Stage III Chorioamnionitis is Associated with Reduced Risk of Severe Retinopathy of Prematurity.

OBJECTIVE: To identify whether histologically confirmed chorioamnionitis (hCAM) is associated with development of retinopathy of prematurity (ROP). STUDY DESIGN: We retrospectively analyzed 2 different cohorts. Cohort 1 was the national database of newborns in Japan born at ≤1500g or <32 weeks' gestation (January 2003 through April 2021, n = 38 013). Cohort 2 was babies born at <1500g from a single institution in Tsuchiura, Japan, (April 2015 through March 2018, n = 118). RESULTS: For Cohort1, after adjusting for potential confounders, stage III CAM (n = 5554) was associated with lower odds of severe ROP (stage ≥3 or required peripheral retinal ablation) by 14% (OR: 0.86; 95% CI: 0.78-0.94]. CAM of stage I (n = 3277) and II (n = 4319) was not associated with the risk of ROP. For Cohort 2, the odds of severe ROP were significantly reduced in moderate to severe hCAM groups (stage II, OR: 0.06, 95% CI: 0.05-0.82; stage III, OR: 0.10, 95% CI: 0.01-0.84). Neonates with funisitis, comorbidity of hCAM, and a finding of fetal inflammatory response had lower odds of severe ROP (OR: 0.11; 95% CI: 0.01-0.93). CONCLUSIONS: After adjusting for confounders, severe hCAM with fetal inflammatory response was associated with reduced risk of ROP.

Methylation levels of the IL10 gene in peripheral blood are related to the intractability of Graves' disease.

The prognosis of autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), is difficult to predict. DNA methylation regulates gene expression of immune mediating factors. Interleukin (IL)-10 is a Th2 cytokine that downregulates inflammatory cytokines produced by Th1 cells. To clarify the role of methylation of the IL10 gene in the prognosis of AITD, we evaluated the methylation levels of two CpG sites in the IL10 promoter using pyrosequencing. The methylation levels of the -185 CpG site of the IL10 gene were related to age and GD intractability in GD patients. Furthermore, the C carrier of the IL10-592 A/C polymorphism was related to low methylation levels of the -185 CpG site. The methylation levels of the IL10-185 CpG site of the IL10 gene were related to the intractability of GD and were lower in individuals with the C allele of the IL10-592 A/C polymorphism.

Clinical Usefulness of T-Cell Receptor Vß Repertoire Analysis for Differentiating Multisystem Inflammatory Syndrome in Japanese Children From Toxic Shock Syndrome and Kawasaki Disease.

The specific expansion of T-cell receptor ß chain variable region (TCR-Vß21.3 + ) CD4 + and CD8 + T cells was observed in Japanese patients with multisystem inflammatory syndrome in children. In contrast, these findings were not observed in patients with toxic shock syndrome and Kawasaki disease. T-cell receptor ß chain variable region repertoire analysis to detect specific expansion of Vß21.3 + T cells might be useful for differentiating multisystem inflammatory syndrome in children from toxic shock syndrome and Kawasaki disease.

Intraindividual variation in histone acetylation and its impact on autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITDs), such as Graves' disease (GD) and Hashimoto's disease (HD), are organ-specific autoimmune diseases. Histone acetylation, especially that of histone H3, is an epigenetic mechanism that regulates gene expression and is associated with the development of autoimmune diseases. However, physiological variations in histone acetylation are not yet clear, and we believe that physiological variations should be examined prior to analysis of the role of histone H3 in the pathogenesis of AITDs. In this study, we analyzed histone H3 acetylation levels in peripheral blood mononuclear cells (PBMCs) using a histone H3 total acetylation detection fast kit. Blood samples were collected before meals, between 8:30-9:00 am, daily for 10 weeks to evaluate the daily variation. At 4 days, blood was also collected before meals three times a day (at 8:30-9:00, 12:30-13:00, and 16:30-17:00) to evaluate circadian variation. Then, histone H3 acetylation levels were evaluated in AITD patients to clarify the association with the pathogenesis of AITD. Although we could not find a common pattern of circadian variance, we observed daily variation in histone H3 acetylation levels, and their coefficient of variances (CVs) were approximately 48.3%. Then, we found that histone H3 acetylation levels were significantly lower in GD and HD patients than in control subjects and these differences were larger than the daily variation in histone acetylation. In conclusion, histone H3 acetylation levels were associated with the development of AITD, even allowing for daily variation.

