HLA typing of patients who developed subacute thyroiditis and Graves' disease after SARS-CoV-2 vaccination: a case report.

BACKGROUND: Cases of subacute thyroiditis (SAT) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination have been reported. A human leukocyte antigen (HLA) allele, HLA-B*35, appears to be involved in the pathogenesis of SAT. CASE PRESENTATION: We conducted HLA typing of one patient with SAT and another with both SAT and Graves' disease (GD), which developed after SARS-CoV-2 vaccination. Patient 1, a 58-year-old Japanese man, was inoculated with a SARS-CoV-2 vaccine (BNT162b2; Pfizer, New York, NY, USA). He developed fever (38 °C), cervical pain, palpitations, and fatigue on day 10 after vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum C-reactive protein (CRP) and slightly increased serum antithyroid-stimulating antibody (TSAb) levels. Thyroid ultrasonography revealed the characteristic findings of SAT. Patient 2, a 36-year-old Japanese woman, was inoculated twice with a SARS-CoV-2 vaccine (mRNA-1273; Moderna, Cambridge, MA, USA). She developed fever (37.8 °C) and thyroid gland pain on day 3 after the second vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum CRP, TSAb, and antithyroid-stimulating hormone receptor antibody levels. Fever and thyroid gland pain persisted. Thyroid ultrasonography revealed the characteristic findings of SAT (i.e., slight swelling and a focal hypoechoic area with decreased blood flow). Prednisolone treatment was effective for SAT. However, thyrotoxicosis causing palpitations relapsed thereafter, for which thyroid scintigraphy with 99mtechnetium pertechnetate was conducted, and the patient was diagnosed with GD. Thiamazole treatment was then initiated, which led to improvement in symptoms. CONCLUSION: HLA typing revealed that both patients had the HLA-B*35:01, -C*04:01, and -DPB1*05:01 alleles. Only patient 2 had the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles. The HLA-B*35:01 and HLA-C*04:01 alleles appeared to be involved in the pathogenesis of SAT after SARS-CoV-2 vaccination, and the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles were speculated to be involved in the postvaccination pathogenesis of GD.

Simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death-1 therapy: A case report.

We present the first case of simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death 1 therapy. A 48-year-old man with parotid gland adenocarcinoma and lung metastasis had received five courses of nivolumab. Fourteen days after administration of the sixth course, his casual plasma glucose and hemoglobin A1c levels were 379 mg/dL and 7.2%, respectively. Furthermore, thyrotoxicosis was detected with a blood test. Serum total ketone body and thyroid-stimulating hormone receptor antibody levels increased, and serum C-peptide level decreased to 0.01 ng/mL thereafter. Thus, we concluded that he simultaneously developed anti-programmed cell death 1 therapy-associated type 1 diabetes and Graves' disease. Among Japanese patients with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen-DRB1*04:05 is higher in those with both type 1 diabetes and Graves' disease. Our case had human leukocyte antigen-DRB1*04:05, which might be associated with the simultaneous development of the two diseases.

Small RNAs detected in exosomes derived from the MH7A synovial fibroblast cell line with TNF-α stimulation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes the chronic inflammation of the joints. Intercellular communication containing synovial fibroblasts seems to play a major role in RA pathogenesis. In this study, to better understand intercellular communication related to RA pathogenesis, we identified exosomal microRNAs (miRNAs) derived from synovial fibroblasts. Exosomes were collected from an RA synovial fibroblast (RASF) cell line, namely, MH7A, with or without stimulation by tumor necrosis factor alpha (TNF-α). We used small RNA sequencing to analyze the profile of small RNAs, including miRNAs, in MH7A exosomes and cells. By using differential expression analysis, we identified four miRNAs (miR-155-5p, miR-146a-5p, miR-323a-5p, and miR-1307-3p) that are upregulated in exosomes with TNF-α stimulation. The identification of miR-155-5p and miR-146a-5p which have been reported in RA patients demonstrated the validity of our experimental model. Other two miRNAs were newly identified. miR-323a-5p was predicted to target the protein encoding gene CD6, which attenuates T-cell activation signals, and miR-1307-3p was predicted to target the protein encoding gene N-myc downstream-regulated gene 2 (NDRG2), which inhibits osteoclast-related gene expression. The results suggested that these miRNAs might be involved in RA pathogenesis. We hope our results will help us understand the role of RASF exosomes in RA pathogenesis.

