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.

Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9-23-related peptides in subtypes of type 1 diabetes.

Type 1 diabetes is largely caused by ß-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9-23-related peptides (B:9-23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9-23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9-23rPep-specific IFN-γ immunoreactivity reflects decreased functional ß-cell mass and greater disease activity of type 1 diabetes.

Impact of interventions by an antimicrobial stewardship program team on appropriate antimicrobial therapy in patients with bacteremic urinary tract infection.

BACKGROUND: Inappropriate antimicrobial therapy often leads to poor outcomes. This study aimed to evaluate the impact of an antimicrobial stewardship program (ASP) team on appropriate therapy, in patients with bacteremic urinary tract infection (UTI). PATIENTS AND METHODS: We retrospectively reviewed the interventions by the ASP team in 807 patients with bacteremic UTI. Interventions were divided into 3 groups: group A (conventional report), group B (conventional report and written alert on the chart), and group C (conventional report and oral recommendation with/without written alert). The appropriateness of antimicrobial therapy was assessed at 2 time points, based on blood culture results. RESULTS: The ASP team estimated that 166 and 576 patients received inappropriate antimicrobial therapy based on the results of Gram staining, and final report, respectively. Appropriate therapy after intervention was administered to 53.2% of group A, 63.5% of group B, and 89.3% of group C patients, respectively. Mortality was significantly lower in patients of de-escalation than in those with no antimicrobial changes, without prolonged hospital stay. CONCLUSION: This study provides one plausible benchmark for appropriate antimicrobial therapy by ASP, while observer bias and survivor treatment selection bias exist, and further studies including evaluation for severity are needed.

[Association of blood pressure control effects on renal impairment with urinary protein: a study on the validity of the Japanese Society of Hypertension Guidelines for Management of Hypertension 2014].

BACKGROUND AND OBJECTIVE: Progression of chronic kidney disease (CKD) leads to the onset of cardiovascular dis- eases and an increase in the number of patients requiring dialysis initiation. In prder to promote the early detection and treatment of CKD, we assessed the effects of blood pressure control on renal impairment based on common test items and verified the usefulness of the target blood pressure for patients with CKD described in the Japanese Society of Hypertension Guidelines for the Management of Hypertension in 2014 (JSH 2014). SUBJECTS AND METHODS: Among patients who had been regularly visiting the outpatient clinic of Kasukabe Kisen Hospital for 24 months or more, 67 with a serum creatinine level of 1.2 mg/dL or higher were included in this study. Clinical blood pressure measurements obtained at the start of follow-up and at 6, 12, 18, and 24 months were averaged to serve as the 2-year mean blood pressure, and the progression rates of renal impairment were com- pared between patients achieving and those not achieving the target blood pressure of the JSH 2014. RESULTS: Among the diabetic patients with CKD, significant differences in renal impairment progression rates were observed between those achieving and those not achieving the target blood pressure. Among the non-diabetic patients with CKD, those achieving the target blood pressure tended to show slower progression of renal impair- ment, but their progression rates were not significantly different from those of the patients not achieving the target blood pressure. CONCLUSION: Blood pressure control is essential for patients with CKD. In patients with diabetes mellitus, the pro- gression rates of renal impairment can be substantially reduced by maintaining blood pressure below the target blood pressure described in the JSH 2014.

Diminished complement-activating capacity through the classical pathway in sera from type 2 diabetes mellitus.

Complement-activating capacity through the classical pathway in type 2 diabetes mellitus (T2DM) was examined in the context of free sialic acid as a potential modulator of complement activation. Complement-activating capacity was investigated in an incubation study of heat-aggregated IgG (HAG) and sera from 42 T2DM patients. The study demonstrated diminished in-vitro complement-activating capacity through the classical pathway in T2DM. Various doses of N-acetyl neuraminic acid (NANA) were incubated with normal serum and HAG. Complement activation product levels decreased in a NANA dose-dependent manner. Isoelectrofocusing analysis in a mixture of NANA and purified C3 indicated that C3 changed pI dose-dependently, resulting in the downregulation of complement activation. The serum levels of free sialic acid were determined by fluorometric assay in the 42 T2DM sera samples, and were significantly increased in patients with diminished complement activation. These data indicate that increased serum sialic acid may become a candidate for decreasing complement-activating capacity in T2DM.

Real-world management of patients with neuromyelitis optica spectrum disorder using satralizumab: Results from a Japanese claims database.

