysalis ticks by p28-PCR screening and analyzed five additional housekeeping genes (16S rRNA, groEL, gltA, ftsZ, and rpoB) from 11 p28-PCR-positive ticks. Phylogenetic analyses of the respective genes showed similar trees but with some differences. Furthermore, we found that V1 in the V1–V9 regions of Ehrlichia 16S rRNA exhibited the greatest variability. From an ecological viewpoint, the amounts of ehrlichiae in a single tick were found to equal approx. 6.3E+3 to 2.0E+6. Subsequently, core-partial-RGGFR-based phylogenetic analysis based on the concatenated sequences of the five housekeeping loci revealed six Ehrlichia genotypes, which included potentially new Ehrlichia species. Thus, our approach contributes to the taxonomic profiling and ecological quantitative analysis of uncultured or unidentified Ehrlichia species or genotypes worldwide.

Japanese spotted fever (JSF) and scrub typhus (ST) are endemic to Japan and share similar clinical features. To document the clinical and epidemiologic characteristics that distinguish these 2 rickettsial diseases, during 2004–2015 we recruited 31 JSF patients, 188 ST patients, and 97 nonrickettsial disease patients from the southern Boso Peninsula of Japan. JSF occurred during April–October and ST during November–December. Patients with JSF and ST were significantly older and more likely to reside in wooded areas than were patients with nonrickettsial diseases. Spatial analyses revealed that JSF and ST clusters rarely overlapped. Clinical findings more frequently observed in JSF than in ST patients were purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed defervescence after treatment. Although their clinical features are similar, JSF and ST differ in seasonality, geographic distribution, physical signs, and severity. Because a considerable percentage of patients did not notice rash and eschar, many rickettsial diseases might be underdiagnosed in Japan.

Abstract Background Clear cell sarcoma of soft tissue (CCSST) and clear cell sarcoma-like gastrointestinal tumor (CCSLGT) are malignant mesenchymal tumors that share some pathological features, but they also have several different characteristics. They are well known to express chimeric fusions of Ewing sarcoma breakpoint region 1 (EWSR1) and cAMP response element-binding protein (CREB) family members; namely, EWSR1-activating transcription factor 1 (ATF1) and EWSR1-CREB1. In addition, recent studies have suggested the presence of other fusions. Methods We used fluorescence in situ hybridization to detect specific rearrangements including EWSR1, ATF1, CREB1, and cAMP response element modulator (CREM) in 16 CCSST and 6 CCSLGT cases. We also used reverse transcription polymerase chain reaction (RT-PCR) to detect specific chimeric fusions of EWSR1-ATF1 and EWSR1-CREB1 using fresh tumor samples in available cases. Results A total of 15 of 16 CCSST cases (93.8%) had EWSR1 rearrangement, of which 11 (68.8%) also had ATF1 rearrangement, suggestive of the presence of EWSR1-ATF1 fusions. One CCSST case (6.3%) was found to have EWSR1 and CREM rearrangements, and 4 of 6 CCSLGT cases (66.7%) had EWSR1 rearrangement, of which 2 (33.3%) showed ATF1 rearrangement and the other 2 cases (33.3%) showed CREB1 rearrangement. These cases most likely had EWSR1-ATF1 and EWSR1-CREB1 fusions, respectively. RT-PCR was performed in 8 available cases, including 6 CCSSTs and 2 CCSLGTs. All CCSSTs showed EWSR1-ATF1 fusions. Among the 2 CCSLGT cases, one had EWSR1-ATF1 fusion and the other had EWSR1-CREB1 fusion. Conclusions Rearrangements of EWSR1 and ATF1 or EWSR1-ATF1 fusion were predominantly found in CCSST, whereas those of EWSR1 and CREB1 or EWSR1-CREB1 tended to be detected in CCSLGT. A novel CREM fusion was also detected in a few cases of CCSST and CCSLGT. The cases in which EWSR1 rearrangement was detected without definitive partner genes should be considered for the presence of CREM rearrangement.

Huntington’s disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice. Our miR-132 supplemental treatment, i.e., supplying miR-132 to the brain, produced symptomatic improvement or retarded disease progression in R6/2 mice; interestingly, it had little effect on disease-causing mutant HTT mRNA expression and its products. Therefore, the findings suggest that there may be a therapeutic way to treat HD without inhibiting and/or repairing disease-causing HTT genes and gene products. Although miR-132 supplement may not be a definitive treatment for HD, it may become a therapeutic method for relieving HD symptoms and delaying HD progression.

We report a case of Rickettsia japonica infection in an 81-year-old man in central Japan. The patient had fever, rash, and an eschar but no evidence of a tick bite. His symptoms began 8 days after a land leech bite. The land leech is a potential vector of R. japonica.

