Publications by authors named "Hiroshi Goto"

283 Publications

Impact of different bilateral knee extension strengths on lower extremity performance.

Medicine (Baltimore) 2021 Sep;100(38):e27297

Faculty of Health Sciences, Tokyo Kasei University, Saitama, Japan.

Abstract: Despite the impact of leg muscle strength on lower extremity motor performance-including walking and sit-to-stand transfer-it remains difficult to predict the relationship between bilateral leg muscle strength and lower extremity performance. Therefore, this study was designed to predict lower extremity function through the differential modeling of logarithmic and linear regression, based on knee extension strength.The study included 121 individuals living in the same community. The bilateral strengths of the knee extensors were measured using a handheld dynamometer, and the Timed Up & Go test (TUG) performance time and 5-m minimum walking times were assessed to predict lower extremity motor functions. Bilateral normalized knee extension muscle strengths and lower extremity motor function scores, including walking or TUG performance times, were assessed on the logarithmic and linear models. The Akaike information criterion (AIC) was used to evaluate the coefficient compatibility between the logarithmic regression model and the linear regression model.The AIC value for the linear model was lower than that for the logarithmic model regarding the walking time. For walking time estimation in the linear model, the coefficient value of knee extension strength was larger on the strong than on the weak side; however, the AIC value for the logarithmic model was lower than that for the linear model regarding TUG performance time. In the logarithmic model's TUG performance time estimation, the coefficient value of knee extension strength was larger on the weak than on the strong side.In conclusion, our study demonstrated different models reflecting the relationship between both legs' strengths and lower extremity performance, including the walking and TUG performance times.
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http://dx.doi.org/10.1097/MD.0000000000027297DOI Listing
September 2021

Intraocular surgery under adalimumab therapy in patients with refractory uveitis: a single center study of 23 eyes.

Jpn J Ophthalmol 2021 Sep 7. Epub 2021 Sep 7.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan.

Purpose: We assessed the efficacy and safety of performing intraocular surgery for refractory uveitis under adalimumab (ADA) therapy.

Study Design: Single-center cohort study between 2016 and 2019.

Methods: In uveitis patients undergoing intraocular surgery under ADA treatment, we collected clinical data before surgery, and at the first visit, 6 months and last visit after surgery (follow-up 19.3 ± 8.1 months). Primary outcomes were visual acuity (VA) improvement in patients after cataract surgery, intraocular pressure (IOP) in patients after trabeculectomy and intraocular inflammation in all patients. Secondary outcomes were activated inflammation, vitreous opacity (OCV), uveitic macula edema (UME) and infection.

Results: Of 81 patients (161 eyes) initiated ADA therapy for uveitis, 19 patients (23 eyes) underwent intraocular surgery and were analyzed. Twelve of 18 eyes (66.6%) that underwent cataract surgery or vitrectomy with/without cataract surgery had improved VA at the last visit compared to before surgery. All 5 eyes that underwent trabeculectomy showed controlled IOP 6 months after surgery. Intraocular inflammation was resolved in 22 of 23 eyes at the first postoperative visit. Postoperative intraocular inflammation recurred in 3 eyes; 2 with UME, 1 with OCV. No eyes developed infection postoperatively. Preoperative ADA therapy duration was unrelated to relapse of intraocular inflammation.

Conclusion: Surgery for refractory uveitis under ADA treatment is safe and achieves good visual outcome and uveitis control if inflammation exists before surgery. ADA does not increase the risk of infections. Intraoperative findings of UME at surgery requires attention for postoperative relapse.
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http://dx.doi.org/10.1007/s10384-021-00871-3DOI Listing
September 2021

Clinico-epidemiological analysis of 1000 cases of orbital tumors.

Jpn J Ophthalmol 2021 Sep 27;65(5):704-723. Epub 2021 Jul 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To clarify the incidence, demography and clinical features of orbital tumors diagnosed in a single institute in Japan.

Study Design: Retrospective, observational case series.

Methods: Patients with primary orbital tumors including tumor-like lesions diagnosed clinically or histopathologically at Tokyo Medical University Hospital between 1995 and 2019 were analyzed. Incidence of all orbital tumors, demographic profile and clinical features of major benign and malignant tumors were reviewed retrospectively.

Results: Totally 1000 cases of primary orbital tumor were diagnosed clinically or histopathologically during the study period. Benign tumors accounted for 72% and malignant tumors 28%. 55% of benign tumors and 99% of malignant tumors were proven histopathologically. The most common benign orbital tumor was idiopathic orbital inflammation (27%), followed by IgG4-related ophthalmic disease (17%), cavernous venous malformation (13%) and pleomorphic adenoma (9%). The most common malignant tumor was lymphoma (70%), followed by adenoid cystic carcinoma (7%) and solitary fibrous tumor (5%).