Association of B7H3 and B7H4 gene polymorphisms and protein expression with the development and prognosis of autoimmune thyroid diseases.

BACKGROUND: The prognosis of autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's disease (HD), varies among patients. B7-H3 and B7-H4, members of the B7 family of proteins, regulate immune response. To clarify the association of B7-H3 and B7-H4 with the pathogenesis and prognosis of AITDs, we examined the expression of the soluble and membrane form of B7-H3 and B7-H4 and genotyped single nucleotide polymorphisms (SNPs) in the B7H3 and B7H4 genes. METHODS: We examined the expression of the membrane form of B7-H3 and B7-H4 by flow cytometry and their soluble forms by enzyme-linked immunosorbent assay. We genotyped SNPs in B7H3 and B7H4 in 187 GD patients, 217 HD patients, and 110 healthy volunteers using the PCR-RFLP method. RESULTS: The frequency of the B7H3 rs3816661 CC genotype was higher in patients with severe HD. G carriers of B7H4 rs10754339 A/G and B7H4 rs13505 T/G were more frequent in patients with AITD. A carrier of B7H4 rs10158166 A/G and C carriers of B7H4 rs3806373 C/T were more frequent in patients with intractable GD. The proportion of B7-H3+ monocytes was higher in the CC genotype of B7H3 rs3816661 C/T than in the other genotypes and was lower in patients with GD and HD than in healthy controls. The concentration of soluble B7-H4 was lower in the TG genotype of B7H4 rs13505 T/G than in the TT genotype and was higher in patients with AITD than in healthy controls. CONCLUSION: B7H3 and B7H4 are associated with AITD susceptibility and prognosis.

Transcriptome analysis of umbilical cord mesenchymal stem cells revealed fetal programming due to chorioamnionitis.

Although chorioamnionitis (CAM) has been demonstrated to be associated with numerous short- and long-term morbidities, the precise mechanisms remain unclear. One of the reasons for this is the lack of appropriate models for analyzing the relationship between the fetal environment and chorioamnionitis and fetal programming in humans. In this study, we aimed to clarify the fetal programming caused by CAM using the gene expression profiles of UCMSCs. From nine preterm neonates with CAM (n = 4) or without CAM (n = 5), we established UCMSCs. The gene expression profiles obtained by RNA-seq analysis revealed distinctive changes in the CAM group USMSCs. The UCMSCs in the CAM group had a myofibroblast-like phenotype with significantly increased expression levels of myofibroblast-related genes, including α-smooth muscle actin (p < 0.05). In the pathway analysis, the genes involved in DNA replication and G1 to S cell cycle control were remarkably decreased, suggesting that cellular proliferation was impaired, as confirmed by the cellular proliferation assay (p < 0.01-0.05). Pathway analysis revealed that genes related to white fat cell differentiation were significantly increased. Our results could explain the long-term outcomes of patients who were exposed to CAM and revealed that UCMSCs could be an in vitro model of fetal programming affected by CAM.

Current status of eye disorders caused by docetaxel administration every 3 weeks: A case-control study in Japanese patients.

PURPOSE: Docetaxel is known to cause eye disorders. In this study, current status of eye disorders caused by docetaxel administration every 3 weeks in Japanese patients was examined. METHODS: This case-control study targeted patients who were newly administered docetaxel at the Kyoto Okamoto Memorial Hospital between 1 July 2015 and 30 June 2018. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. RESULTS: Of the 89 subjects, 7 (7.9%) had eye disorders. The symptoms were watering eyes (7.9%), a stye and eye discharge (2.2% each), corneal and conjunctival disorder, visual acuity reduction, and blepharedema (1.1% each). Four patients who presented with watering eyes, eye discharge, or corneal and conjunctival disorder showed improvement with the use of eye drops such as artificial tears. Two patients who presented with a stye showed improvement with the use of oral cefcapene. One patient with mild symptoms showed spontaneous improvement. However, one patient had irreversible visual acuity reduction. The multivariate logistic regression analysis revealed that a cumulative docetaxel dose of ≥300 mg/m2 (odds ratio: 15.50, 95% confidence interval: 1.37-175.00, p = 0.027) and concomitant cyclophosphamide use (odds ratio: 13.20, 95% confidence interval: 1.13-153.00, p = 0.039) were significant risk factors associated with eye disorders. CONCLUSION: In conclusion, it was determined that docetaxel-related eye disorders might be influenced by the cumulative dose of docetaxel and concomitant cyclophosphamide use. In addition, relatively mild symptoms improved with medication.