We found Rickettsia raoultii infection in 6/261 brucellosis-negative patients with fever of unknown origin in brucellosis-endemic Inner Mongolia, China. We further identified Hyalomma asiaticum ticks associated with R. raoultii, H. marginatum ticks associated with R. aeschlimannii, and Dermacentor nuttalli ticks associated with both rickettsiae species in the autonomous region.

In Japan, most tularemia cases occur after contact with hares (hunting, cooking) and involve the glandular or ulceroglandular form. Here, we present a case of typhoidal tularemia in a 72-year-old Japanese male farmer who presented with fever, fatigue, and right lower abdominal pain. Computed tomography revealed intestinal wall thickening at the ascending colon, pleural effusion, and ascites. Following an initial diagnosis of bacterial enteric infection, his symptoms deteriorated after a week-long cephalosporin treatment course. The patient lived in an area endemic for scrub typhus; the antibiotic was changed to a tetracycline on suspicion of scrub typhus infection. His symptoms rapidly improved after initiation of minocycline treatment. Later, blood tests revealed marked increases in serological tests against Francisella tularensis exclusively, and the patient was diagnosed with typhoidal tularemia. Typhoidal tularemia may be characterized by any combination of general symptoms, but does not exhibit the local manifestations associated with other forms of tularemia. The patient, in this case, had no direct contact with hares or other wild animals and did not present with local manifestations of tularemia. Physicians should consider this disease, especially when tick-borne disease is suspected in the absence of local wounds, eschar, ulcers, or lymphadenopathy.

We present a case of ovarian clear-cell carcinoma that was initially diagnosed as adenocarcinoma of lung origin. This is an instructive diagnostic pitfall for clinicians and pathologists because of the unusual clinical course, small biopsy material, and noteworthy immunophenotype of the carcinoma. Imaging analysis identified only lung and liver lesions. In addition, the biopsy specimen from the lung was TTF-1 negative and napsin A positive, which is still possible for cancer of lung origin. Postmortem examination found that the cancer should be classified as ovarian clear-cell carcinoma distinguished by positive staining for napsin A and paired-box gene 8 (PAX8). Although PAX8 may not be usually investigated when tumoral lesions are identified in only the lung and liver, it is important to keep the necessity of PAX8 in mind to excluding carcinoma of Müllerian, renal, or thyroid origin. Keywords: Occult cancer, Ovarian clear-cell carcinoma, Adenocarcinoma of lung, Napsin A

BACKGROUND:Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam. METHODOLOGY/PRINCIPAL FINDINGS:We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%). Dominant IIP reactions against a single antigen were identified in 15 ST cases, whereas indistinguishably high reactions against multiple antigens were seen in 11 ST cases. The most frequently observed dominant IIP reaction was against Karp antigen (eight cases) followed by Gilliam (four cases). The highest diagnostic accuracy of IgM ELISA in acute samples was 78%. In a phylogenetic analysis of the 56-kDa type-specific antigen gene, the majority (14 cases) were located in the Karp-related branch followed by the Gilliam-related (two cases), Kato-related (two cases), and TA763-related clades (one case). CONCLUSIONS/SIGNIFICANCE:Both the clinical and laboratory diagnoses of ST remain challenging at a tertiary hospital. Implementation of both serological and nucleic acid amplification assays covering endemic O. tsutsugamushi strains is essential.

Rickettsia heilongjiangensis is the causative agent of Far-Eastern spotted fever (FESF). In Japan, a human case of FESF was identified in Sendai in Miyagi Prefecture in 2008, and R. heilongjiangensis bacteria were isolated from Haemaphysalis concinna ticks collected in the suspected geographical area of infection. Although the intraspecies genome diversity of Rickettsia has been poorly investigated, our recent analysis revealed extremely low genomic diversity of R. japonica, the agent of Japanese spotted fever, which is a close relative of R. heilongjiangensis. In this study, to investigate the genomic diversity of R. heilongjiangensis and understand the genetic relationship between Japanese and Chinese isolates, we sequenced three isolates from H. concinna ticks collected in Sendai and one isolate from a H. concinna tick collected in Inner Mongolia, China, and performed genomic comparisons between these isolates and strain 054, the type strain isolated from a Dermacentor silvarum tick in Heilongjiang Province, China. Although the three Japanese strains were isolated in 2008, 2009, and 2012, their genome sequences were identical, indicating that H. concinna ticks carrying a single R. heilongjiangensis clone have been distributed in Sendai, Japan. Among the five R. heilongjiangensis isolates, only 81 SNPs and 13 insertion/deletion sites were identified, despite the significant differences in these isolates both geographically and temporally. A significant portion of the 81 SNPs (16/81) were found to be recombinogenic. These results indicate low genomic diversity of R. heilongjiangensis, as observed in R. japonica. We further performed a detailed genomic comparison of R. heilongjiangensis and R. japonica to accurately define conserved and species-specific genes. This analysis revealed that although notable variations were found in the genomic loci encoding RelA/SpoT family proteins and tandem repeats in major surface proteins, there was only a small difference in the gene repertoire between the two species, suggesting that SNPs and small InDels are responsible for the functional or physiological differences between the two species, if present. Through this analysis, several species-specific genomic regions that can serve as ideal PCR targets for distinguishing R. heilongjiangensis and R. japonica were also identified.