Conclusions: Epidemiology of orbital tumors has changed by the improvement of imaging techniques, establishment of novel clinical and histopathological criteria, and changes in population age structure associated with the aging society. Currently, lymphoproliferative diseases including lymphoma and IgG4-related ophthalmic diseases form the major orbital tumors in Japan.
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http://dx.doi.org/10.1007/s10384-021-00857-1DOI Listing
September 2021

Histopathology and immunohistochemistry of choroidal melanocytoma demonstrated by local resection: A case report.

Am J Ophthalmol Case Rep 2021 Sep 19;23:101147. Epub 2021 Jun 19.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Purpose: To describe the clinical and histopathological features of a case of choroidal melanocytoma treated by local resection.

Observations: A 73-year-old man was referred to our hospital with a clinical diagnosis of choroidal melanoma. His best corrected visual acuity at presentation was 20/20 OU. Ocular fundus examination of his right eye showed a pigmented intraocular tumor. Local resection of the tumor was performed under general anesthesia. Histopathological examination of the excised tumor showed proliferation of round to ovoid cells with abundant cytoplasm containing many melanosomes and uniform nuclei and these histopathological findings were compatible with a diagnosis of choroidal melanocytoma. Visual acuity of 20/200 OD has been maintained for over 4 years without local recurrence.

Conclusions And Importance: Clinical diagnosis of choroidal melanocytoma, especially differentiation from melanoma, is difficult and challenging. Local resection of the tumor allowed study of the histopathological features of the choroidal melanocytoma and maintained tolerable vision in the current case.
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http://dx.doi.org/10.1016/j.ajoc.2021.101147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242962PMC
September 2021

Prevalence and incidence rates and treatment patterns of non-infectious uveitis in Japan: real-world data using a claims database.

Jpn J Ophthalmol 2021 Sep 28;65(5):657-665. Epub 2021 Jun 28.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To estimate the nationwide, longitudinal prevalence and incidence rates and assess treatment patterns of non-infectious uveitis (NIU) in Japan.

Study Design: A retrospective study.

Methods: Health insurance claims' data of patients with NIU were extracted from the Japan Medical Data Center (JMDC) database and analyzed descriptively (data extraction period, January 2011 to May 2017). Behçet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, and sarcoidosis were selected as the primary diseases of NIU.

Results: From 2011 to 2016, the mean and median age of patients increased. Most (> 90%) patients were categorized as "undifferentiated NIU" (NIU without specific primary disease information after excluding BD-, VKH disease-, and sarcoidosis-associated NIU). Over 60% of patients with NIU were treated at non-hospital clinics, while the rest were treated at university, public, or other hospitals. The estimated prevalence rate of NIU was 386.5 per 100,000 persons (95% confidence interval [CI], 374.5-398.6) in 2011 and 439.3 per 100,000 persons (95% CI, 432.3-446.3) in 2016; the estimated incidence rate was 189.7 per 100,000 persons (95% CI, 181.2-198.5) in 2012 and 207.8 per 100,000 persons (95% CI, 202.2-213.5) in 2016. Most patients' prescribed uveitis drugs were ophthalmic drops over the first 6 months after patient presentation and entry into the JMDC database, followed by systemic corticosteroids.

Conclusion: The estimated prevalence of NIU in Japan in recent years was approximately 400 with incidence of 200 per 100,000 persons.
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http://dx.doi.org/10.1007/s10384-021-00850-8DOI Listing
September 2021

Clinical features and symptoms of IgG4-related ophthalmic disease: a multicenter study.

Jpn J Ophthalmol 2021 Sep 19;65(5):651-656. Epub 2021 Jun 19.

Kanazawa University, Kanazawa, Japan.

Purpose: The aim of this study was to elucidate the clinical features and symptoms of IgG4-related ophthalmic disease (IgG4-ROD).

Study Design: Retrospective, multicenter study.

Methods: The medical charts of 378 patients with IgG4-ROD diagnosed at 9 hospitals in Japan were reviewed. The demographic profiles, clinical findings, and ocular symptoms of the patients were analyzed.

Results: On the basis of the diagnostic criteria for IgG4-ROD, the diagnosis was definite in 261 patients (69%), probable in 45 patients (12%), and possible in 72 patients (19%). The patients' mean age at the time of diagnosis was 60.6 ± 13.9 years; 195 (52%) were male. The mean IgG4 serum level at the time of the initial diagnosis was 578.9 mg/dL. Imaging studies showed pathologic lesions as follows: lesions in the lacrimal glands (86%), extraocular muscles (21%), trigeminal nerve (20%), and eyelids (12%); isolated orbital mass (11%); diffuse orbital lesion (8%); lesion in the perioptic nerve (8%); and lesion in the sclera (1%). The ophthalmic symptoms included dry eye (22%), diplopia (20%), decreased vision (8%), and visual field defects (5%). IgG4-ROD with extraocular lesions was observed in 182 patients (48%).

