Influences of the Interactions of Genetic Variations of Seven Core Circadian Clock Genes with Lifestyle Factors on Metabolic Parameters.

INTRODUCTION: In mammals, circadian rhythms regulate many behavioral and physiological processes. Genetic and epidemiological studies have shown that dysregulation of the circadian rhythm induces chronic metabolic diseases, such as obesity, diabetes, and dyslipidemia. We aimed to know the interactions of genetic variations of seven core circadian clock genes with lifestyle factors on the determination of metabolic parameters. METHODS: We have analyzed the impacts of genotype of seven core circadian clock genes (i.e., CLOCK, BMAL1, PER1, PER2, PER3, CRY1, and CRY2) and lifestyle factors (i.e., physical activity and sleep duration) in 575 Japanese males on the determination of metabolic parameters (i.e., body mass index [BMI], serum glucose, glycated hemoglobin [HbA1c], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C] levels). RESULTS: We have detected the associations between genotypes of PER3 and serum HbA1c level and genotypes of CRY1 and serum LDL-C level. Additionally, the interactions of the genotypes of PER1 and PER3 with physical activity for determining BMI, the genotypes of CLOCK with physical activity for determining serum HbA1c levels were observed. Furthermore, for determining serum HDL-C levels, the interactions of the genotypes of CRY2 with physical activity or sleep duration were observed. DISCUSSION/CONCLUSION: Our findings indicate that the interactions of genotypes for core circadian clock genes and lifestyle factors (i.e., physical activity and sleep duration) are important for determining metabolic parameters.

Serum insulin-like growth factor-binding protein 2 levels as an indicator for disease severity in enterohemorrhagic Escherichia coli induced hemolytic uremic syndrome.

BACKGROUND: Insulin-like growth factor-binding protein (IGFBP) 2 plays an important role in the regulation of cell adhesion, migration, growth, and apoptosis. This study aimed to investigate the clinical significance of serum IGFBP2 as a biomarker for disease activity and severity in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). METHODS: IGFBP2 production by human renal glomerular endothelial cells (RGECs) after exposure to Shiga toxin 2 (Stx-2) was investigated in vitro. Serum IGFBP2 levels in blood samples obtained from 22 patients with HUS and 10 healthy controls (HCs) were quantified using an enzyme-linked immunosorbent assay. The results were compared to the clinical features of HUS and serum tau and cytokine levels. RESULTS: Stx-2 induced the production of IGFBP2 in RGECs in a dose-dependent manner. Serum IGFBP2 levels were significantly higher in patients with HUS than in HCs and correlated with disease severity. Additionally, serum IGFBP2 levels were significantly higher in patients with encephalopathy than in those without encephalopathy. A serum IGFBP2 level above 3585 pg/mL was associated with a high risk of encephalopathy. Furthermore, serum IGFBP2 levels significantly correlated with serum levels of tau and inflammatory cytokines associated with the development of HUS. CONCLUSIONS: Correlation of serum IGFBP2 level with disease activity in patients with HUS suggests that IGFBP2 may be considered as a possible indicator for disease activity and severity in HUS. Larger studies and additional experiments using various cells in central nervous system should elucidate the true value of IGFBP2 as a clinical diagnostic marker. ABBREVIATIONS: IGFBP: insulin-like growth factor-binding protein; HUS: hemolytic uremic syndrome; EHEC: enterohemorrhagic Escherichia coli; RGECs: renal glomerular endothelial cells; STx-2: Shiga toxin 2; HCs: healthy controls; LPS: lipopolysaccharide; ROC: receiver operating characteristic; sTNFR: soluble tumor necrosis factor receptor.

Interleukin-33 as a marker of disease activity in rheumatoid factor positive polyarticular juvenile idiopathic arthritis.

OBJECTIVE: To investigate clinical usefulness of serum interleukin (IL)-33 levels as an indicator of disease activity in juvenile idiopathic arthritis (JIA). METHODS: We measured serum levels of IL-33 in 39 patients with JIA, including 7 patients with rheumatoid factor positive poly-JIA (RF + poly-JIA), 8 patients with RF negative poly-JIA (RF-poly-JIA), 20 patients with oligoarticular JIA (Oligo-JIA), 4 patients with enthesitis-related arthritis (ERA) and 30 age-matched healthy controls. Furthermore, we determined their correlation with measures of disease activity. RESULTS: Serum IL-33 levels in patients with RF + poly-JIA were significantly elevated compared to those in patients with RF-poly-JIA, oligo-JIA and HC. Serum IL-33 levels in patients with RF-poly-JIA, oligo-JIA and ERA were not elevated compared to those in HC. Serum IL-33 levels in RF + poly-JIA patients normalized in remission phase. Serum IL-33 levels correlated positively with RF in patients with RF + poly-JIA. CONCLUSIONS: These results indicate that serum IL-33 levels in RF + poly-JIA patients correlated with disease activity, suggesting a potential role of IL-33 as a promising indicator of disease activity.

Rotavirus gastroenteritis-associated urinary ammonium acid urate crystals.

Although ammonium acid urate (AAU) calculi are extremely rare renal stone components, it was recently found that many urinary tract calculi that cause post-renal renal failure in rotavirus (RV) gastroenteritis are AAU calculi. The mechanism of AAU calculi development in RV gastroenteritis has not been fully elucidated. We analyzed data from eight RV gastroenteritis patients who transiently had AAU crystals in their urinary sediment. In these patients, formation of AAU crystals occurred earlier than the formation of AAU calculi. No difference was observed in serum and urine uric acid levels between RV gastroenteritis patients with or without AAU crystals. Interestingly, fractional excretion of sodium was extremely low among patients with AAU crystals. These results suggest that the formation of AAU crystals might not be due to excretion of uric acid, but excretion of sodium.