A 60-year-old woman experienced fever, headache, rash, and altered vision after returning to Japan from India. Testing detected elevated antibody titers to spotted fever group rickettsia; PCR on blood yielded positive results for the rickettsial outer membrane protein A gene. We isolated a unique rickettsial agent and performed a full-genome analysis.

The authors wish to make the following corrections to this paper [...]

The rickettsial diseases Japanese spotted fever (JSF) and scrub typhus (ST) are caused by Rickettsia japonica and Orientia tsutsugamushi, respectively. The diseases share clinical symptoms, such as fever, rash, and eschar. However, there are no systematical investigations of the serological cross-reactivity between R. japonica and O. tsutsugamushi. Also, the serological cross-reactivity among O. tsutsugamushi serotypes is still unclear. We analyzed 1406 cases tested by indirect immunoperoxidase assay using seven rickettsial antigens—one R. japonica and six O. tsutsugamushi serotypes—between 2003 and 2016 at two reference centers in Japan. Of these, 167 JSF and 190 ST cases were serologically diagnosed. None of the ST cases had a significant increase in IgM titers against R. japonica. Six JSF cases showed IgG titers of ≥40 against O. tsutsugamushi, but no IgG titer showed a significant elevation in the convalescent phase sample. We observed a substantial degree of cross-reactivity between O. tsutsugamushi serotypes. Cross-reactivity was significant among Karp, Hirano/Kuroki, and Kato types and between Gilliam and Irie/Kawasaki types in IgM, while the Shimokoshi type was less cross-reactive than the others. In conclusion, there is no serological cross-reaction between R. japonica and O. tsutsugamushi. The cross-reactivity among O.tsutsugamushi varies depending on serotypes.

We developed a specific and rapid detection system for Rickettsia japonica and R. heilongjiangensis, the causative agents of spotted fever, using a TaqMan minor groove binder probe for a particular open reading frame (ORF) identified by the R. japonica genome project. The target ORF was present only in R. japonica–related strains.

One of the major routes of transmission of rickettsial and ehrlichial diseases is via ticks that infest numerous host species, including humans. Besides mammals, reptiles and amphibians also carry ticks that may harbor Rickettsia and Ehrlichia strains that are pathogenic to humans. Furthermore, reptiles and amphibians are exempt from quarantine in Japan, thus facilitating the entry of parasites and pathogens to the country through import. Accordingly, in the current study, we examined the presence of Rickettsia and Ehrlichia spp. genes in ticks associated with reptiles and amphibians originating from outside Japan. Ninety-three ticks representing nine tick species (genera Amblyomma and Hyalomma) were isolated from at least 28 animals spanning 10 species and originating from 12 countries (Ghana, Jordan, Madagascar, Panama, Russia, Sri Lanka, Sudan, Suriname, Tanzania, Togo, Uzbekistan, and Zambia). None of the nine tick species are indigenous in Japan. The genes encoding the common rickettsial 17-kDa antigen, citrate synthase (gltA), and outer membrane protein A (ompA) were positively detected in 45.2% (42/93), 40.9% (38/93), and 23.7% (22/93) of the ticks, respectively, by polymerase chain reaction (PCR). The genes encoding ehrlichial heat shock protein (groEL) and major outer membrane protein (omp-1) were PCR-positive in 7.5% (7/93) and 2.2% (2/93) of the ticks, respectively. The p44 gene, which encodes the Anaplasma outer membrane protein, was not detected. Phylogenetic analysis showed that several of the rickettsial and ehrlichial sequences isolated in this study were highly similar to human pathogen genes, including agents not previously detected in Japan. These data demonstrate the global transportation of pathogenic Rickettsia and Ehrlichia through reptile- and amphibian-associated ticks. These imported animals have potential to transfer pathogens into human life. These results highlight the need to control the international transportation of known and potential pathogens carried by ticks in reptiles, amphibians, and other animals, in order to improve national and international public health.

A case of Rickettsia heilongjiangensis infection in Japan was identified in a 35-year-old man who had rash, fever, and eschars. Serum contained R. heilongjiangensis antibodies, and eschars contained R. heilongjiangensis DNA. R. heilongjiangensis was also isolated from ticks in the suspected geographic area of infection.

The polyglutamine (polyQ) diseases such as Huntington's disease (HD), are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1) and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5) expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.