Conclusion: Although the lacrimal glands are well known to be the major pathologic site of IgG4-ROD, various ocular tissues can be affected and cause ophthalmic symptoms including visual loss.
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http://dx.doi.org/10.1007/s10384-021-00847-3DOI Listing
September 2021

Magnetic Resonance Imaging of Orbital Solitary Fibrous Tumors: Radiological-Pathological Correlation Analysis.

J Belg Soc Radiol 2021 Mar 16;105(1):14. Epub 2021 Mar 16.

Tokyo Medical University, JP.

Background: Solitary fibrous tumors (SFTs) are rare and can be misdiagnosed because of their various radiological appearances.

Purpose: To clarify the characteristic MRI findings of SFTs by analyzing their radiological-pathological correlation.

Material And Methods: Nine consecutive patients with SFT who underwent magnetic resonance imaging (MRI) prior to surgery were analyzed. Eight patients underwent contrast-enhanced MRI, and three underwent dynamic MRI. Radiological-pathological correlation analysis, co-occurrence matrix, run-length matrix, and histogram analysis were performed to assess the relationship between pathological findings T1- and T2-weighted images (T1-WI and T2-WI).

Results: All nine lesions ranged in size from 20 to 36 mm. Seven lesions were located in the superior portion of the retrobulbar space found outside of the muscle cone, and two lesions in the inferior portion were located within it. No significant correlation was observed between the amount of collagenous tissue and the qualitative evaluation of the signal on T1-WI and T2-WI. Kurtosis on T2-WI was significantly correlated with the amount of collagenous tissue ( = -0.97, < 0.0001) and endothelial cells ( = -0.49, = 0.0479).

Conclusion: Kurtosis in the histogram analysis on T2WI showed a strong correlation with the amount of collagenous tissue.
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http://dx.doi.org/10.5334/jbsr.2097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977021PMC
March 2021

Distinguishing Features of Anterior Uveitis Caused by Herpes Simplex Virus, Varicella-Zoster Virus, and Cytomegalovirus.

Am J Ophthalmol 2021 07 25;227:191-200. Epub 2021 Mar 25.

Department of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (H.T, N.H, M.I, M.M). Electronic address:

Purpose: To determine distinguishing features of the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV).

Design: Retrospective, multicenter case series.

Methods: Consecutive patients with herpetic AU examined at 11 tertiary centers in Japan between January 2012 and December 2017 and who were followed for ≥3 months were evaluated. Diagnosis was made by polymerase chain reaction (PCR) for HSV, VZV, or CMV in the aqueous humor, or classical signs of herpes zoster ophthalmicus.

Results: This study enrolled 259 herpetic AU patients, including PCR-proven HSV-AU (30 patients), VZV-AU (50), and CMV-AU (147), and herpes zoster ophthalmicus (32). All HSV-AU and VZV-AU patients were unilateral, while 3% of CMV-AU patients were bilateral. Most HSV-AU and VZV-AU patients were sudden onset with an acute clinical course, while CMV-AU had a more insidious onset and chronic course. There were no significant differences for all surveyed symptoms, signs, and complications between HSV-AU and VZV-AU. However, significant differences were detected for many items between CMV-AU and the other two herpetic AU types. Ocular hyperemia and pain, blurring of vision, ciliary injection, medium-to-large keratic precipitates (KPs), cells and flare in the anterior chamber, and posterior synechia significantly more often occurred in HSV-AU and VZV-AU vs CMV-AU. In contrast, small KPs, coin-shaped KPs, diffuse iris atrophy, elevated intraocular pressure, and glaucoma surgery were significantly more frequent in CMV-AU vs HSV-AU and VZV-AU.

Conclusion: This multicenter, retrospective study identified distinguishing features of HSV-AU, VZV-AU, and CMV-AU.
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http://dx.doi.org/10.1016/j.ajo.2021.03.020DOI Listing
July 2021

Effects of ranibizumab on growth factors and mediators of inflammation in the aqueous humor of patients with diabetic macular edema.

Graefes Arch Clin Exp Ophthalmol 2021 Sep 26;259(9):2597-2603. Epub 2021 Mar 26.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

Purpose: The study aims to investigate changes in the aqueous humor levels of 8 growth factors and inflammatory mediators after intravitreal ranibizumab injection (IRI) and the relationship between these substances and functional-morphological parameters in patients with diabetic macular edema (DME).

Methods: We recruited 25 patients with DME who were scheduled to receive 2 doses of IRI at monthly intervals. At baseline and 1 month after IRI, we measured aqueous levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, and interferon-gamma inducible protein 10 (IP-10) by the suspension array method. Central macular edema (CMT) or macular volume (MV) was examined by optical coherence tomography before and 1 month after IRI, and the improvement of macular edema was evaluated by calculating the percent change of CMT or MV.