BACKGROUND: Satralizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has been approved globally for the treatment of neuromyelitis optica spectrum disorder (NMOSD), based on positive results from two randomized, double-blind, phase 3 studies: SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279). There remains an unmet need to understand the real-world management of NMOSD, especially in patients undergoing tapering of concomitant therapy. We examined real-world treatment patterns, including concomitant glucocorticoids and immunosuppressants, and relapse in satralizumab-treated patients with NMOSD, using a Japanese administrative hospital claims database. METHODS: We used retrospective data from the Medical Data Vision hospital-based administrative claims database. The index date was the date of first satralizumab prescription and the study period was set between August 2018 and March 2022. Patients were included in the overall population if they had a first prescription for satralizumab between August 2020 and March 2022, an International Classification of Disease, Version10 code of G36.0 prior to March 2022, and were observable for ≥90 days prior to the index date. The primary endpoint was the percentage of patients with relapse-free reduction of oral glucocorticoids to 0 mg/day at 360 days of continued satralizumab treatment. Secondary endpoints included time to relapse, number of relapses after the index date while being on continuous satralizumab treatment, annualized relapse rate before and after the index date, and concomitant medication use. Relapse and dose reduction were identified using definition specifically developed for this study. RESULTS: Of the 131 patients included in the overall population, most were female (90.8 %), aged 18-65 years (75.6 %), and were prescribed oral glucocorticoids (93.1 %). Azathioprine (19.1 %) and tacrolimus, a calcineurin inhibitor (18.3 %), were the most common immunosuppressants at index date. Six (4.6 %) patients had a history of biologic use (tocilizumab, 1 [0.8 %]; eculizumab, 5 [3.8 %]). Among 111 patients observable for 360 days pre-index, there were 0.6 ± 0.8 (mean ± SD) relapses during 360 days before the index date. The median (interquartile range) duration of satralizumab exposure was 197.0 (57.0-351.0) days. Most (125/131; 95.4 %) patients were relapse-free post-index; 6 (4.6 %) patients relapsed within 90 days after the index date, of which 2 had the first relapse within 7 days after the index date. Among 21 patients with 360-day follow-up, 6 (28.6 %) patients were on 0 mg/day dose of glucocorticoid prescription without relapse 360 days post-index. Of these 6 patients, 2 had no prescription of oral glucocorticoids at the index date and remained glucocorticoid- and relapse-free 360 days after the index date. CONCLUSION: These real-world data support the phase 3 clinical trials. Our results, over a median duration of satralizumab exposure of 197.0 days, showed that a majority (125/131, 95.4 %) of patients were relapse-free after initiating satralizumab treatment. The number of glucocorticoid-free patients without relapse increased over time under continuous satralizumab prescription. Further studies are needed to confirm if satralizumab can be used as a potential immunosuppressant- and glucocorticoid-sparing agent.

High glutamic acid decarboxylase antibody titers may be associated with a decline in ß-cell function over time and future insulin deficiency in latent autoimmune diabetes in adults.

AIMS: Latent autoimmune diabetes in adults (LADA) is characterized by positive islet-associated autoantibodies including glutamic acid decarboxylase antibody (GADA), and gradual decline in insulin secretion, progressing to insulin dependency. This cross-sectional study aimed to determine whether GADA by enzyme-linked immunosorbent assay (GADA-ELISA) titer of ≥180 U/mL could be associated with decline in ß-cell function in participants with LADA. METHODS: Sixty-three participants with LADA were recruited and an association between insulin secretion capacity and disease duration was investigated. Insulin peptide-specific inflammatory immunoreactivity was investigated to determine the disease's activity. RESULTS: There was a significant inverse correlation between disease duration and C-peptide index in participants with GADA-ELISA titer of ≥180 U/mL (Spearman's r (rs) = -0.516, p < 0.01). The positivity rate of insulin peptide-specific inflammatory immunoreactivity was significantly higher in those with ≥180 U/mL than in those with <180 U/mL (p < 0.05). In participants with human leukocyte antigen (HLA)-DRB1*04:05, a significant inverse correlation was observed between disease duration and C-peptide index in those with ≥180 U/mL (rs = -0.751, p < 0.01). CONCLUSIONS: GADA-ELISA titer of ≥180 U/mL, especially with HLA-DRB1*04:05, might reflect higher disease activity and may be associated with decline in ß-cell function over time and future insulin dependency in LADA.

Complement-mediated chronic inflammation is associated with diabetic microvascular complication.

