Interferon-stimulated gene 56 positively regulates Toll-like receptor 3-mediated CXCL10 expression in human renal proximal tubular epithelial cells.

Viral infections in tubular epithelial cells lead to the production of inflammatory cytokines by innate immunity, causing tubulointerstitial nephritis. TLR3 recognizes viral infections and acts via the activation of interferon (IFN)/IFN-stimulated genes (ISGs). This study investigates the role of ISG56, a representative ISG, in TLR3 signaling in cultured human renal proximal tubular epithelial cells (hRPTECs). To this end, hRPTECs were stimulated by a synthetic TLR3 ligand, polyinosinic-polycytidylic acid (poly IC), recombinant human interferon-ß [r(h)IFN-ß] or Japanese encephalitis virus (JEV) infection and assayed for inflammatory cytokine mRNA expression by RT-qPCR, and protein expression via western blotting or ELISA. ISG56 was expressed by poly IC or r(h)IFN-ß and IFN-ß knockdown reduced poly IC-induced expression of ISG56 and CXCL10. Moreover, ISG56 knockdown reduced poly IC- or r(h)IFN-ß-induced expression of CXCL10 at the same time as increasing JEV growth and reducing CXCL10 expression induced by JEV infection. Overall, TLR3 signaling induced IFN-ß-dependent expression of ISG56 and CXCL10. We show that ISG56 possibly plays a critical role in antiviral immunity of hRPTECs by positive regulation of IFN-ß-mediated CXCL10 expression downstream of TLR3.

Development of a neopentyl 211At-labeled activated ester providing in vivo stable 211At-labeled antibodies for targeted alpha therapy.

In this study we developed a neopentyl 211At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At-labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At-astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin-Assisted Purification and Deprotection (RAPD) protocol involving a solid-phase extraction of the protected 211At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At-labeled activator from the resin. This method allows the synthesis of an 211At-labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At-labeled activated ester, we efficiently synthesized 211At-labeled cetuximab in 27±1% radiochemical yield with 95% radiochemical purity. This 211At-activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose.

Factors determining the short-term clinical outcomes of conservative treatment in patients with supraspinatus tear.

INTRODUCTION: To identify factors influencing the better and worse changes in the Western Ontario Rotator Cuff Index of patients undergoing conservative treatment for supraspinatus tendon tear. METHODS: The study included 30 patients with supraspinatus tendon tear who underwent conservative treatment. The average duration of intervention was 35.4 days. The Western Ontario Rotator Cuff Index, shoulder range of motion, isometric muscle strength, supraspinatus tendon thickness, thickness of the supraspinatus, infraspinatus, and teres minor muscles, and acromiohumeral interval were assessed before and after the intervention. In the statistical analyses, change in the Western Ontario Rotator Cuff Index was the dependent variable, and the amount of change in each measurement variable before and after the intervention was the independent variable. RESULTS: The average Western Ontario Rotator Cuff Index improved from 1067 at pre-treatment to 997 at post-treatment, but without a significant difference (p = 0.29). A multiple regression analysis revealed that supraspinatus tendon thickness and muscle strength in shoulder external rotation at 90° scaption had a significant effect on the change in the Western Ontario Rotator Cuff Index (R2 = 0.44, p < 0.01). CONCLUSION: Supraspinatus tendon thickness and muscle strength in shoulder external rotation at 90° scaption were important factors for the Western Ontario Rotator Cuff Index score in the early stages of conservative treatment for patients with supraspinatus tendon tear.

Characteristics and clinical outcomes of patients with combined burns and trauma in Japan: Analysis of a nationwide trauma registry database.