Results: Aqueous humor levels of VEGF, PlGF, PDGF-AA, and IP-10 were significantly decreased 1 month after IRI (P < 0.001, P = 0.002, P = 0.002, and P = 0.005, respectively). In addition, the baseline aqueous humor levels of PlGF, MCP-1, and IL-6 were significantly correlated with the improvement in best corrected visual acuity (P = 0.036, P = 0.024, and P = 0.049, respectively). The baseline aqueous humor level of sICAM-1 was significantly negatively correlated with the change in CMT (P = 0.005), and the baseline aqueous humor levels of VEGF and PlGF were significantly correlated with the change in MV (P = 0.020 and P = 0.003, respectively). Furthermore, the percentage reduction in VEGF after IRI was significantly correlated with the change in MV (P = 0.037).

Conclusions: Our findings suggest that the change in aqueous humor levels of VEGF, PlGF, and ICAM-1 in DME may not only be an anatomic response but also a potential therapeutic target.

Clinical Trial Registration: This study was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry. The registration number is UMIN000030301.
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http://dx.doi.org/10.1007/s00417-021-05154-8DOI Listing
September 2021

Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice.

Am J Pathol 2021 06 8;191(6):1077-1093. Epub 2021 Mar 8.

Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Saitama, Japan. Electronic address:

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1) mice. Histopathologic analysis showed that Pdcd1 mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3 T cells and only a small proportion of CD19 B cells. Among infiltrating T cells, the CD4 Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1 mice. Experiments of lymphocyte transfer from Pdcd1 into irradiated wild-type mice confirmed that CD4 T cells from Pdcd1 mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4 Th1 cells.
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http://dx.doi.org/10.1016/j.ajpath.2021.02.014DOI Listing
June 2021

Epidemiology of uveitis in Japan: a 2016 retrospective nationwide survey.

Jpn J Ophthalmol 2021 Mar 11;65(2):184-190. Epub 2021 Mar 11.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Purpose: To investigate the epidemiology of uveitis in Japan and assess its changes over time.

Study Design: Retrospective multicenter study METHODS: Sixty-six hospitals in Japan with uveitis specialty clinics participated in this retrospective nationwide survey. A questionnaire was sent to each hospital to survey the total number of patients who made a first visit to the outpatient uveitis clinic of each hospital between 1 April 2016 and 31 March 2017. The diagnosis of uveitis was based on guidelines when available or on commonly used diagnostic criteria.

Results: In 2016, new patients with uveitis accounted for 3.2% of the total number of new patients with ophthalmic diseases. A total of 5378 patients were enrolled in the survey; 3408 cases could be classified with a specific uveitis entity, and 1970 cases were described as unclassified intraocular inflammation. Among the classified cases, the most frequent disease was sarcoidosis (10.6%), followed by Vogt-Koyanagi-Harada disease (8.1%), herpetic iritis (6.5%), acute anterior uveitis (5.5%), sclerouveitis (4.4%), Behçet's disease (4.2%), malignant disease (2.6%), acute retinal necrosis (1.7%), Posner-Schlossman syndrome (1.7%), and diabetic iritis (1.4%). The rates of sarcoidosis, Vogt-Koyanagi-Harada disease, and Behçet's disease were similar; however, the rate of herpes iritis increased (4.2-6.5%) when compared with the 2009 survey.

Conclusions: Some changes were observed between the previous nationwide surveys (2002 and 2009) and the present survey. It must be valuable to continue such nationwide epidemiologic surveys at regular intervals.
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http://dx.doi.org/10.1007/s10384-020-00809-1DOI Listing
March 2021

Continuous measurement of surface electrical potentials from transplanted cardiomyocyte tissue derived from human-induced pluripotent stem cells under physiological conditions in vivo.

Heart Vessels 2021 Jun 8;36(6):899-909. Epub 2021 Mar 8.

Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.

Recording the electrical potentials of bioengineered cardiac tissue after transplantation would help to monitor the maturation of the tissue and detect adverse events such as arrhythmia. However, a few studies have reported the measurement of myocardial tissue potentials in vivo under physiological conditions. In this study, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSCM) sheets were stacked and ectopically transplanted into the subcutaneous tissue of rats for culture in vivo. Three months after transplantation, a flexible nanomesh sensor was implanted onto the hiPSCM tissue to record its surface electrical potentials under physiological conditions, i.e., without the need for anesthetic agents that might adversely affect cardiomyocyte function. The nanomesh sensor was able to record electrical potentials in non-sedated, ambulating animals for up to 48 h. When compared with recordings made with conventional needle electrodes in anesthetized animals, the waveforms obtained with the nanomesh sensor showed less dispersion of waveform interval and waveform duration. However, waveform amplitude tended to show greater dispersion for the nanomesh sensor than for the needle electrodes, possibly due to motion artifacts produced by movements of the animal or local tissue changes in response to surgical implantation of the sensor. The implantable nanomesh sensor utilized in this study potentially could be used for long-term monitoring of bioengineered myocardial tissue in vivo under physiological conditions.
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http://dx.doi.org/10.1007/s00380-021-01824-zDOI Listing
June 2021

Clinicopathologic analysis of 32 ciliary body tumors.

