New liposidomycin congeners produced by Streptomyces sp. TMPU-20A065, anti-Mycobacterium avium complex agents with therapeutic efficacy in a silkworm infection model.

Three new liposidomycin congeners (1, 2, and 4), together with 14 known liposidomycins (3 and 5-17), were isolated from the culture broth of Streptomyces sp. TMPU-20A065 as anti-Mycobacterium avium complex agents. The structures of liposidomycins were elucidated by spectroscopic analyses, including NMR and MS. Compounds 1, 2, and 4 belong to type-I liposidomycin-containing sulfate groups and methylglutaric acid, each with a different acyl side chain in the structure. Compounds 1-17 exhibited in vitro anti-M. avium and M. intracellulare activities with MIC values ranging between 2.0 and 64 µg ml-1. Furthermore, 1-17 exerted potent therapeutic effects in an in vivo-mimic silkworm infection model with ED50 values ranging between 0.12 and 3.7 µg larva-1 g-1.

Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an idiopathic inflammatory myopathy (IIM). Though patients with IMNM were not considered to show skin rash, several reports have showed atypical skin conditions in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive IMNM (HMGCR-IMNM). The incidence and phenotype of skin conditions in patients with HMGCR-IMNM are not fully known. RESULTS: Among the 100 IIM patients diagnosed from April 2015 through August 2022, 34 (34%) presented some form of skin condition, with 27 having typical skin rashes; this included 13 patients with dermatomyositis (DM), 8 with anti-synthetase syndrome (ASS), and 6 with IMNM. Meanwhile, 8 of 19 patients with HMGCR-IMNM (42%) presented atypical skin lesions, but no patients with other IIMs did (p < 0.001). Skin eruption with ash-like scales was observed in four HMGCR-IMNM patients, and non-scaly red patches and lumps in the other four patients; accordingly, their skin manifestations were considered as other dermal diseases except for IIM. However, skin and muscle biopsies revealed the atypical skin conditions of patients with HMGCR-IMNM to have the same pathological background, formed by Bcl-2-positive lymphocyte infiltrations. CONCLUSIONS: HMGCR-IMNM patients frequently have atypical skin conditions of the neck and back. Skin biopsy specimens from these lesions showed the same Bcl-2-positive lymphocytic infiltrations as muscle biopsy specimens regardless of the different gross dermal findings. Thus, such atypical skin conditions may be suggestive for HMGCR-IMNM.

Cutaneous manifestations of adult-onset Still's disease: A comparative study between young-onset and elderly-onset groups.

We investigated the detailed characteristics and proportions of typical and atypical rashes in 28 patients with adult-onset Still's disease (AOSD) by retrospectively examining the clinical symptoms and pathological features. The patients consisted of six males and 22 females aged between 23 and 85 years. The skin rashes observed in the study population were as follows: (i) typical rash in six cases, (ii) atypical rash in 19, and (iii) both typical and atypical rash in three cases (in all three cases, typical rash preceded atypical rash). Furthermore, we classified atypical rashes into persistent pruritic papules and plaques (PPPP) and others. In 22 cases of atypical rashes, 10 cases had PPPP. In a comparison between young-onset (<65 years) (n = 16) and elderly-onset (≥65 years) (n = 12) AOSD cases, typical rashes were observed more frequently in the young-onset cases. Regarding atypical rashes, PPPP was significantly more common in the elderly-onset cases.

Reversible cerebral vasoconstriction syndrome shows different clinical pictures at different times during the perinatal period: Two case reports.

OBJECTIVE: With the development of diagnostic imaging, a new clinical entity called reversible cerebral vasoconstriction syndrome (RCVS), which is considered to be a cause of secondary headache, has emerged. We herein present two cases of RCVS with different patterns of clinical progression. CASE REPORT: Case 1 occurred during labor, whereas case 2 occurred after delivery. Neither case presnted thunderclap headache at the onset of symptoms. Hypertensive disorders of pregnancy did not occur during the pregnancy or the puerperium in either case. Neurological symptoms following mild headache (Case 1: coma; Case 2: paralysis of the right extremities) were observed. CONCLUSION: Even when a patient has no risk factors for RCVS and had no severe headache, it is important not to miss any of the neurological symptoms. Magnetic resonance imaging (MRI) strongly supports the diagnosis, even during pregnancy. In addition, the diagnosis should always be reviewed while excluding eclampsia.

Prophylactic activity of orally administered dry-heat-sterilized Acremonium egyptiacum against Trypanosoma congolense-induced animal African trypanosomosis.

