Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

Characterization of perivascular alveolar epithelial stem cells and their niche in lung homeostasis and cancer.

Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44high subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44high cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1+ endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44high AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44high AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44high AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.

Initial spinal epidural hematoma symptoms mimic artery dissection.

An elderly patient with upper back pain and hypertension was diagnosed as having spontaneous spinal epidural hematoma (SSEH) after excluding artery dissection. The initial symptoms of SSEH mimic those of artery dissection, and the symptoms of spinal damage frequently appear later. Physicians should, therefore, be mindful of SSEH.

Concurrent bacterial liver abscess and mild encephalitis/encephalopathy with reversible splenial lesion in a patient with poorly controlled type 2 diabetes.

A 34-year-old man with poorly controlled type 2 diabetes was admitted to our hospital because of fever, headache, vomiting, and impaired consciousness. His hemoglobin A1c level was as high as 11.0%. Abdominal computed tomography revealed a bacterial liver abscess, while head magnetic resonance imaging simultaneously showed a high-signal lesion on diffusion-weighted imaging and a low-signal lesion on the apparent diffusion coefficient map of the splenium of the corpus callosum. No significant findings were detected in the cerebrospinal fluid. The latter findings led to a diagnosis of mild encephalitis/encephalopathy with reversible splenial lesions. His impaired consciousness resolved on Day 5 after treatment with ceftriaxone and metronidazole infusion and intensive insulin therapy; magnetic resonance imaging on Day 20 showed that the lesion in the splenium of the corpus callosum had disappeared. We propose that when a person with poorly controlled diabetes develops a bacterial infection and presents with impaired consciousness and headache, clinicians should consider the complications of mild encephalitis/encephalopathy with reversible splenial lesion.

MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.

Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.

Psychological burden predicts new-onset diabetes in men: A longitudinal observational study in the Fukushima Health Management Survey after the Great East Japan earthquake.

Background: The burden of psychological distress and post-traumatic stress disorder (PTSD) has been suggested as a factor in developing type 2 diabetes mellitus. However, longitudinal features in psychological distress- and PTSD-related new-onset diabetes mellitus have not been thoroughly evaluated. Methods: The association between probable depression and probable PTSD and the risk of developing new-onset diabetes mellitus was evaluated in a 7-year prospective cohort of evacuees of the Great East Japan Earthquake in 2011. Probable depression was defined as a Kessler 6 scale (K6) ≥ 13 and probable PTSD as a PTSD Checklist-Stressor-Specific Version (PCL-S) ≥ 44. Results: The log-rank test for the Kaplan-Meier curve for new-onset diabetes mellitus was significant between K6 ≥ 13 vs. < 13 and PCL-S ≥ 44 vs. < 44 in men but not in women. In men, both K6 ≥ 13 and PCL-S ≥ 44 remained significant in the Cox proportional hazards model after multivariate adjustment for established risk factors and disaster-related factors, including evacuation, change in work situation, sleep dissatisfaction, and education. Conclusion: The post-disaster psychological burden of probable depression and probable PTSD was related to new-onset diabetes in men but not in women. In post-disaster circumstances, prevention strategies for new-onset diabetes might consider sex differences in terms of psychological burden.

Dietary Patterns and New-Onset Type 2 Diabetes Mellitus in Evacuees after the Great East Japan Earthquake: A 7-Year Longitudinal Analysis in the Fukushima Health Management Survey.

Background: Dietary patterns may be linked to the incidence of type 2 diabetes mellitus (T2DM) after disasters. We investigated the association between dietary patterns and new-onset T2DM in evacuees of the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. Methods: Among the 22,740 non-diabetic participants aged 20-89 years who completed the dietary assessment in the Fukushima Health Management Survey between July 2011 and November 2012, the incidence of T2DM was evaluated until 2018. Principal component analysis with varimax rotation was applied to derive dietary patterns based on a validated, short-form food frequency questionnaire. The identified dietary patterns were categorized as typical Japanese, juice, and meat. Results: The cumulative incidence of T2DM was 18.0 and 9.8 per 1000 person-years in men and women, respectively, during the follow-up period. The multiple-adjusted hazard ratio (95% confidence interval) of the highest vs. lowest quartile of the typical Japanese pattern scores for T2DM was 0.80 (0.68, 0.94; P for trend = 0.015) in total, 0.85 (0.68, 1.06; P for trend = 0.181) in men, and 0.76 (0.60, 0.95; P for trend = 0.04) in women. Conclusions: A typical Japanese dietary pattern may be associated with a reduced new-onset T2DM risk in evacuees, especially women, after the Great East Japan Earthquake and the FDNPP accident.

Detecting Sarcopenia Risk by Diabetes Clustering: A Japanese Prospective Cohort Study.