Jpn J Ophthalmol 2021 Mar 19;65(2):237-249. Epub 2021 Feb 19.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To describe the demographic profile, clinical and histopathologic features, and treatment of ciliary body tumors.

Study Design: Retrospective, observational case series.

Methods: Thirty-two patients (32 eyes) with ciliary body tumors diagnosed histopathologically at Tokyo Medical University Hospital between 1994 and 2017 were retrospectively reviewed.

Results: The patients' mean age at diagnosis was 45.4 ± 17.0 (range, 14-87) years. Ten of the patients were male, and 22, female. Twenty-four cases (75%) were benign tumors, comprising 9 melanocytomas, 7 adenomas, 4 mesectodermal leiomyomas, 2 leiomyomas, and 2 other tumors; and 8 cases (25%) were malignant tumors, comprising 6 melanomas and 2 low-grade adenocarcinomas. Local resection of the tumor was performed in 20 patients, including 3 cases of melanoma and 2 cases of adenocarcinoma. Enucleation was initially performed in 3 cases of melanoma, 1 case of melanocytoma with iris melanoma, and 2 cases of benign tumors difficult to differentiate clinically from melanoma. In the 17 patients who underwent local resection and were followed for at least 3 years, the outcome was best-corrected visual acuity better than 0.1 logMAR in 8 patients (47%), but hand motions in 2 patients (12%).

Conclusions: Melanocytoma and adenoma of the ciliary epithelium were the major ciliary body tumors found in this study. Management of ciliary body tumors with accurate clinical diagnosis remains challenging because of the anatomic characteristics and clinical similarities to melanoma in the majority of the cases.
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http://dx.doi.org/10.1007/s10384-021-00814-yDOI Listing
March 2021

Using machine learning to investigate the relationship between domains of functioning and functional mobility in older adults.

PLoS One 2021 11;16(2):e0246397. Epub 2021 Feb 11.

Faculty of Health Sciences, Tokyo Kasei University, Saitama, Japan.

Previous studies have shown that functional mobility, along with other physical functions, decreases with advanced age. However, it is still unclear which domains of functioning (body structures, body functions, and activities) are most closely related to functional mobility. This study used machine learning classification to predict the rankings of Timed Up and Go tests based on the results of four assessments (soft lean mass, FEV1/FVC, knee extension torque, and one-leg standing time). We tested whether assessment results for each level could predict functional mobility assessments in older adults. Using support vector machines for machine learning classification, we verified that the four assessments of each level could classify functional mobility. Knee extension torque (from the body function domain) was the most closely related assessment. Naturally, the classification accuracy rate increased with a larger number of assessments as explanatory variables. However, knee extension torque remained the highest of all assessments. This extended to all combinations (of 2-3 assessments) that included knee extension torque. This suggests that resistance training may help protect individuals suffering from age-related declines in functional mobility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246397PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877571PMC
July 2021

Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles.

Ophthalmology 2021 Aug 21;128(8):1197-1208. Epub 2021 Jan 21.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Purpose: Various immune mediators have crucial roles in the pathogenesis of intraocular diseases. Machine learning can be used to automatically select and weigh various predictors to develop models maximizing predictive power. However, these techniques have not yet been applied extensively in studies focused on intraocular diseases. We evaluated whether 5 machine learning algorithms applied to the data of immune-mediator levels in aqueous humor can predict the actual diagnoses of 17 selected intraocular diseases and identified which immune mediators drive the predictive power of a machine learning model.

Design: Cross-sectional study.

Participants: Five hundred twelve eyes with diagnoses from among 17 intraocular diseases.

Methods: Aqueous humor samples were collected, and the concentrations of 28 immune mediators were determined using a cytometric bead array. Each immune mediator was ranked according to its importance using 5 machine learning algorithms. Stratified k-fold cross-validation was used in evaluation of algorithms with the dataset divided into training and test datasets.

Main Outcome Measures: The algorithms were evaluated in terms of precision, recall, accuracy, F-score, area under the receiver operating characteristic curve, area under the precision-recall curve, and mean decrease in Gini index.

Results: Among the 5 machine learning models, random forest (RF) yielded the highest classification accuracy in multiclass differentiation of 17 intraocular diseases. The RF prediction models for vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma achieved the highest classification accuracy, precision, and recall. Random forest recognized vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma with the top 5 F-scores. The 3 highest-ranking relevant immune mediators were interleukin (IL)-10, interferon-γ-inducible protein (IP)-10, and angiogenin for prediction of vitreoretinal lymphoma; monokine induced by interferon γ, interferon γ, and IP-10 for acute retinal necrosis; and IL-6, granulocyte colony-stimulating factor, and IL-8 for endophthalmitis.