INTRODUCTION: Patients with combined burns and trauma are often seen in the United States. The combination of trauma with burns increases mortality. In contrast, the characteristics and outcomes of these cases remain unknown in Japan. This study investigated the characteristics and outcomes of trauma associated with burns in Japan. METHODS: This multicenter retrospective cohort study was conducted by utilizing data from the Japan Trauma Data Bank for the period between 2004 and 2017. We evaluated the characteristics of burn patients (n = 5783) divided into two groups: burns only (n = 5537) and combined burns and trauma (n = 246). Clinical characteristics, including patient background, severity of trauma, injury mechanism, total body surface area affected, injury location, treatments, and clinical outcomes, were examined. RESULTS: Most patients in both the groups were injured by flames. The number proportion of patients with 40-89% of the total body surface area affected was 1069/5537 (19.3%) in the burn-only group and 23/246 (9.3%) in the combined burn and trauma group. The in-hospital mortality was 1006/5537 (18.2%) in the burn-only group and 17/246 (6.9%) in the combined burn and trauma group. CONCLUSIONS: We demonstrated the characteristics of Japanese patients with burns only compared with those with combined burns and trauma. Flames were the main cause of burns, and in-hospital mortality was lower in the combined burn and trauma group associated with a smaller burn area.

Syntheses of α(2,8) Sialosides Containing NeuAc and NeuGc by Using Double Carbonyl-Protected N-Acyl Sialyl Donors.

We report on the syntheses of NeuAc and NeuGc-containing glycosides via the use of double carbonyl-protected N-acetyl sialyl donors. The 7-O,9-O-carbonyl protection of an N-acyl-5-N,4-O-carbonyl-protected sialyl donor markedly increased the α-selectivity during glycosylation, particularly when glycosylating the C-8 hydroxyl group of sialic acids. The N-acyl carbamates were selectively opened with ethanethiol under basic conditions to provide N-acyl amines. It is noteworthy that N-glycolyl carbamate was more reactive to nucleophiles by comparison with the N-acetyl carbamate due to the electron-withdrawing oxygen in the N-acyl group and however, allowed selective opening of the carbamates without the loss of N-glycolyl groups. To demonstrate the utility of the approach, we began by synthesizing α(2,3) and α(2,6) sialyl galactosides. Glycosylation of the hydroxy groups of galactosides at the C-6 position with the NeuAc and NeuGc donors provided the corresponding sialyl galactoses in good yields with excellent α-selectivity. However, glycosylation of the 2,3-diol galactosyl acceptor selectively provided Siaα(2,2)Gal. Next, we prepared a series of α(2,8) disialosides composed of NeuAc and NeuGc. Glycosylation of NeuGc and NeuAc acceptors at the C-8 hydroxyl group with NeuGc and NeuAc sialyl donors provided the corresponding α(2,8) disialosides, and no significant differences were detected in the reactivities of these acceptors.

A new surgical approach for the treatment of a refractory foveal microaneurysm: A case report.

Purpose: To report a case of a refractory foveal microaneurysm (MA) that was successfully treated by use of a new surgical procedure. Observations: This study involved a 79-year-old female with an active foveal MA associated with branch retinal vein occlusion in her left eye. Despite anti-vascular endothelial growth factor treatments, the MA remained active without closure, and best-corrected visual acuity (VA) gradually decreased from 20/20 to 20/200. After our new surgical procedure was explained in detail to the patient, written informed consent was obtained from the patient and the surgery was performed. Briefly, following pars plana vitrectomy, the internal limiting membrane in her left eye was peeled and the retina of the external wall of the MA was then gently incised. The exposed MA was then directly grabbed and pulled up onto the retina using 27-gauge microforceps, and photocoagulation was performed. At 3-months postoperative, closure of the MA and improvement in the retinal findings were observed, and best-corrected VA improved to 20/67. Conclusions and importance: We report a case of a refractory foveal MA that was successfully treated with a novel surgical technique that closed the MA, avoided thermal damage to the surrounding tissue, and resulted in improved postoperative VA.

Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women.

Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

Utility of positive core number on MRI-ultrasound fusion targeted biopsy in combination with PI-RADS scores for predicting unexpected extracapsular extension of clinically localized prostate cancer.