Retrospective evaluation of the clinical characteristics associated with Corynebacterium species bacteremia

ABSTRACT Objectives: Corynebacterium spp. are becoming recognized as pathogens that potentially cause various infections. We aimed to evaluate the clinical characteristics associated with Corynebacterium spp. bacteremia. Patients and methods: We retrospectively reviewed the medical records of all adult patients who had positive blood cultures for Corynebacterium spp. in a single university hospital between January 2014 and December 2016. Patients were divided into a bacteremia group and a contamination group based on microbiological test results and clinical characteristics. Patients' characteristics, antimicrobial susceptibility of isolated species, antimicrobials administered, and patient outcomes were evaluated. Results: Corynebacterium spp. were isolated from blood samples of 63 patients; Corynebacterium striatum was the predominant isolate. Twenty-eight patients were determined to have bacteremia. Younger age (p = 0.023), shorter time to positivity (p = 0.006), longer hospital stay (p = 0.009), and presence of an indwelling vascular catheter (p = 0.002) were observed more often in the bacteremia group compared to the contamination group. The source of infection in most patients with bacteremia was an intravenous catheter. All tested strains were susceptible to vancomycin. Four of the 27 patients with bacteremia died, despite administration of appropriate antimicrobial therapy. Conclusions: We found that younger age, shorter time to positivity, and presence of an indwelling catheter were related to bacteremia caused by Corynebacterium spp. Appropriate antimicrobials should be administered once Corynebacterium spp. are isolated from the blood and bacteremia is suspected.

Plasma C1q/TNF-related protein 9: a promising biomarker for diabetic renal vascular injury.

BACKGROUND: Adipocytokines are associated with the pathophysiology of type 2 diabetes (T2DM). METHODS: We analyzed the relationship between levels of the plasma C1q/tumor necrosis factor-related protein 9 (CTRP9) and other adipocytokines or the endothelial function in patients with T2DM, and analyzed their trending manner. RESULTS: CTRP9 was detected in plasma from 14 out of a total of 28 patients. The values were not normally distributed. In comparing between groups in which CTRP9 was or was not detected, there were statistically significant differences in the high molecular weight adiponectin (HAN) and the urinary albumin/creatinine ratio (ACR). This indicates that both CTRP9 and HAN reflect the pathophysiology of renal involvement in T2DM. HAN correlated with Body Mass Index, ACR, and homeostasis model assessment of insulin resistance. However, CTRP9 did not correlate with HAN or any other parameters. CONCLUSIONS: CTRP9 independently trends in a different manner from HAN, and may reflect diabetic renal vascular risk in association with atherosclerosis and abnormal glucose metabolism besides of impaired vaso-relaxation in patients with T2DM.

Reconstruction of thermotolerant yeast by one-point mutation identified through whole-genome analyses of adaptively-evolved strains.

Saccharomyces cerevisiae is used as a host strain in bioproduction, because of its rapid growth, ease of genetic manipulation, and high reducing capacity. However, the heat produced during the fermentation processes inhibits the biological activities and growth of the yeast cells. We performed whole-genome sequencing of 19 intermediate strains previously obtained during adaptation experiments under heat stress; 49 mutations were found in the adaptation steps. Phylogenetic tree revealed at least five events in which these strains had acquired mutations in the CDC25 gene. Reconstructed CDC25 point mutants based on a parental strain had acquired thermotolerance without any growth defects. These mutations led to the downregulation of the cAMP-dependent protein kinase (PKA) signaling pathway, which controls a variety of processes such as cell-cycle progression and stress tolerance. The one-point mutations in CDC25 were involved in the global transcriptional regulation through the cAMP/PKA pathway. Additionally, the mutations enabled efficient ethanol fermentation at 39 °C, suggesting that the one-point mutations in CDC25 may contribute to bioproduction.

Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the α-galactosidase A Gene.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

Fabry disease: biochemical, pathological and structural studies of the α-galactosidase A with E66Q amino acid substitution.

Recently, male subjects harboring the c.196G>C nucleotide change which leads to the E66Q enzyme having low α-galactosidase A (GLA) activity have been identified at an unexpectedly high frequency on Japanese and Korean screening for Fabry disease involving dry blood spots and plasma/serum samples. Individuals with the E66Q enzyme have been suspected to have the later-onset Fabry disease phenotype leading to renal and cardiac disease. However, there has been no convincing evidence for this. To determine whether c.196G>C (E66Q) is disease-causing or not, we performed biochemical, pathological and structural studies. It was predicted that the E66Q amino acid substitution causes a small conformational change on the molecular surface of GLA, which leads to instability of the enzyme protein. However, biochemical studies revealed that subjects harboring the E66Q enzyme exhibited relatively high residual enzyme activity in white blood cells, and that there was no accumulation of globotriaosylceramide in cultured fibroblasts or an increased level of plasma globotriaosylsphingosine in these subjects. An electron microscopic examination did not reveal any pathological changes specific to Fabry disease in biopsied skin tissues from a male subject with the E66Q enzyme. These results strongly suggest that the c.196G>C is not a pathogenic mutation but is a functional polymorphism.

Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

TGF-beta1 and CTGF mRNAs are correlated with urinary protein level in IgA nephropathy.

The degree of tubulointerstitial fibrosis is a poor prognostic indicator in IgA nephropathy (IgAN). Recently, connective tissue growth factor (CTGF) was observed to be strongly up-regulated in human proliferative and fibrogenic diseases. Renal biopsy specimens were obtained from the 20 patients with IgAN. Based on a previously reported study (MDRD study), all cases were categorized into 2 groups. Group A included patients with urinary protein (u-protein) <1.0 g/day, and group B, those with u-protein > or =1.0 g/day. Expressions of transforming growth factor beta1 (TGF-beta1) and CTGF mRNAs in tubular epithelial cells (TECs) were examined in all cases using rapid in situ hybridization (rISH). Significantly strong and diffuse expressions of TGF-beta1 and CTGF mRNAs were observed in proximal TECs in group B, while the expressions of these 2 mRNAs were weak in proximal TECs in group A and in glomerular resident cells in both groups. These results closely correlated with the degree of disorder in conventional pathohistological findings and clinical parameters except for u-protein level. The increase of u-protein level is one of the most important factors influencing the expression of TGF-beta1 and CTGF mRNAs in TECs. Therefore, the authors conclude that both u-protein level and expressions of these 2 mRNAs in TECs were significantly correlated with the degree of tubulointerstitial damage in IgAN.

[Evaluation of urinary factor H excretion in patients with idiopathic membranous nephropathy].

BACKGROUND: The complement system plays an important role in renal pathogenesis, and C5b-9, a terminal complement complex, is regarded as the principal mediator of proteinuria in idiopathic membranous nephropathy(MN). Since factor H regulates complement activation at the C3 step and is a crucial factor in complement-mediated tissue injury, the urinary excretion of factor H in patients with idiopathic MN was investigated. METHODS: Seven patients with biopsy-proven idiopathic MN were studied for twenty-four weeks. Urinary factor H levels were measured by ELISA from regularly collected urine samples, and then evaluated and compared with assays of urinary protein and C5b-9 excretion. RESULTS: During the study, five patients were treated with steroid therapy. All seven patients maintained stable renal function and showed a decline in urinary protein excretion. The mean level of urinary factor H was markedly elevated (156.1 +/- 47.1 U/mg U-Cr) before treatment (0 week), and gradually declined to 127.2 +/- 43.5 U/mg U-Cr at 12 weeks, and to 64.7 +/- 26.9 U/mg U-Cr) at 24 weeks. This followed decreases in urinary protein and urinary C5b-9 excretion. Percent change in urinary factor H level significantly decreased 24 weeks after treatment without affecting the plasma factor H level. CONCLUSION: These results suggest that factor H contributes to the regulatory mechanism of in situ complement activation, and thus the study of urinary factor H levels, as well as urinary C5b-9, may be significant in idiopathic MN.

Stevens-Johnson syndrome induced by mizoribine in a patient with systemic lupus erythematosus.

A 32-year-old Japanese woman, who had a treatment history of systemic lupus erythematosus (SLE) with lupus nephritis World Health Organization class IV for 11 months, visited our hospital due to fever, facial erythema, and erosion of the oral cavity on November 10, 2003. Her mucosal erosion and facial skin erythema progressed over the following week, and Stevens-Johnson syndrome was diagnosed due to pathological findings of the skin. Among the administrated drugs, only mizoribine, started 6 months earlier, produced a positive reaction in the drug lymphocyte stimulation test. Increased prednisolone and high dose intravenous gamma-globulin were given successfully. Cyclosporine at 50 mg was administered to control the SLE, followed by an increase to 100 mg on January 7, 2004. She suffered from abdominal pain, blindness, and convulsion on January 9. The magnetic resonance image of her brain prompted a diagnosis of reversible posterior leukoencephalopathy syndrome. After withdrawal of cyclosporine and control of hypertension, symptoms disappeared rapidly. Cyclophosphamide pulse therapy was successfully administrated to control lupus nephritis. This is the first report describing the relationship between Stevens-Johnson syndrome and mizoribine. Although the use of mizoribine is thought to be safe, careful observation is necessary.