Conclusions: Random forest algorithms based on 28 immune mediators in aqueous humor successfully predicted the diagnosis of vitreoretinal lymphoma, acute retinal necrosis, and endophthalmitis. Overall, the findings of the present study contribute to increased knowledge on new biomarkers that potentially can facilitate diagnosis of intraocular diseases in the future.
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http://dx.doi.org/10.1016/j.ophtha.2021.01.019DOI Listing
August 2021

[Assessment for Local Treatment for Elderly Breast Cancer Cases].

Gan To Kagaku Ryoho 2020 Dec;47(13):2098-2100

Dept. of Surgery, Tokyo Metropolitan Ohtsuka Hospital.

The number of elderly breast cancer patients has been increasing recently nevertheless the optimal treatment for the elderly breast cancer patients still remains controversial. In this study, 21 primary breast cancer cases who were equal or older than 85 years old at our hospital were examined their clinical and pathological features. These 21 cases were divided into 2 group; Group A; ten cases who received operations, Group B; eleven cases who did not receive operations. T categories, M categories and clinical stages in Group B were significantly higher than those of Group A. The main causing reason why Group B cases had not received operations was that their primary breast cancer were too advanced to perform operation. Instead of operation, most Group B cases received endocrine therapy or radiotherapy. Group A cases received standard operative procedures including partial or total mastectomy and biopsies or dissection of axillary lymph nodes. Besides, their post- operative courses were good and safe. These results suggest that even for elderly patients, early diagnosis and treatment could improve their prognosis and quality of life. In addition, careful surveillances for elderly breast cancer patients, those who tend to stop attending regular check up to their hospital, should be considered for further assessment for characteristics of elderly breast cancer patients.
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December 2020

Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma.

Invest Ophthalmol Vis Sci 2021 01;62(1):15

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers.

Methods: We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromatography time-of-flight mass spectrometry. The altered metabolomic profiles were visualized by heat map and principal component analysis. Metabolic pathway analysis was performed by Metabo Analyst 4.0 using differentially expressed metabolites. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. Machine learning algorithms were implemented by random forest using the R environment. Finally, an independent set of 18 IgG4-ROD and 17 orbital MALT lymphoma specimens were used to validate the identified biomarkers.

Results: The principal component analysis showed a significant difference of both IgG4-ROD and orbital MALT lymphoma for biopsy specimens and controls. Interestingly, lesions in IgG4-ROD were uniquely enriched in arachidonic metabolism, whereas those in orbital MALT lymphoma were enriched in tricarboxylic acid cycle metabolism. We identified spermine as the best discriminator between IgG4-ROD and orbital MALT lymphoma, and the area under the receiver operating characteristic curve of the spermine to discriminate between the two diseases was 0.89 (95% confidence interval, 0.803-0.984). A random forest model incorporating a panel of five metabolites showed a high area under the receiver operating characteristic curve value of 0.983 (95% confidence interval, 0.981-0.984). The results of validation revealed that four tissue metabolites: N1,N12-diacetylspermine, spermine, malate, and glycolate, had statistically significant differences between IgG4-ROD and orbital MALT lymphoma with receiver operating characteristic values from 0.708 to 0.863.

Conclusions: These data revealed the characteristic differences in metabolomic profiles between IgG4-ROD and orbital MALT lymphoma, which may be useful for developing new diagnostic biomarkers and elucidating the pathogenic mechanisms of these common orbital lymphoproliferative disorders.
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http://dx.doi.org/10.1167/iovs.62.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814356PMC
January 2021

Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis.

J Clin Med 2020 Dec 17;9(12). Epub 2020 Dec 17.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo 160-0023, Japan.

Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features.

Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored.

Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement ( < 0.001). The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D ( = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement (25% versus 6%, = 0.004). Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA (37% versus 5%, ≤ 0.001).

Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients.
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http://dx.doi.org/10.3390/jcm9124084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766793PMC
December 2020

Intravitreal ranibizumab reduced ocular blood flow and aqueous cytokine levels and improved retinal morphology in patients with diabetic macular edema.