OBJECTIVES: To evaluate the utility of magnetic resonance imaging (MRI) and MRI-ultrasound fusion targeted biopsy (TB) for predicting unexpected extracapsular extension (ECE) in clinically localized prostate cancer (CLPC). METHODS: This study enrolled 89 prostate cancer patients with one or more lesions showing a Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 but without morphological abnormality in the prostatic capsule on pre-biopsy MRI. All patients underwent TB and systematic biopsy followed by radical prostatectomy (RP). Each lesion was examined by 3-core TB, taking cores from each third of the lesion. The preoperative variables predictive of ECE were explored by referring to RP specimens in the lesion-based analysis. RESULTS: Overall, 186 lesions, including 81 (43.5%), 73 (39.2%), and 32 (17.2%) with PI-RADS 3, 4, and 5, respectively, were analyzed. One hundred and twenty-two lesions (65.6%) were diagnosed as cancer on TB, and ECE was identified in 33 (17.7%) on the RP specimens. The positive TB core number was ≤2 in 129 lesions (69.4%) and three in 57 lesions (30.6%). On the multivariate analysis, PI-RADS ≥4 (p = 0.049, odds ratio [OR] = 2.39) and three positive cores on TB (p = 0.005, OR = 3.07) were independent predictors of ECE. Lesions with PI-RADS ≥4 and a positive TB core number of 3 had a significantly higher rate of ECE than those with PI-RADS 3 and a positive TB core number ≤2 (37.5% vs. 7.8%, p < 0.001). CONCLUSIONS: Positive TB core number in combination with PI-RADS scores is helpful to predict unexpected ECE in CLPC.

Impact of frailty and prefrailty on the mid-term outcomes and rehabilitation course after cardiac surgery.

PURPOSE: This study examined the impact of frailty and prefrailty on mid-term outcomes and rehabilitation courses after cardiac surgery. METHODS: A total of 261 patients (median age: 73 years; 30% female) who underwent elective cardiac surgery were enrolled in this study. The Japanese version of the Cardiovascular Health Study Frailty Index classified 86, 131, and 44 patients into frailty, prefrailty, and robust groups, respectively. We examined the recovery of walking ability, outcomes at discharge, mid-term all-cause mortality, and rehospitalization related to major adverse cardiovascular and cerebrovascular events (MACCE) across the three cohorts. RESULTS: The 3-year survival rates in the frailty, prefrailty, and robust groups were 87%, 97%, and 100%, respectively (p = 0.003). The free event rates of all-cause mortality and re-hospitalization related to MACCE were 59%, 79%, and 95%, respectively (p < 0.001), with a graded elevation in adjusted morbidity among patients in the prefrailty (hazard ratio [HR], 4.57; 95% confidence interval [CI], 1.08-19.4) and frailty (HR, 9.29; 95% CI 2.21-39.1) groups. Patients with frailty also experienced a delayed recovery of walking ability and a reduced number of patients with frailty were discharged home. CONCLUSION: Frailty and prefrailty adversely affect the mid-term prognosis and rehabilitation course after cardiac surgery.

Stereoselective synthesis of D-glycero-D-manno-heptose-1ß,7-bisphosphate (HBP) from D-mannurono-2,6-lactone.

The synthesis of D-glycero-D-manno-heptose-1ß,7-bisphosphate (HBP) from D-mannose is described. This synthetic approach is notable for the elongation of the seventh carbon, employing mannurono-2,6-lactone, the substrate-controlled establishment of the C-6 configuration, and the nucleophilic introduction of phosphate at the C-1 position through the utilization of 4,6-O-benzylidene-α-triflate.

Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.

Uncovering a Severe Patient Group With Pollen-Related Extrarespiratory Allergic Symptoms: A Year-Long Diary Survey in Japan.