Animal African trypanosomosis (AAT) is an important global disease of livestock that causes economic losses of up to 4.5 billion US dollars per year. Thus, eliminating AAT in endemic countries will improve agricultural productivity and economic growth. To prevent AAT, vector control and the development of prophylactic drugs are crucial. Ascofuranone (AF) is a bioactive fungal compound with proven in vitro trypanocidal potency and in vivo treatment efficacy. However, the complex stereoselective synthesis of AF has prevented its cost-effective industrial production. Recently, a genetically modified strain of Acremonium egyptiacum fungus that produces a high yield of AF was developed. Therefore, we hypothesized that the oral administration of the AF-producing fungus itself may be effective against AAT. Hence, this study aimed to evaluate the prophylactic activity of orally administered dry-heat-sterilized A. egyptiacum against Trypanosoma congolense IL3000 infection using a mouse model. The survival rate was significantly prolonged (p = 0.009), and parasitemia was suppressed in all AF-fungus-treated groups (Group 1-9) compared with that in the untreated control group (Group 10). Hence, the trypanocidal activity of AF was retained after dry-heat-sterilization of the AF-producing fungus and that its oral administration effectively prevented AAT. Since AAT is endemic to rural areas with underdeveloped veterinary infrastructure, dry-heat-sterilized A. egyptiacum would be the most cost-effective potential treatment for AAT.

Behavioral photosensitivity of multi-color-blind medaka: enhanced response under ultraviolet light in the absence of short-wavelength-sensitive opsins.

BACKGROUND: The behavioral photosensitivity of animals could be quantified via the optomotor response (OMR), for example, and the luminous efficiency function (the range of visible light) should largely rely on the repertoire and expression of light-absorbing proteins in the retina, i.e., the opsins. In fact, the OMR under red light was suppressed in medaka lacking the red (long-wavelength sensitive [LWS]) opsin. RESULTS: We investigated the ultraviolet (UV)- or blue-light sensitivity of medaka lacking the violet (short-wavelength sensitive 1 [SWS1]) and blue (SWS2) opsins. The sws1/sws2 double or sws1/sws2/lws triple mutants were as viable as the wild type. The remaining green (rhodopsin 2 [RH2]) or red opsins were not upregulated. Interestingly, the OMR of the double or triple mutants was equivalent or even increased under UV or blue light (λ = 350, 365, or 450 nm), which demonstrated that the rotating stripes (i.e., changes in luminance) could fully be recognized under UV light using RH2 alone. The OMR test using dichromatic stripes projected onto an RGB display consistently showed that the presence or absence of SWS1 and SWS2 did not affect the equiluminant conditions. CONCLUSIONS: RH2 and LWS, but not SWS1 and SWS2, should predominantly contribute to the postreceptoral processes leading to the OMR or, possibly, to luminance detection in general, as the medium-wavelength-sensitive and LWS cones, but not the SWS cones, are responsible for luminance detection in humans.

The emerging threat of methicillin-resistant Staphylococcus aureus (MRSA) clone ST22-PT, carrying both Panton-Valentine leucocidin and toxic shock syndrome toxin 1 genes.

OBJECTIVES: Some MRSA strains produce Panton-Valentine leucocidin (PVL) and/or toxic shock syndrome toxin 1 (TSST-1), which are associated with severe infectious diseases. Although PVL- or TSST-1-positive strains have been isolated worldwide, strains carrying both PVL and TSST-1 genes are rare and sporadic. The objective of this study was to characterize these strains from Japan. METHODS: A total of 6433 MRSA strains isolated in Japan between 2015 and 2021 were analysed. Molecular epidemiological and comparative genomic analyses were conducted on PVL- and TSST-1-positive MRSA strains. RESULTS: A total of 26 strains from 12 healthcare facilities were PVL positive and TSST-1 positive, and all were classified as clonal complex (CC) 22. These strains exhibited similar genetic features to each other and were named as ST22-PT according to a previous report. Twelve and one of the ST22-PT strains were identified in patients with deep-seated skin infections and toxic shock syndrome-like symptoms, which are typical clinical features of PVL-positive and TSST-1-positive Staphylococcus aureus, respectively. Whole-genome comparative analysis revealed that the ST22-PT strains were highly similar to PVL- and TSST-1-positive CC22 strains isolated in several countries. Evaluation of the genome structure showed that ST22-PT possessed ΦSa2 harbouring PVL genes and a unique S. aureus pathogenicity island harbouring the TSST-1 gene. CONCLUSIONS: ST22-PT strains have recently emerged from several healthcare facilities in Japan, and ST22-PT-like strains have been identified in several countries. Our report highlights that the risk of international spread of PVL- and TSST-1-positive MRSA clone ST22-PT needs to be further investigated.