Risk Factors for Eye Disorders Caused by Paclitaxel: A Retrospective Study.

Paclitaxel and nanoparticle albumin-bound paclitaxel are known to cause adverse events of eye disorders, such as cystoid macular edema. However, at present, the risk factors remain unclear. Therefore, risk factors for eye disorders caused by paclitaxel and nanoparticle albumin-bound paclitaxel were studied. This retrospective study targeted patients who were newly administered paclitaxel or nanoparticle albumin-bound paclitaxel at Kyoto Okamoto Memorial Hospital between April 1, 2012, and March 31, 2017. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. To analyze the risk factors, logistic regression analysis using 41 factors was performed. Of 128 subjects, 13 (10.2%) had eye disorders with symptom degrees of Grades 1 and 2. The symptoms were conjunctivitis or subconjunctival hemorrhage (3.1%), visual acuity reduction (2.3%), blurred vision and eye pain (1.6% each), eye mucus, blepharitis, stye, watering eyes, photopsia, and muscae volitantes (0.8% each). In eight patients, the conditions patients improved with spontaneously or with medication use; no improvements were observed the cases of visual acuity reduction, blurred vision, or muscae volitantes. Multivariate logistic regression analysis revealed that a cumulative dose of ≥819 mg/m2 (odds ratio: 5.34, 95% confidence interval: 1.32-21.60, p=0.019) and baseline alkaline phosphatase ≥256 U/L (odds ratio: 3.74, 95% confidence interval: 1.02-13.70, p=0.046) were significant risk factors associated with eye disorders. In conclusion, it was determined that paclitaxel- and nanoparticle albumin-bound paclitaxel-related eye disorders might be influenced by cumulative dose and baseline alkaline phosphatase.

Hematopoietic cell transplantation for myeloid/NK cell precursor acute leukemia in second remission.

Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia-type chemotherapy combined with L-Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.

[A Retrospective Analysis of Epiphora Due to Docetaxel].

Docetaxel is an antineoplastic agent used to treat breast cancer and several other types of cancer. Typical adverse drug reactions with docetaxel include myelosuppression and edema, but there have also been numerous reports of eye disorders, such as epiphora and lacrimal duct obstruction. Reports from Japan on such reactions, however, are limited; the duration and frequency of their appearance and other factors have not been elucidated. Since this information would be useful in routine medical practice, we conducted a retrospective analysis of epiphora due to docetaxel. Of the 48 breast cancer patients who commenced new 3-weekly docetaxel dosage regimens during the study period, 6 (12.5%) presented with epiphora. The patients with epiphora were receiving docetaxel at a significantly greater dose intensity (mg/m 2/3 weeks) than those in whom epiphora did not present (72.7 vs 67.1, p=0.0427). The timing of the reaction had no fixed pattern, and the symptoms were reversible in all cases, recorded as Grade 1 or 2. Thus, epiphora due to docetaxel during a 3-weekly dosage regimen presented rather frequently in Japanese patients, and the symptoms were reversible and mild. We found that greater dose intensity might be a risk factor for epiphora. More detailed studies that include data from a large number of facilities should be conducted in the future.

[An Undeniable Case of Optic Neuropathy Due to Cabazitaxel].

Cabazitaxelis a taxane-type antineoplastic agent used for treating prostate cancer. Although typical side effects include neutropenia and fatigue, no studies have investigated eye disorders as a possible side effect, and the details are not clear. Herein, we report our experience of an undeniable case of optic neuropathy caused by cabazitaxel. A 78-year-old man had been diagnosed with prostate cancer (cT3aN1M1b, stage IV) 3 years previously, with a treatment history of bicalutamide, leuprorelin, flutamide, docetaxel, abiraterone, and enzalutamide. Because of a decline in vision during the second and third administration cycles of cabazitaxel, the patient visited an ophthalmologist. He was found to have reduced visual acuity, reduced central critical flicker frequency, narrowed field of vision, and impaired color vision, and was diagnosed with optic neuropathy. Although cabazitaxel administration was continued through 6 cycles, the symptoms were unchanged, and no drastic exacerbation was seen. This patient undeniably developed optic neuropathy due to cabazitaxel. Optic neuropathy due to taxane-type antineoplastic agents has also been reported with paclitaxel or docetaxel, and all precautions should be taken when administering such drugs. Detailed studies that include data from a larger number of facilities should be conducted in the future.