CONTEXT: Previous studies have assessed the usefulness of data-driven clustering for predicting complications in patients with diabetes mellitus. However, whether the diabetes clustering is useful in predicting sarcopenia remains unclear. OBJECTIVE: To evaluate the predictive power of diabetes clustering for the incidence of sarcopenia in a prospective Japanese cohort. DESIGN: Three-year prospective cohort study. SETTING AND PATIENTS: We recruited Japanese patients with type 1 or type 2 diabetes mellitus (n = 659) between January 2018 and February 2020 from the Fukushima Diabetes, Endocrinology, and Metabolism cohort. INTERVENTIONS: Kaplan-Meier and Cox proportional hazards models were used to measure the predictive values of the conventional and clustering-based classification of diabetes mellitus for the onset of sarcopenia. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia (AWGS) 2019 consensus update. MAIN OUTCOME MEASURES: Onset of sarcopenia. RESULTS: Cluster analysis of a Japanese population revealed 5 diabetes clusters: cluster 1 [severe autoimmune diabetes (SAID)], cluster 2 [severe insulin-deficient diabetes (SIDD)], cluster 3 (severe insulin-resistant diabetes, cluster 4 (mild obesity-related diabetes), and cluster 5 (mild age-related diabetes). At baseline, 38 (6.5%) patients met the AWGS sarcopenia criteria, and 55 had newly developed sarcopenia within 3 years. The SAID and SIDD clusters were at high risk of developing sarcopenia after correction for known risk factors. CONCLUSIONS: This study reveals that among the 5 diabetes clusters, the SAID and SIDD clusters are at a high risk for developing sarcopenia. Clustering-based stratification may be beneficial for predicting and preventing sarcopenia in patients with diabetes.

Maternal Urinary Cotinine Concentrations During Pregnancy Predict Infant BMI Trajectory After Birth: Analysis of 89617 Mother-Infant Pairs in the Japan Environment and Children's Study.

Background: Clinical or epidemiological conclusions remain undecided on the direct effects of active and second-hand smoking during pregnancy on childhood obesity. Urinary cotinine (UC) concentration, an accurate and quantitative marker for smoking, may elucidate the dose-dependent relationship between smoking during pregnancy and childhood obesity. To analyze the relationship between UC concentration and smoking questionnaire (SQ) classes for active and second-hand smoking in pregnant mothers and trajectory of infant Kaup index (body mass index: BMI). Methods: This multicenter prospective cohort study was conducted using a list-wise complete set of 35829 among 89617 mother-infant singleton pairs, recruited between 2011 and 2014, in the Japan Environment and Children's Study (JECS). Pairs were categorized according to UC levels (1 to 4 classes) or SQ (0 to 4 classes). Results: Maternal BMI at delivery was the highest in UC class 4 (highest). Maternal and paternal education of ≥16 years and annual household income were lowest in UC class 4. Infant BMI was lower at birth, but trends in BMI and ΔBMI were higher from six to 36 months step-wise in the UC classes. The above tendency was observed in the list-wise complete dataset but was emphasized after multiple imputations and corrections of cofounders. UC concentration in five SQ classes largely fluctuated, and the relationship between SQ classes and trends in BMI and ΔBMI was not statistically significant. Conclusion: Infants from high UC mothers had a low BMI at birth, increasing from six to 36 months of age. UC concentrations, but not smoking questionnaire classes, predict infant BMI trajectory, suggesting that active and second-hand smoking affect child obesity in a dose-dependent manner.

Terminal differentiation of keratinocytes was damaged in type 2 diabetic mice.

AIMS: Although skin manifestations are common in diabetic patients, its characteristics are poorly identified. This study explored the differentiation process of keratinocytes in type 2 diabetes mellitus (T2DM) in vivo. METHODS: Back skin of T2DM model KKAy/TaJcl mice (KKAy) and C57BL/6JJcl mice (control) aged 8 and 12 weeks was used. The mRNA expression of differentiation markers of keratinocytes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of each marker in situ was examined immunohistochemically. RESULTS: KKAy mice showed hyperglycemia versus control mice. The histological findings showed increased thickness and structural impairment of epidermal tissue in KKAy mice. The qRT-PCR revealed that the expression of integrin beta 1 and keratin 14 in KKAy and control mice was identical. However, the expression of involucrin at 8 weeks, keratin 10 at 12 weeks, and filaggrin and loricrin at 8 and 12 weeks was decreased in KKAy mice. Immunohistochemical findings showed that filaggrin was markedly decreased in KKAy mice, though Ki-67 remained unchanged. CONCLUSION: The terminal differentiation process was impaired in the diabetic skin, while keratinocyte proliferation was preserved. Damaged terminal differentiation of keratinocytes may contribute to impairment of the skin barrier function in diabetic dermatoses.

The sodium/glucose cotransporters as potential therapeutic targets for CF lung diseases revealed by human lung organoid swelling assay.

Cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the present work, we derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying disease-causing CFTR mutations. We evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner. Using this assay, we examined the effects of the sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and sotagliflozin on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts. Unexpectedly, both drugs promoted dF/dF HLO swelling. These results reveal SGLTs, especially SGLT1, as potential therapeutic targets for treating CF lung diseases and demonstrate the use of PSC-derived HLOs as a preclinical tool in CF drug development.

Distribution of flagellin CD2-1, flg22, and flgII-28 recognition systems in plant species and regulation of plant immune responses through these recognition systems.

The first layer of active plant immunity relies upon the recognition of pathogen-associated molecular patterns (PAMPs), and the induction of PTI. Flagellin is the major protein component of the bacterial flagellum. Flagellin-derived peptide fragments such as CD2-1, flg22, and flgII-28 function as PAMPs in most higher plants. To determine the distribution of CD2-1, flg22, and flgII-28 recognition systems within plant species, the inducibility of PTI by CD2-1, flg22, and flgII-28 in 8 plant species, including monocotyledonous and dicotyledonous plants, was investigated. CD2-1 caused PTI responses in Oryza sativa, Brachypodium distachyon, and Asparagus persicus; flg22 caused PTI responses in Phyllostachys nigra, A. persicus, Arabidopsis thaliana, Nicotiana tabacum, Solanum lycopersicum, and Lotus japonicus; and flgII-28 caused PTI responses only in S. lycopersicum. Furthermore, quantitative analysis of FLS2 receptor revealed that the responsiveness of flg22 in plants was dependent on the expression level of the receptor.

Influence of Maternal Active and Secondhand Smoking during Pregnancy on Childhood Obesity at 3 Years of Age: A Nested Case-Control Study from the Japan Environment and Children's Study (JECS).

Maternal smoking during pregnancy is a risk factor for childhood obesity; however, the combined effect of secondhand smoking during pregnancy on children in the early years is unclear. We examined the effects of maternal active and secondhand smoking during pregnancy on childhood obesity in a large population-based cohort. A nested case-control study originating from the Japan Environment and Children's Study was performed. The maternal smoking status was collected via self-administered questionnaires during mid/late pregnancy. Obesity in children was determined based on BMI measured at 3 years of age. In total, 4875 cases and 19,491 controls were included in the analyses. Conditional logistic regression models with a significance level of 5% (two-tailed test) were used to test the association. The proportion of mothers who continued smoking and who were exposed to secondhand smoking daily during pregnancy were 3.9% and 13.0% in cases and 2.9% and 10.8% in controls, respectively. Continuous maternal smoking was associated with increased odds of obesity compared to those who never smoked or quit smoking before the pregnancy (adjusted odds ratio, 1.39; 95% confidence interval, 1.01-1.92). The odds increased further when combined with secondhand smoking. The promotion of non-smoking among family members, in public and workplace could benefit pregnant women and offspring.

Lanreotide and diazoxide have comparable effects on glucose levels in an elderly Japanese insulinoma patient: a case report.

An insulinoma is a pancreatic neuroendocrine tumor that causes hypoglycemia. In the elderly, as surgery is not always possible, drugs are an important alternative. However, the effects of lanreotide on insulinomas have not yet been elucidated. We report the case of an 85-year-old Japanese woman who was admitted for loss of consciousness and hypoglycemia, which was resolved after intravenous glucose infusion. Insulin secretion was not inhibited during hypoglycemia. Enhanced computed tomography and OctreoScan scintigraphy revealed a pancreatic tumor (diameter, 13 mm) with radiotracer accumulation. Thus, clinical insulinoma was confirmed. However, the patient refused further examination and surgery. Diazoxide (150 mg/day) therapy resolved hypoglycemia but caused fluid retention. Consequently, we switched to lanreotide (120 mg/6 weeks). Continuous glucose monitoring revealed that both drugs had comparable effects on interstitial glucose normalization. Furthermore, 447 days after the initiation of lanreotide treatment, the patient had no hypoglycemic symptoms. Therefore, lanreotide may be a useful alternative treatment option for inoperable insulinomas in elderly individuals.

Suboptimal diabetic control and psychological burden after the triple disaster in Japan: the Fukushima Health Management Survey.