Coexistence of Superficial Thrombophlebitis and Cutaneous Venulitis in Behçet's Disease: Report of 5 Cases.

Previous studies have shown that erythema nodosum-like lesions in patients with Behçet's disease show cutaneous vasculitis of either phlebitis or dermal venulitis. To analyse the clinicopathological characteristics of superficial thrombophlebitis as well as cutaneous venulitis in Behçet's disease. We re-evaluated the histopathological features of superficial thrombophlebitis in patients with Behçet's disease. Five patients, one man and four women, developed superficial thrombophlebitis on the lower extremities. Two of the patients had vascular Behçet's disease, both also developed deep vein thrombosis. One patient had intestinal Behçet's disease. In all cases, venulitis in the overlying lower dermis or adjacent subcutis spreading from the main affected subcutaneous thrombophlebitis lesions was observed. Both neutrophilic venulitis (n = 2) and lymphocytic venulitis (n = 3) were observed at the same depth level or upper/lower location of the thrombophlebitis in the same specimens. In addition, concurrent venulitis with fibrin thrombus and fibrinoid necrosis was observed in one case, suggesting that fibrin thrombus affected both venules and muscular veins. By contrast, arteritis or arteriolitis at the same depth level was not observed. Our results showed histopathological features of coexistent thrombophlebitis and venulitis without involvement of either arteries or arterioles in the biopsied specimens of superficial thrombophlebitis. Further studies are necessary to support that those unique histopathological findings are the characteristic features and significant diagnostic indicators of Behçet's disease.

Complete Genome Sequence of Sphingomonas paucimobilis Strain Kira, Isolated from Human Neuroblastoma SH-SY5Y Cell Cultures Supplemented with Retinoic Acid.

Because of its small size, Gram-negative Sphingomonas paucimobilis can pose a risk of nosocomial infection. We report the complete circular genome sequence of S. paucimobilis strain Kira, which was isolated from retinoic acid-supplemented SH-SY5Y human cell cultures, to be 3,917,410 bp (G+C content, 65.7%; 3,672 protein-coding sequences), with two plasmids (79,575 bp and 44,333 bp).

Asymptomatic coronary aneurysms in a patient with eosinophilic granulomatosis with polyangiitis who developed a digital gangrene.

A 33-year-old male with a history of bronchial asthma and allergic rhinitis was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) eight years ago. The diagnosis was based on the presence of fever, remarkable eosinophilia, and painful digital ulcer. His signs and symptoms improved with a moderate dose of glucocorticoids. Thereafter, he was lost to follow-up, failing to attend any of the scheduled appointments. Three years later, he presented with painful digital gangrene on the lateral fold of the right ring fingernail and abdominal pain triggered by meals. Angiography showed multiple occlusions and severe stenoses of the peripheral arteries and coronary aneurysms, which confirmed the diagnosis of medium vessel vasculitis of the coronary and peripheral arteries due to flare up of EGPA. EGPA predominantly affects the small-sized vessels, but rarely the medium-sized vessels. Coronary vasculitis might occur asymptomatically, until the coronary stenosis becomes severe or myocardial infarction develops; hence, its prevalence is underestimated. In this case, a digital gangrene prompted us to perform a systemic angiography, leading to the diagnosis of coronary vasculitis. Careful observation for coronary lesions is necessary in patients with EGPA who develop digital gangrene.

Hypocomplementemic cutaneous small vessel vasculitis in a patient with IgG4-related disease.

A 62-year-old man was diagnosed with IgG4-related disease based on multiple sites of lymphadenopathy, lymph node biopsy, and elevated serum levels of IgG4. Hypocomplementemia was also observed. During admission, he was referred to our department complaining of multiple areas of purpura on the lower legs. Histological examination revealed leukocytoclastic vasculitis with fibrinoid necrosis, neutrophil infiltration, and nuclear dust in the upper dermis. To date, only a few cases of cutaneous vasculitis have been reported in IgG4-related disease, all of which showed hypocomplementemia. The role of IgG4 in the etiology of leukocytoclastic vasculitis in IgG4-related disease remains unknown and further studies are necessary.

Increase in antibiotic resistant Helicobacter pylori in a University Hospital in Japan.