[A Retrospective Analysis of Eye Disorders Due to Oxaliplatin].

In recent years, the incidence of eye disorders due to antineoplastic agents such as S-1 has increased. Eye disorders including visual field defect, visual field impairment, optic neuritis, and visual acuity reduction have been reported as serious adverse effects of oxaliplatin, an agent that is frequently used as a standard therapy for colorectal cancer. However, specific details about these conditions, such as the timing relative to oxaliplatin administration and frequencies at which they appear, remain to be clarified; therefore, we conducted a retrospective analysis of patients with eye disorders due to oxaliplatin in order to obtain evidence that would be useful in routine medical practice. Of the 55 patients who were treated with oxaliplatin in this analysis 10 (18.2%) presented with eye disorders, including blepharoptosis (5 patients, 9.1%), visual field impairment (2 patients, 3.6%), visual acuity reduction (2 patients, 3.6%), eye pain (1 patient, 1.8%), congestion (1 patient, 1.8%), watering eyes (1 patient, 1.8%), and blurred vision (1 patient, 1.8%). These symptoms appeared during the early period of treatment, such as after the first or the second dose. We found that all patients had mild symptoms (Grade 1 or 2), and most improved spontaneously. Thus, eye disorders due to oxaliplatin affect Japanese patients somewhat frequently, although the symptoms are reversible and are mild in most cases. Detailed studies that include data from a larger number of facilities should be conducted in the future.

[A case of lacrimal duct obstruction caused by capecitabine].

In recent years, the incidence of adverse ocular reactions, including corneal problems and lacrimal duct obstruction, due to antineoplastic agents such as S-1 has increased. Very few reports of adverse ocular reactions caused by capecitabine, a fluorinated pyrimidine antineoplastic agent like S-1, exist, and consequently, the mechanism underlying these reactions is not well understood. This report describes our recent experience with a case of lacrimal duct obstruction caused by capecitabine. The patient was a 71-year-old woman who was being administered trastuzumab plus capecitabine combination chemotherapy for breast cancer-related bone metastasis. She complained of epiphora 7 days after capecitabine was initiated. Thereafter, her capecitabine dose was reduced owing to exacerbation of hand-foot syndrome, but the epiphora persisted. Capecitabine was discontinued 287 days after initiation owing to exacerbation of the hand-foot syndrome. However, because the epiphora persisted, the patient visited the ophthalmology department. The ophthalmologist diagnosed the patient with binocular nasolacrimal duct obstruction and cataract, and prescribed a 0.3% gatifloxacin ophthalmic solution and 0.1% fluorometholone ophthalmic suspension. Thereafter, the epiphora reduced. When the patient returned to the ophthalmology department, symptom improvement was confirmed. In this case, lacrimal duct obstruction likely developed due to capecitabine. The symptoms were reversible with discontinuation of capecitabine and ophthalmic treatment. We believe that reporting this case could be valuable in discussing capecitabine-induced lacrimal duct obstruction.

[Survey of the current status of capecitabine-induced hypertriglyceridemia].

We encountered cases of capecitabine-induced increase in blood triglyceride (TG) levels, which is relatively rare in routine medical practice. Although capecitabine-induced hypertriglyceridemia (CI-HTG) has been occasionally reported in other countries, such cases have not been reported in Japan. Therefore, the details of this condition remain to be clarified. To obtain evidence that would be useful in routine medical practice, we conducted a retrospective study of patients with CI-HTG. The study included 56 patients, of whom, 14 (25.0%) had TG levels < 150 mg/dL before capecitabine treatment that increased to ≥ 150 mg/dL after treatment. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, v4.0, Japanese edition, Japan Clinical Oncology Group version (CTCAE v4.0-JCOG). We found that TG levels were markedly elevated (≥ Grade 3) in 2 patients (3.6%). Thus, CI-HTG also affects Japanese patients, although its frequency is relatively low. Detailed studies including a larger number of facilities should be conducted in future.