Sci Rep 2020 12 10;10(1):21713. Epub 2020 Dec 10.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

We investigated the relationship between aqueous cytokine levels, changes in ocular blood flow, and morphological and functional improvements after intravitreal ranibizumab injection (IRI) in treatment-naïve eyes with center-involving diabetic macular edema (DME). Thirty-three eligible patients with DME (33 eyes) were recruited. At the first IRI, we collected a sample of aqueous humor from each eye and measured levels of the cytokines/chemokines. Mean blur rate (MBR) was used to evaluate retinal and choroidal flow by laser speckle flowgraphy at the time of the first IRI and 1 month later. One month after IRI, both retinal and choroidal MBR had significantly decreased from baseline. The reduction ratio of the retinal MBR was significantly correlated with aqueous levels of monocyte chemotactic protein (MCP)-1 and interleukin-8, and with reduction of central macular thickness, but not with improvement of best corrected visual acuity. The reduction ratio of choroidal MBR showed no statistical correlation with any cytokine levels or changes in clinical parameters. We conclude that IRI reduces both retinal and choroidal blood flow in treatment-naïve DME. Reduction of retinal blood flow correlated with regression of morphological pathology, which is regulated by the initial aqueous levels of some cytokines.
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http://dx.doi.org/10.1038/s41598-020-78792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728747PMC
December 2020

Serum Metabolomic Profiling of Patients with Non-Infectious Uveitis.

J Clin Med 2020 Dec 6;9(12). Epub 2020 Dec 6.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

The activities of various metabolic pathways can influence the pathogeneses of autoimmune diseases, and intrinsic metabolites can potentially be used to diagnose diseases. However, the metabolomic analysis of patients with uveitis has not yet been conducted. Here, we profiled the serum metabolomes of patients with three major forms of uveitis (Behҫet's disease (BD), sarcoidosis, and Vogt-Koyanagi-Harada disease (VKH)) to identify potential biomarkers. This study included 19 BD, 20 sarcoidosis, and 15 VKH patients alongside 16 healthy control subjects. The metabolite concentrations in their sera were quantified using liquid chromatography with time-of-flight mass spectrometry. The discriminative abilities of quantified metabolites were evaluated by four comparisons: control vs. three diseases, and each disease vs. the other two diseases (such as sarcoidosis vs. BD + VKH). Among 78 quantified metabolites, 24 kinds of metabolites showed significant differences in these comparisons. Four multiple logistic regression models were developed and validated. The area under the receiver operating characteristic (ROC) curve (AUC) in the model to discriminate disease groups from control was 0.72. The AUC of the other models to discriminate sarcoidosis, BD, and VKH from the other two diseases were 0.84, 0.83, and 0.73, respectively. This study provides potential diagnostic abilities of sarcoidosis, BD, and VKH using routinely available serum samples that can be collected with minimal invasiveness.
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http://dx.doi.org/10.3390/jcm9123955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762156PMC
December 2020

The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD.

Mod Rheumatol 2021 May 28;31(3):529-533. Epub 2021 Jan 28.

Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.
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http://dx.doi.org/10.1080/14397595.2020.1859710DOI Listing
May 2021

Long-Term Safety and Efficacy of Adalimumab in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis.

Ophthalmology 2021 Jun 3;128(6):899-909. Epub 2020 Nov 3.

Departments of Ophthalmology and Medicine, Oregon Health & Science University and Legacy Devers Eye Institute, Portland, Oregon.

Purpose: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.

Design: Open-label, multicenter, phase 3 extension study (VISUAL III).

Participants: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis).

Methods: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose.

Main Outcome Measures: Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids.

Results: At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively.

Conclusions: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab.
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http://dx.doi.org/10.1016/j.ophtha.2020.10.036DOI Listing
June 2021

Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing.

J Clin Med 2020 Oct 27;9(11). Epub 2020 Oct 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls ( = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ≥ 2 and < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs.
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http://dx.doi.org/10.3390/jcm9113458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693346PMC
October 2020

Clinical Characteristics, Management, and Factors Associated with Poor Visual Prognosis of Acute Retinal Necrosis.

Ocul Immunol Inflamm 2020 Sep 18:1-6. Epub 2020 Sep 18.

Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

: To identify the clinical characteristics of acute retinal necrosis (ARN) and clarify factors associated with poor visual prognosis.: a nationwide multi-center retrospective chart review study was performed in Japan using data from the medical records of 149 consecutive ARN patients. Demographics, ocular signs, virologic testing of intraocular fluids, and treatment were examined. Factors associated with poor visual prognosis were investigated by regression analysis.: At initial presentation, anterior chamber cells or mutton-fat keratic precipitates (97%), unilaterality (93%), and yellow-white retinal lesions (86%) were recognized. In the clinical course, rapid circumferential expansion of retinal lesions (39%), development of retinal break or retinal detachment (55%), and optic atrophy (43%) were recorded. Four variables were identified as associated with poor visual prognosis.: The present study identified clinical characteristics and factors associated with poor visual prognosis of ARN.
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http://dx.doi.org/10.1080/09273948.2020.1789179DOI Listing
September 2020

Comprehensive miRNA Analysis Using Serum From Patients With Noninfectious Uveitis.