BACKGROUND: Eradication effectively prevents Helicobacter pylori-associated diseases; however, H. pylori antibiotic resistance has increased throughout Japan and worldwide. This study aimed to assess rates of resistance to antibiotics; amoxicillin, clarithromycin and metronidazole in a University Hospital in Japan. MATERIALS AND METHODS: H. pylori (208 strains) were isolated from patients at the Okayama University Hospital in Japan. The minimum inhibitory concentrations (MIC) were determined using the mean values of the E-test to determine the antimicrobial susceptibilities of the strains. Sequencing and gene analysis were performed to analyze resistance genes to clarithromycin and amoxicillin. RESULTS: Rates of amoxicillin, clarithromycin, and metronidazole resistance were 13%, 48%, and 49%, respectively. Genetic analysis indicated that the A2143G point mutation in 23S rDNA is closely associated with the MIC of clarithromycin. The MIC in amoxicillin-resistant strains increased with an increase in the number of PBP1A amino acids mutations. CONCLUSION: Genetic analysis for resistant strains is not clinically effective in cases of amoxicillin resistance. Numerous bacteria with already high antibiotic resistance rates have been isolated in large hospitals such as a University Hospital. For effective eradication therapy, MIC measurement should be considered via several methods.

Association of host immunity with Helicobacter pylori infection in recurrent gastric cancer.

BACKGROUND: Helicobacter pylori infection is associated with the incidence of gastric cancer. Endoscopic resection has been developed as a proper technique to treat early stage of gastric cancer. However, some patients develop recurrent gastric cancer within 5 years after endoscopic treatment. The aim of the present study is to explore a biomarker for detecting people who has high risk of gastric cancer recurrence. METHODS: We analyzed the Interleukin-10 (IL-10) single nucleotide polymorphism (SNP) and IgG subclass responses to the bacteria in patients with early gastric cancer and recurrent gastric cancer. RESULTS: Patients with hetero-type in the 1082 SNP and CC genotype in the 592 SNP were at high risk of recurrence of gastric cancer. In patients with genotype carrying high risk of recurrence, IgG1 level tended to be higher than that in patients with other genotypes. CONCLUSIONS: Dominance of T helper 2 (Th2) immunity controlled by IL-10 cytokine may be associated with H. pylori-associated gastric cancer recurrence.

Production of Cisplatin-Incorporating Hyaluronan Nanogels via Chelating Ligand-Metal Coordination.

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand-metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or malonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand-platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.

A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response.

Diacylglycerol kinase (DGK) consists of 10 isozymes. The α-isozyme enhances the proliferation of cancer cells. However, DGKα facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGKα enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGKα activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. As a result, we have obtained a promising compound, 5-[(2E)-3-(2-furyl)prop-2-enylidene]-3-[(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one) (CU-3), which selectively inhibited DGKα with an IC50 value of 0.6 µM. CU-3 targeted the catalytic region, but not the regulatory region, of DGKα. CU-3 competitively reduced the affinity of DGKα for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells. Taken together, these results indicate that CU-3 is a selective and potent inhibitor for DGKα and can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses including anticancer immunity.

Preparation of uniform-sized hemoglobin-albumin microspheres as oxygen carriers by Shirasu porous glass membrane emulsification technique.

We have developed a new type of artificial oxygen carrier composed of bovine hemoglobin (bHb) and bovine serum albumin (BSA) prepared by Shirasu porous glass (SPG) membrane emulsification technique. The resultant emulsion droplets containing 10 wt% bHb and 5-20 wt% BSA were subsequently cross-linked by glutaraldehyde to form the microspheres. Due to the uniform pore structure of SPG membranes, the average diameters of bHb10-BSAm microspheres were successfully controlled at around 5 µm with a coefficient of variation of around 10%. In addition, the biocompatibility of the carriers depended on their oxyhemoglobin percentage regardless of their same size. Finally, the P50 values of these microspheres ranged from 8.08 to 11.60 mmHg, which showed a high oxygen affinity and an oxygen delivery function.

Evaluations of the selectivities of the diacylglycerol kinase inhibitors R59022 and R59949 among diacylglycerol kinase isozymes using a new non-radioactive assay method.

Ten mammalian diacylglycerol kinase (DGK) isozymes (α-κ) have been identified. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of pathophysiological functions. Thus, it is important to be able to easily check DGK activity in each pathophysiological event. Moreover, the conventional DGK assay is quite laborious because it requires the use of a radioisotope and thin-layer chromatography including multiple extraction steps. In order to minimize the laborious procedures, we established a non-radioactive, single well, two-step DGK assay system. We demonstrated that, compared to the conventional method, the new assay system has comparable sensitivity and much higher efficiency, and is effective in detecting potential agents with high reliability (Z'-factor = 0.69 ± 0.12; n = 3). Using the newly developed assay, we comprehensively evaluated the DGK isozyme selectivities of commercially available DGK inhibitors, R59022 and R59949, in vitro. We found that among 10 isozymes, R59022 strongly inhibited type I DGKα and moderately attenuated type III DGKε and type V DGKθ, and that R59949 strongly inhibited type I DGK α and γ, and moderately attenuated type II DGK δ and κ.