[A case of hepatitis B virus reactivation in a patient with prior resolved hepatitis B infection during bevacizumab plus FOLFIRI treatment].

Hepatitis Bvirus (HBV)reactivation induced by cancer chemotherapy is increasingly being observed. However, most reports of resolved HBV[hepatitis Bsurface antigen(HBs-Ag)negative and hepatitis Bsurface antibody(HBs-Ab)positive and/or hepatitis Bcore antibody(HBc-Ab)positive]infection involve patients with hematological malignancies, whereas few describe patients with solid cancers. In this study, we report our experience with a patient with resolved HBV infection who was undergoing bevacizumab plus FOLFIRI treatment for rectal cancer when HBV reactivation was noted. This 74-year-old man was HBs-Ag negative, HBs-Ab negative, HBcAb positive, hepatitis B e antigen(HBe-Ag)negative, and hepatitis Be antibody(HBe-Ab)negative and had HBV-DNA levels below the detection limit. Forty-two days after the 21st cycle of bevacizumab plus FOLFIRI treatment, his aspartate aminotransferase and alanine aminotransferase levels increased. At followup examination, he was HBs-Ag positive, HBs-Ab negative, HBc-Ab positive, HBe-Ag positive, and HBe-Ab positive, while his HBV-DNA levels had increased to>9.0 log copies/mL, confirming HBV reactivation. His treatment included entecavir(0.5mg/ day)administration and plasmapheresis, but he succumbed to liver failure 82 days after his final dose of bevacizumab plus FOLFIRI. Thus, HBV reactivation can occur during bevacizumab plus FOLFIRI treatment in rectal cancer patients with a resolved prior HBV infection. No similar report has been published to date, and we believe that this study will be important when discussing HBV reactivation in patients with resolved HBV infection. Future studies will require detailed investigations in a larger number of institutions.

[Survey of current status of adverse ocular reactions to paclitaxel and a retrospective analysis for aiding in early detection of adverse reactions].

We have observed several cases of adverse reactions to paclitaxel, including visual impairment and lacrimation. Therefore, we conducted a survey of the current status of adverse reactions to paclitaxel and also performed a retrospective analysis of the initial symptoms and the times of their appearance. Of the 22 study patients, 8(36. 4%)presented with adverse ocular reactions, such as visual impairment and lacrimation, and for 3(13. 6%), an ophthalmologist confirmed that paclitaxel could not be ruled out as the direct cause of their adverse reactions. The group of patients who presented with adverse ocular reactions included significantly more patients with ocular complications and a previous history of ocular ailments, compared to the group showing no such reactions. The timing of reaction appearance did not show a consistent pattern. The results of this study suggest that the initial symptoms were mainly visual impairment and lacrimation, and that caution must be taken when administering paclitaxel to patients with a previous history of ocular ailments and ocular complications because of the risk of adverse ocular reactions. Thus, adverse ocular reactions to paclitaxel were indicated as a possible risk, in addition to other adverse events such as myelosuppression and peripheral neuropathy.

Astrocytes protect neurons against methylmercury via ATP/P2Y(1) receptor-mediated pathways in astrocytes.

Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y1 receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y1 receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y1 receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y1 receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.

Morphology and physical-chemical properties of baked nanoporous frustules.

We investigated the morphology and physical-chemical properties of baked and unbaked nanoporous frustules. Scanning electron microscopy (SEM) observations showed that the nanoporous structures of frustules unchanged at 400 degrees C even after baking for 6 h. During baking at 800 degrees C, the frustule structures changed dramatically. On the other hand, Fourier transform infrared spectroscopy (FTIR) of bulk frustule samples indicated that physical-chemical properties of the frustules had clearly changed after baking at not only 800 degrees C but also 400 degrees C. These results showed that the reconstruction of the structures had occurred inside the frustules, even though the morphology of the frustules had not apparently changed at 400 degrees C. In order to characterize the exact shape of the frustules, living diatom cells were grown on a functionalized mica surface, and then baked without any chemical treatment for SEM study. This 'direct baking' technique is effective for comparing minute structures of the frustules, because completed combination of every part of the frustules can be observed.