Invest Ophthalmol Vis Sci 2020 09;61(11)

Department of Ophthalmology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Purpose: MicroRNAs (miRNAs) are noncoding RNAs and have attracted attention as a biomarker in a variety of diseases. However, extensive unbiased miRNAs analysis in patients with uveitis has not been completely explored. In the present study, we comprehensively analyzed the deregulated miRNAs in three major forms of uveitis (Behҫet's disease [BD], sarcoidosis and Vogt-Koyanagi-Harada disease [VKH]) to search for potential biomarkers.

Methods: This study included 10 patients with BD, 17 patients with sarcoidosis, and 13 patients with VKH. Eleven healthy subjects were used as controls. The miRNAs expression levels were studied by microarray using serum samples from patients with uveitis and healthy controls.

Results: A total of 281 upregulated miRNAs and 137 downregulated miRNAs were detected in patients with BD, 35 upregulated miRNAs and 86 downregulated miRNAs in patients with sarcoidosis, and 153 upregulated miRNAs and 35 downregulated miRNAs in patients with VKH. Some deregulated miRNAs were involved in the mitogen-activated protein kinase signaling pathway and inflammatory cytokine pathways. Furthermore, we identified miR-4708-3p, miR-4323, and let-7g-3p as the best predictor miRNAs for BD, sarcoidosis, and VKH, respectively. Panels of miRNAs with diagnostic potential for the three diseases were generated using machine learning.

Conclusions: In this study, comprehensive miRNA analysis identified deregulated miRNAs in three major forms of noninfectious uveitis. This study provides new insights into molecular pathogenetic mechanisms and useful information toward developing novel diagnostic biomarkers and therapeutic targets for BD, sarcoidosis, and VKH.
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http://dx.doi.org/10.1167/iovs.61.11.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476662PMC
September 2020

Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Commun Biol 2020 08 21;3(1):465. Epub 2020 Aug 21.

Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.
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http://dx.doi.org/10.1038/s42003-020-01185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442816PMC
August 2020

Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients.

Ocul Immunol Inflamm 2020 Aug 20:1-8. Epub 2020 Aug 20.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: The efficacy of infliximab (IFX) and adalimumab (ADA) for treating Behçet's syndrome (BS) and sarcoidosis has not been compared adequately.

Methods: We reviewed the medical records of patients with uveitis diagnosed at Tokyo Medical University Hospital and compared the efficacy of IFX and ADA for BS and the efficacy of ADA for sarcoidosis and BS.

Results: 68 patients in IFX group and 63 patients in ADA group were analyzed. In BS patients, IFX and ADA were both effective in improving uveitic macular edema (UME). ADA improved UME in BS but not in sarcoidosis patients. The efficacy of ADA in reducing doses of corticosteroids and glaucoma medications was better in sarcoidosis than in the BS group.

Conclusion: Both IFX and ADA are efficacious in improving UME in BS patients. The reason that ADA improves UME better in BS than in sarcoidosis may be due to the difference in pathogenesis between these diseases.
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http://dx.doi.org/10.1080/09273948.2020.1791346DOI Listing
August 2020

Blockade of costimulatory CD27/CD70 pathway promotes corneal allograft survival.

Exp Eye Res 2020 10 14;199:108190. Epub 2020 Aug 14.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To determine whether the CD27/CD70 pathway plays a significant role in corneal allograft rejection by investigating the effect of blocking the CD27/CD70 pathway by anti-CD70 antibody on corneal allograft survival.

Methods: Orthotopic penetrating keratoplasty was performed using C57BL/6 donor grafts and BALB/c recipients. Expression of CD27 and CD70 on rejected cornea was examined by immunohistochemistry. Corneal transplant recipients received intraperitoneal injection of anti-CD70 antibody (FR70) or control rat IgG. Alloreactivity was measured by mixed lymphoid reaction (MLR) in recipients administered control rat IgG and those administered anti-CD70 antibody. Corneal expression of IFN-γ and IL-12 was also examined in both groups. Graft opacity was assessed over an 8-week period and graft survival was evaluated using Kaplan-Meier survival curves. Proportion of CD4CD44 memory T cells in lymph nodes was measured by flow cytometry.

Results: CD4CD27 cells and CD11cCD70 cells were present in rejected cornea. Anti-CD70 antibody administration suppressed alloreactivity in corneal allograft recipients, and inhibited IFN-γ expression in recipient cornea (p < 0.05). Anti-CD70 antibody suppressed opacity score of recipient cornea and prolonged corneal allograft survival (p < 0.05). Proportion of CD4CD44 memory T cells in recipient lymph nodes was reduced by anti-CD70 antibody treatment.

Conclusion: The CD27/CD70 pathway plays a significant role in corneal allograft rejection by initiating alloreactive Th1 cells and preserving memory T cells. Anti-CD70 antibody administration prolongs corneal allograft survival indicating the potential therapeutic effect of CD27/CD70 pathway blockade on corneal allograft rejection.
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http://dx.doi.org/10.1016/j.exer.2020.108190DOI Listing
October 2020
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