BACKGROUND: Chronic inflammation is characteristic of type 2 diabetes mellitus (T2DM). Obesity-activated adipocytes release adipocytokines, which induce the secretion of proinflammatory cytokines, resulting in vascular endothelial dysfunction and organ injury. C3a is a candidate to induce tissue inflammation. METHODS: We investigated the association between diabetic microangiopathy and complement-mediated inflammation in 32 obese T2DM patients and 32 normal donors. Plasma levels of complement components and their activation intermediates were examined and related to the level of complication. An incubation study of post-prandial serum was carried out to measure the in vitro production of acylation stimulating protein (ASP/C3a desArg) by chylomicron. RESULTS: Plasma levels of C3, C4, factor B, iC3b, Bb, and ASP were significantly increased in T2DM patients. Levels of C4d and membrane attack complex (C5b-9) were not significantly elevated. The activation rate of these factors indicated that only the early phase of alternative complement pathway was excessively activated. A statistical study revealed close correlation between ASP, body mass index, and highly sensitive C-reactive protein. Plasma ASP was significantly increased in the macroalbuminuric and proliferative retinopathy patient groups. An incubation study revealed that ASP was produced after the in vitro incubation of post-prandial serum from a T2DM patient with hyperchylomicronaemia. CONCLUSIONS: Activation of the alternative complement pathway occurs in obese T2DM patients and is enhanced in the post-prandial hyperchylomicronic condition, which induces overproduction of ASP and C3a-mediated tissue inflammation. Therefore, complement-mediated inflammation may contribute to the acceleration of diabetic microangiopathy in addition to the development of macroangiopathy.

A patient with ketosis-prone type 2 diabetes showing nearly normalized glucose tolerance after recovery from severe diabetic ketoacidosis.

Unprovoked A-ß+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies ("A- "), and preservation of ß-cell function ("ß+ ") after recovery from DKA using insulin therapy. However, there have been few reports on glucose tolerance after recovery. We present a case of KPD with nearly normalized glucose tolerance after recovery from severe DKA. A 41-year-old obese woman first presented with unprovoked severe DKA, i.e., ketonuria, plasma glucose 570 mg/dL, pH 7.18, and HCO3 - 5.2 mmol/L, without anti-islet autoantibodies. She achieved insulin-free glycemic remission after recovery from DKA, leading to the diagnosis of KPD. Thereafter, 75 g oral glucose tolerance test showed impaired fasting glucose and time-in-range using intermittently scanned continuous glucose monitoring was 97% without medication. These findings suggest that, despite the initial severe DKA, some patients with KPD might achieve normalized glucose tolerance after recovery. The similar onset patterns of DKA necessitates appropriately distinguishing KPD from acute-onset type 1B (idiopathic) diabetes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00599-6.

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.

High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), glomerular involvement often progresses with the activity of the disease. Immune complexes and abnormal secretion of cytokines are thought to be involved in the central mechanism of the development of lupus nephritis. We investigated serum levels of interleukin 18 (IL-18), a proinflammatory cytokine, and its natural antagonist IL-18 binding protein (IL-18 BP) in 45 patients with lupus nephritis. IL-18 levels were significantly increased in patients with Class II, Class III, and Class IV lupus nephritis compared with the level in a healthy control group. However, the levels stayed within the non-significant range in Class V. IL-18 BP levels were significantly increased in patients with Class III and Class IV lupus nephritis, in which histological activity and chronicity are severe. However, IL-18 BP levels stayed within the non-significant range in Class II and Class V, in which histological markers are mild. We also compared the levels of IL-18 and IL-18 BP in patients with and without glomerular infiltration of inflammatory cells. IL-18 was increased regardless of glomerular infiltration. However, IL-18 BP was increased only in patients with glomerular infiltration. These data suggest that IL-18 levels indicate the extent of the offending inflammatory response not only in the bloodstream but also in renal tissue, and that high IL-18 BP levels indicate the severity of existing glomerular injury.

Clinical Significance of Insulin Peptide-specific Interferon-γ-related Immune Responses in Ketosis-prone Type 2 Diabetes.