BACKGROUND: The most common symptoms of pollen allergy are rhinitis and conjunctivitis. However, in real-world clinical practice, we sometimes encounter patients with pollen allergy suffering from severe extrarespiratory symptoms including skin, gastrointestinal, or flu-like symptoms in relation to exposure to sensitized pollen. OBJECTIVE: To elucidate the extrarespiratory symptoms in patients with pollen allergy. METHODS: We performed a non-drug-focused prospective study of patients with pollen allergy (n = 384). During the 1-year observational period, they were asked to complete a weekly electronic diary consisting of visual analog scale (VAS) scores to assess all symptoms experienced in various organs over the past week. An association between seasonal pollen levels and seasonal increase in VAS scores was evaluated using a mixed-effects model for repeated measures. A k-means cluster analysis was performed to identify a group of patients experiencing stronger extrarespiratory symptoms. RESULTS: In patients sensitized to grass or birch pollen, higher seasonal levels of these pollen grains were associated with higher VAS scores for headache, gastrointestinal symptoms, skin symptoms, and fatigue. A cluster analysis identified a group of severe pollen-allergic patients with higher extrarespiratory symptoms (n = 42). This group was characterized by a higher frequency of comorbid food allergy/atopic dermatitis, higher rate of IgE sensitization to pollens, and higher impaired activity and work productivity. CONCLUSIONS: This 1-year survey identified a small but nonnegligible group of patients with pollen-related extrarespiratory symptoms. More attention should be paid to this patient group considering their impaired activity and work productivity.

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Clinical features of early recurrence of type I thoracolumbar intervertebral disk herniation in Miniature Dachshunds.

Some reports have been published on clinical features in dogs with early recurrence of type I thoracolumbar intervertebral disk herniation (TL-IVDH), but there is little understanding of the changes involved. This retrospective study describes the clinical features, including radiographic image results at the time of recurrence, of dogs with type I TL-IVDH that had undergone hemilaminectomy but then suffered early recurrence. Our medical records were searched between June 2007 and December 2022. Nine dogs showed deterioration in neurological signs within 4 to 6 weeks after surgery. All nine were Miniature Dachshunds. Radiographic images at initial onset showed calcification at the affected intervertebral disk space in all 9 dogs. Disk herniations at the initial onset were located between T11-12 and L1-2. After the first surgery, neurological function improved in all dogs. Recurrence occurred at the same site as at initial onset in all dogs. No calcification was observed at the affected intervertebral disk space on images at the time of recurrence. The extruded disk materials were surgically removed, and neurological function improved after the second surgery. In conclusion, calcification at the affected disk space at the time of initial onset is indicative of residual nucleus materials not yet fully extruded, and is a risk factor for early recurrence of type I TL-IVDH.

Kidney donor age of 50 years or above is a risk factor for calcineurin inhibitor-induced nephrotoxicity.

INTRODUCTION: Calcineurin inhibitor (CNI)-induced nephrotoxicity (CNI-T) is a post-transplantation complication that leads to graft dysfunction. Older-donor kidney grafts may be susceptible to chronic CNI exposure because of long-term arteriolar damage. The primary aim of this study was to examine the CNI-T incidence and time-course changes in the graft function according to donor age. METHODS: We included 334 kidney transplant recipients. CNI-T was defined by Banff arteriolar hyaline thickening scores of ≥2 based on allograft protocol biopsy. Depending on donor age, participants were divided into the D > 70 (≥70 years), D60 (60-69 years), D50 (50-59 years), and D < 49: (≤49 years) groups. We investigated the extent to which CNI-T affected the transplanted kidney function. Patients who did not develop CNI-T during the study period were included in the non-CNI-T group; the remaining were grouped into the CNI-T group. RESULTS: The CNI-T incidence was higher in donors aged >50 years. Compared to D < 49, the CNI-T risk was 1.86 times higher in D50 and 2.9 times higher in D > 70. Furthermore, the CNI-T group exhibited a significantly lower graft function 10 years after transplantation. CONCLUSION: CNI-T incidence increases in donors aged ≥50 years and affects renal function after 10 years.