INTRODUCTION: A triple disaster struck eastern Japan in March 2011. We investigated the psychological distress and post-traumatic stress disorder (PTSD) symptoms caused by the disaster in people without or with diabetes mellitus. RESEARCH DESIGN AND METHODS: This cross-sectional analysis examined the 16 097 evacuees (1820 (11.3%) with and 14 277 (88.7%) without diabetes mellitus) included in the Fukushima Health Management Survey. Non-specific mental health distress was assessed using the Kessler-6 Scale, and traumatic symptoms were evaluated using the PTSD Checklist. Logistic regression analyses were used to estimate the OR and 95% CI associated with symptoms, adjusted for diabetes-related and disaster-related factors. RESULTS: In the age-adjusted and sex-adjusted logistic models, suboptimal diabetic control (hemoglobin A1c (HbA1c) ≥7%) was associated with both psychological distress and possible PTSD. In the same models, current smoking, evacuation, and sleep dissatisfaction were associated with psychological distress and possible PTSD. In the multivariate-adjusted logistic models, HbA1c ≥7% was associated with psychological distress, independent of job change, evacuation, or sleep dissatisfaction. CONCLUSION: After the triple disaster, non-specific mental health distress was associated with suboptimal diabetic control. Thus, patients with diabetes, especially those with suboptimal diabetic control, may be vulnerable to postdisaster psychological burden.

Novel Effector RHIFs Identified From Acidovorax avenae Strains N1141 and K1 Play Different Roles in Host and Non-host Plants.

Plant pathogenic bacteria inject effectors into plant cells using type III secretion systems (T3SS) to evade plant immune systems and facilitate infection. In contrast, plants have evolved defense systems called effector-triggered immunity (ETI) that can detect such effectors during co-evolution with pathogens. The rice-avirulent strain N1141 of the bacterial pathogen Acidovorax avenae causes rice ETI, including hypersensitive response (HR) cell death in a T3SS-dependent manner, suggesting that strain N1141 expresses an ETI-inducing effector. By screening 6,200 transposon-tagged N1141 mutants based on their ability to induce HR cell death, we identified 17 mutants lacking this ability. Sequence analysis and T3SS-mediated intracellular transport showed that a protein called rice HR cell death inducing factor (RHIF) is a candidate effector protein that causes HR cell death in rice. RHIF-disrupted N1141 lacks the ability to induce HR cell death, whereas RHIF expression in this mutant complemented this ability. In contrast, RHIF from rice-virulent strain K1 functions as an ETI inducer in the non-host plant finger millet. Furthermore, inoculation of rice and finger millet with either RHIF-deficient N1141 or K1 strains showed that a deficiency of RHIF genes in both strains results in decreased infectivity toward each the host plants. Collectively, novel effector RHIFs identified from A. avenae strains N1141 and K1 function in establishing infection in host plants and in ETI induction in non-host plants.

Molecular Basis for the Activation of Human Innate Immune Response by the Flagellin Derived from Plant-Pathogenic Bacterium, Acidovorax avenae.

Acidovorax avenae is a flagellated, pathogenic bacterium to various plant crops that has also been found in human patients with haematological malignancy, fever, and sepsis; however, the exact mechanism for infection in humans is not known. We hypothesized that the human innate immune system could be responsive to the purified flagellin isolated from A. avenae, named FLA-AA. We observed the secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-8 by treating FLA-AA to human dermal fibroblasts, as well as macrophages. This response was exclusively through TLR5, which was confirmed by using TLR5-overexpression cell line, 293/hTLR5, as well as TLR5-specific inhibitor, TH1020. We also observed the secretion of inflammatory cytokine, IL-1ß, by the activation of NLRC4 with FLA-AA. Overall, our results provide a molecular basis for the inflammatory response caused by FLA-AA in cell-based assays.

AKSF1 Isolated From the Rice-Virulent Strain Acidovorax avenae K1 Is a Novel Effector That Suppresses PAMP-Triggered Immunity in Rice.

Microbial pathogens deliver effectors into plant cells to suppress plant immune responses and modulate host metabolism in order to support infection processes. We sought to determine if the Acidovorax avenae rice-virulent K1 strain can suppress pathogen-associated molecular pattern-triggered immunity (PTI) induced by flagellin isolated from the rice-avirulent N1141 strain. The flagellin-triggered PTI, including H2O2 generation, callose deposition, and expression of several immune-related genes were strongly suppressed in K1 preinoculated cultured rice cells in a type III secretion system (T3SS)-dependent manner. By screening 4,562 transposon-tagged mutants based on their suppression ability, we found that 156 transposon-tagged K1 mutants lost the ability to suppress PTI induction. Mutant sequence analysis, comprehensive expression analysis using RNA sequencing, and the prediction of secretion through T3SS showed that a protein named A. avenae K1 suppression factor 1 (AKSF1) suppresses flagellin-triggered PTI in rice. Translocation of AKSF1 protein into rice cells is dependent on the T3SS during infection, an AKSF1-disruption mutant lost the ability to suppress PTI responses, and expression of AKSF1 in the AKSF1-disruption mutant complemented the suppression activity. When AKSF1-disruption mutants were inoculated into the host rice plant, reduction of the disease symptoms and suppression of bacterial growth were observed. Taken together, our results demonstrate that AKSF1 is a novel effector that can suppress the PTI in a host rice plant.[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021.

Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice.

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.