CONTEXT: Unprovoked A-ß+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies ("A-"), and preservation of ß-cell function ("ß+") after recovery from DKA. Although this phenotype often appears with acute hyperglycemia and DK/DKA just like acute-onset type 1 diabetes (AT1D), the involvement of anti-islet immune responses remains unknown. OBJECTIVE: We sought to clarify the immunological role of insulin-associated molecules in unprovoked A-ß+ KPD. METHODS: In this cross-sectional study, blood samples from 75 participants (42 with AT1D and 33 with KPD) were evaluated for interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) reactive to 4 insulin B-chain amino acid 9-23-related peptides (B:9-23rPep) using an enzyme-linked immunospot (ELISpot) assay. RESULTS: Overall, 36.4% (12/33) of KPD participants showed positive IFN-γ ELISpot assay results; the positivity rate in KPD was similar to that in AT1D (38.1%; 16/42) and statistically significantly higher than the previously reported rate in type 2 diabetes (8%; 2/25; P < .0167). Moreover, B:9-23rPep-specific IFN-γ-producing PBMC frequency was negatively correlated with age and ad lib serum C-peptide levels in all KPD participants and positively correlated with glycated hemoglobin A1c level in KPD participants with positive IFN-γ ELISpot results. CONCLUSION: These findings suggest the involvement of B:9-23rPep-specific IFN-γ-related immunoreactivity in the pathophysiology of some unprovoked A-ß+ KPD. Moreover, increased immunoreactivity may reflect transiently decreased ß-cell function and increased disease activity at the onset of DK/DKA, thereby playing a key role in DK/DKA development in this KPD phenotype.

HbA1c level may be a risk factor for oxygen therapy requirement in patients with coronavirus disease 2019.

INTRODUCTION: Many clinical studies have identified significant predictors or risk factors for the severity or mortality of coronavirus disease 2019 (COVID-19) cases. However, there are very limited reports on the risk factors for requiring oxygen therapy during hospitalization. In particular, we sought to investigate whether plasma glucose and HbA1c levels could be risk factors for oxygen therapy requirement. MATERIALS AND METHODS: A single-center, retrospective study was conducted of 131 COVID-19 patients hospitalized at Saitama Medical University Hospital between March 2020 and November 2020. To identify the risk factors for oxygen therapy requirement during hospitalization, a stepwise multivariate binary logistic regression analysis was performed using several clinical parameters commonly obtained on admission, including plasma glucose and HbA1c levels. RESULTS: Of the 131 patients with COVID-19, 33.6% (44/131) received oxygen therapy during hospitalization. According to the logistic regression analysis, male sex (odds ratio [OR]: 8.76, 95% confidence interval [CI]: 1.65-46.5, P < 0.05), age (OR: 1.07, 95% CI: 1.02-1.12, P < 0.01), HbA1c levels (OR: 1.94, 95% CI: 1.09-3.44, P < 0.05), and serum C-reactive protein (CRP) levels (OR: 2.22, 95% CI: 1.54-3.20, P < 0.01) emerged as independent variables associated with oxygen therapy requirement during hospitalization. CONCLUSIONS: In addition to male sex, age, and serum CRP levels, HbA1c levels on admission may serve as a risk factor for oxygen therapy requirement during the clinical course of COVID-19, irrespective of diabetes history and status. This may contribute to the efficient delegation of limited numbers of hospital beds to patients at risk for oxygen therapy requirement.

Clinical features resembling subcutaneous insulin resistance observed in a patient with type 2 diabetes and severe COVID-19-associated pneumonia: a case report.

We report the case of a 52-year-old hyperglycemic woman with type 2 diabetes and severe coronavirus disease 2019 (COVID-19)-associated pneumonia, possibly involving the subcutaneous insulin resistance (SIR) syndrome. After admission for pneumonia, her average daily blood glucose (BG) levels remained at 300-400 mg/dL, although the required dosage of subcutaneous insulin markedly increased (~ 150 units/day; ~ 2.63 units/kg/day). Furthermore, the patient had generalized edema along with hypoalbuminemia, developed extensive abdominal purpuras, and had increased plasma D-dimer levels during treatment, suggestive of coagulation abnormalities. Therefore, intravenous infusion of regular insulin was initiated. The BG level subsequently decreased to < 200 mg/dL 2 days after administering 18 units/day of insulin infusion and 118 units/day of subcutaneous insulin, suggesting that subcutaneous insulin alone might have been ineffective in reducing hyperglycemia, which is clinically consistent with the characteristics of an SIR syndrome. Impaired skin microcirculation arising from coagulation abnormalities, subcutaneous edema associated with inflammation-related hypoalbuminemia or vascular hyperpermeability, and/or reduction in subcutaneous blood flow due to COVID-19-induced downregulation of angiotensin-converting enzyme 2 might be associated with the development of pathological conditions that resemble SIR syndrome, leading to impaired subcutaneous insulin absorption. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00500-x.

Relationship between oligomer and functional serum mannose-binding lectin in chronic renal failure.