Urinary neopterin: an immune activation marker in mesangial proliferative glomerulonephritis.

BACKGROUND: To clarify in vivo neopterin expression within the human kidney and its clinical role as a biomarker for immune complex-mediated mesangial proliferative glomerulonephritis (mesPGN) in children. METHODS: We examined neopterin expression within the kidneys of 14 patients with mesPGN and five patients with minimal changes. We also measured the serum and urinary neopterin levels in fourteen patients with mesPGN and sixteen age-matched healthy controls and correlated the histological findings and clinical features. RESULTS: Neopterin expression was observed within the distal tubular epithelial cells. It was induced within the glomerular endothelial cells and infiltrated CD68-positive macrophages in the glomeruli and interstitial areas. Furthermore, urinary neopterin levels were significantly elevated and positively correlated with histopathological findings and the degree of proteinuria. CONCLUSIONS: These findings indicate that increased urinary neopterin may reflect macrophage activation and active inflammation within the kidney in immune complex-mediated glomerulonephritis. Neopterin may thus represent a useful biomarker of immune complex-mediated glomerulonephritis in the clinical setting.

Tolvaptan therapy for massive edema in a patient with nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is characterized by water and sodium retention, which leads to edema. The non-osmotic stimulation of arginine vasopressin release from the pituitary gland has been implicated as one of the important factors in abnormal water retention in patients with NS. CASE-DIAGNOSIS/TREATMENT: We present the initial description of a patient with massive edema caused by refractory nephrotic syndrome, which was effectively treated with tolvaptan, a selective oral vasopressin V2 receptor antagonist. CONCLUSIONS: Tolvaptan is effective for the treatment of massive edema caused by NS. Larger studies are needed in the future to fully assess the value and safety of tolvaptan use for this condition.

Soluble ST2 as a marker of disease activity in systemic juvenile idiopathic arthritis.

To assess the role of interleukin (IL)-33 and ST2, the receptor for IL-33, in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA), we sequentially measured the serum levels of IL-33 and soluble ST2 (sST2) in patients with s-JIA and determined their correlation with measures of disease activity and severity. Twenty-four patients with s-JIA, 5 with rheumatoid factor positive polyarticular JIA (RF+poly-JIA), and 20 age-matched healthy controls (HCs) were analyzed. IL-33 and sST2 levels were quantified in serum by enzyme-linked immunosorbent assays. Serum IL-33 levels in most patients with active s-JIA were below the lowest detection limit. Serum IL-33 levels in patients with RF+poly-JIA were significantly higher than those in patients with s-JIA and HC. Serum sST2 levels in patients during the active phase of s-JIA were much higher than those in patients with poly-JIA and HC. Serum sST2 levels in patients with s-JIA were significantly elevated even in the inactive phase, when other clinical parameters were normalized. Serum sST2 levels correlated positively with the clinical parameters of disease activity. These findings indicate that ST2 may be an important mediator in s-JIA. Serum sST2 levels in patients with s-JIA correlated with disease activity, suggesting a potential role as a promising indicator of disease activity.

Distinct cytokine profile in juvenile systemic lupus erythematosus-associated macrophage activation syndrome.

Macrophage activation syndrome (MAS) has been observed in patients with systemic lupus erythematosus (SLE). Recognition of MAS in patients with SLE may be particularly challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. Massive hypercytokinemia is strongly associated with the pathogenesis of systemic lupus erythematosus-associated macrophage activation syndrome (SLE-MAS) but the pathogenesis and kinetics of cytokine release in SLE-MAS patients is not well studied. We present a case of SLE-MAS. The patient showed the distinct cytokine profile of SLE-MAS compared to systemic juvenile idiopathic arthritis associated MAS and Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. The observed TNF-α dominant increase appears to be characteristic of SLE-MAS. IgM type antilymphocyte antibody (ALAB) was detected on the surface of lymphocytes during the acute phase and disappeared when the patient was in remission. The patient had a heterozygous P369S-R408Q mutation in the MEFV gene. Our results suggest that ALAB and a MEFV mutation might play important roles in the pathogenesis of SLE-MAS. Furthermore, the cytokine profile of SLE-MAS differs from that of S-JIA-MAS: the TNF-α dominant increase appears to be characteristic.

A distinct lymphocyte distribution in relapse after rituximab for steroid-dependent nephrotic syndrome.

Rituximab (RTX) is a new steroid-sparing therapy for childhood steroid-dependent nephrotic syndrome (NS). However, relapses frequently occur immediately after CD19 recovery. We report the cases of two steroid-dependent NS patients treated with RTX followed by mizoribine (MZB). One patient relapsed, and the other developed proteinuria after CD19 recovery until the MZB was replaced by mycophenolate mofetil. These patients exhibited different lymphocyte phenotypes, with the CD4+/CD8+ profile favoring CD8+ T lymphocytes, while CD3+ HLA-DR-expressing activated T lymphocyte expansion occurred in the relapsed patient. Based on these findings, we suggest that T cell activation may influence outcome and that phenotypic analysis in addition to B cell monitoring may facilitate the detection of NS relapse.

Accumulation of mature B cells in the inflamed muscle tissue of a patient with anti-155/140 antibody-positive juvenile dermatomyositis.

We report the first case of a Japanese patient with anti-155/140 antibody-positive juvenile dermatomyositis (JDM). Her clinical features included severe cutaneous involvement. Serum B cell-activating factor levels were significantly increased. Mature class-switched memory B cells accumulated in inflamed muscle tissue but decreased in peripheral blood. These findings indicate that loss of B cell tolerance and accumulation of mature B cells in inflamed muscle tissue play an important role in the pathogenesis of JDM.