Cryptococcus, Pathological observations of five autopsy cases and one biopsy case

Pathologic, anatomical, and histological findings of 5 autopsy cases and one biopsy case of cryptococcosis have been described. Macroscopically the foci of the lung are grayish white or yellowish white in color and range in size from the small acinous-nodular ones to the larger lobular-nodular ones. In the brain the meninx appears gelatinous and edematous showing many small spots with indistinct boundary and with grayish white color. Lymph nodes infected with fungi are swollen in various degrees. Histologically the foci are mainly consisted of granulomatous inflammation containing giant cells. Besides, there are small degenerative foci having no inflammatory response and the lesions of marked fibrosis; the former will be newly formed foci and the latter the old ones. The size of C. neoformans found in tissue ranges from 3 to 30 &#956;, and the majority of fungi possess thick gelatinous capsule, but some of them in granulative lesions often possess no capsule. From the staining properties the capsule of C. neoformans is believed to be a kind of acid mucopolysaccharide. As for the staining method including general fungi, GOMORI's methenamine silver method is best, especially for the detailed examination of fungus structures, and for the differential diagnosis mucicarmine stain is the most suitable one. In tracing the distribution of the foci in the various organs, it seems that the first attack of this fungus occurs in the lung. The authors have called general attention, through their own experiences, to the fact that the small granulomatous foci caused by Cryptococcus infection, especially in the lung, may often escape the detection at autopsy.</p

Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402

<p>Abstract</p> <p>Background</p> <p>The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma.</p> <p>Methods</p> <p>The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays.</p> <p>Results</p> <p>No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8⁺gp100-in4⁺CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4.</p> <p>Conclusion</p> <p>Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.</p

Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro

Introduction: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. Materials and methods: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. Results: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. Conclusion: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-021-01206-5Miyama A., Ebina K., Hirao M., et al. Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro. Journal of Bone and Mineral Metabolism 39, 639 (2021

A score using left ventricular diastolic dysfunction to predict 90-day mortality in acute ischemic stroke: The DONE score

Purpose: The aim of this study was to identify whether diastolic dysfunction predicts death at 90 days after acute ischemic stroke.Methods: We retrospectively analyzed patients with ischemic stroke. All patients underwent transthoracic echocardiography to evaluate systolic function and diastolic function by means of assessing ejection fraction and septal E/e’.We evaluated the initial National Institute of Health Stroke Scale (NIHSS) score,arterial occlusion, and laboratory data. We used multivariate regression models to identify independent predictors of 90-day mortality. Results: Among 1208 patients, the overall 90-day mortality rate was 8%. In multivariate logistic regression analysis, a higher initial NIHSS score,plasma D-dimer level and E/e’ and occlusion of internal carotid artery or basilar artery were independent predictors of 90-day mortality.The DONE score derived from these valuables showed good discrimination with area under the curve (AUC) value of 0.82 (95% confidence interval [CI],0.78?0.87) to predict 90-day mortality. The DONE score also predicted poor outcome (modified Rankin scale score, 4?6) at 90 days (AUC, 0.82;95% CI 0.80?0.85). Conclusions: Higher E/e’ indicating diastolic dysfunction,may be associated with 90-day mortality in patients with acute ischemic stroke. The DONE score could readily predict poor outcome after acute ischemic stroke

Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomyinduced osteoporosis in mice

NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.Takami K., Okamoto K., Etani Y., et al. Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomyinduced osteoporosis in mice. JCI Insight 8, e171962 (2023); https://doi.org/10.1172/jci.insight.171962

Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration

Synovial mesenchymal stem cell (SMSC) is the promising cell source of cartilage regeneration but has several issues to overcome such as limited cell proliferation and heterogeneity of cartilage regeneration ability. Previous reports demonstrated that basic fibroblast growth factor (bFGF) can promote proliferation and cartilage differentiation potential of MSCs in vitro, although no reports show its beneficial effect in vivo. The purpose of this study is to investigate the promoting effect of bFGF on cartilage regeneration using human SMSC in vivo. SMSCs were cultured with or without bFGF in a growth medium, and 2 × 105 cells were aggregated to form a synovial pellet. Synovial pellets were implanted into osteochondral defects induced in the femoral trochlea of severe combined immunodeficient mice, and histological evaluation was performed after eight weeks. The presence of implanted SMSCs was confirmed by the observation of human vimentin immunostaining-positive cells. Interestingly, broad lacunae structures and cartilage substrate stained by Safranin-O were observed only in the bFGF (+) group. The bFGF (+) group had significantly higher O’Driscoll scores in the cartilage repair than the bFGF (−) group. The addition of bFGF to SMSC growth culture may be a useful treatment option to promote cartilage regeneration in vivo.Okamura G., Ebina K., Hirao M., et al. Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration. International Journal of Molecular Sciences, 22, 1, 1. https://doi.org/10.3390/ijms22010300

Perfusion abnormality in neuronal intranuclear inclusion disease with stroke-like episode: A case report

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease. Some patients with NIID occasionally present with acute symptoms. However, its mechanism remains unclear. We report a patient with NIID who presented with a stroke-like episode. Arterial spin labeling magnetic resonance imaging revealed hypoperfusion in the focal cerebral region at the onset while no apparent arterial occlusion was observed. The abnormal perfusion area was normalized 6 days after admission. Therefore, the perfusion abnormality was likely the main cause of acute neurologic deficits in NIID. NIID should be considered in the differential diagnosis of stroke mimics

Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6–CXCR2 pathway

Objective: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. Methods: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (−) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. Results: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. Conclusion: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.Goshima A., Etani Y., Hirao M., et al. Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6–CXCR2 pathway. Osteoarthritis and Cartilage , (2023); https://doi.org/10.1016/j.joca.2023.07.010