INTRODUCTION: Mannose-binding lectin (MBL) plays an important role in first-line host defence against pathogens via the lectin pathway. The binding affinity for ligands is greatly increased by oligomerization, although the basic triplet does not bind solid phase mannan and cannot activate complement. Besides, MBL is a positive acute-phase protein. In this study, we examined the relationship between oligomer and functional serum MBL in chronic renal failure patients who were either uraemic [Pre-haemodialysis (pre-HD) patients], or who were receiving maintenance haemodialysis treatment (HD patients). MATERIALS AND METHODS: This study included a total of 20 Pre-HD patients, 130 HD patients and 28 healthy subjects. The oligomer and functional serum MBL levels were measured using enzyme-linked immunosorbent assays established previously. RESULTS: The median serum functional MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). Furthermore, the median functional MBL level in Pre-HD patients was significantly lower than that in HD patients (P<0·05). The median serum oligomer MBL levels in both Pre-HD and HD patients were significantly higher compared with healthy subjects (P<0·05 for both). Furthermore, the median oligomer MBL level in HD patients was significantly (P<0·05) higher than that in Pre-HD patients. The ratios of median serum functional MBL levels to oligomer MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). CONCLUSIONS: We found significant reductions in the ratios of serum functional MBL levels to oligomer MBL levels in HD and Pre-HD patients compared with healthy subjects.

Bodyweight threshold for sudden onset of ketosis might exist in ketosis-prone type 2 diabetes patients.

Ketosis-prone type 2 diabetes is recognized as atypical diabetes. These patients are often male, characterized by obesity, sudden onset of ketosis and a transient decrease in insulin secretion capacity that can be recovered with temporal insulin therapy. Here, we report a male patient with ketosis-prone type 2 diabetes who was followed up for 8 years. During the follow-up period, his bodyweight fluctuated and he experienced four episodes of critical ketosis recurrence in association with bodyweight gain. He discontinued insulin therapy after each ketosis episode within the first 4 years, but thereafter, he had to continue insulin therapy because of decreased insulin secretion capacity. Interestingly, his peak bodyweight just before the repeated ketosis episode gradually decreased, and the insulin secretion capacity after the recovery from repeated ketosis decreased in parallel with his peak bodyweight. This long-term clinical course might be a clue to understand the pathophysiology of ketosis-prone type 2 diabetes.

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.

[Longstanding intractable massive ascites caused by chronic lupus peritonitis with nephrotic syndrome: a case report].

A 36-year-old woman with systemic lupus erythematosus (SLE) and nephrotic syndrome showed massive ascites. She was admitted to our hospital because of edema in both legs and a remarkably distended non-tender abdomen. On admission, massive ascites was observed in the abdominal CT scan findings. Laboratory examination of the ascites showed low levels of total protein (1.5 g/dL), albumin (0.5 g/dL) and LDH (89 IU/L), which were characterized as ascites per diapedesis. In addition, she was diagnosed with SLE and nephrotic syndrome from the clinical and laboratory findings. We treated her with steroid therapy, including methylprednisolone plus therapy. Although the serological abnormalities with SLE had normalized and urinary protein almost disappeared on the 51th hospital day, the ascites had not improved at all. These findings indicated that she had suffered from chronic lupus peritonitis, complicated with nephrotic syndrome and we had continued to treat her with prednisolone for a long time. The ascites was remarkably diminished at 220 days after admission. We believe that in addition to nephrotic syndrome, impaired vascular circulation caused by chronic lupus peritonitis might have contributed to accumulation of the massive ascites.

The Role of Transcription Factors and Nuclear Pore Proteins in Controlling the Spatial Organization of the Yeast Genome.

Loss of nuclear pore complex (NPC) proteins, transcription factors (TFs), histone modification enzymes, Mediator, and factors involved in mRNA export disrupts the physical interaction of chromosomal sites with NPCs. Conditional inactivation and ectopic tethering experiments support a direct role for the TFs Gcn4 and Nup2 in mediating interaction with the NPC but suggest an indirect role for factors involved in mRNA export or transcription. A conserved "positioning domain" within Gcn4 controls interaction with the NPC and inter-chromosomal clustering and promotes transcription of target genes. Such a function may be quite common; a comprehensive screen reveals that tethering of most yeast TFs is sufficient to promote targeting to the NPC. While some TFs require Nup100, others do not, suggesting two distinct targeting mechanisms. These results highlight an important and underappreciated function of TFs in controlling the spatial organization of the yeast genome through interaction with the NPC.

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.