Efficacy of mizoribine-tacrolimus-based induction therapy for pediatric lupus nephritis.

BACKGROUND: Recent advances in the management of lupus nephritis (LN) have also contributed to a favorable outcome in patients with pediatric-onset LN. Nevertheless, we believe that a more effective and less toxic treatment is needed to attain optimal control of pediatric-onset LN. METHODS: Seven consecutive children with biopsy-proven LN (four with class III/IV and three with class V) received multitarget induction therapy consisting of mizoribine (MZR), tacrolimus (Tac), and prednisolone (PDN). They were prospectively evaluated at three, six, and 12 months, and at the latest observation point after a mean period of 32 months. Post-treatment renal biopsy was performed in two patients with class III/IV. RESULTS: Despite gradually tapering the dose of concomitantly administered PDN, a significant improvement compared with baseline values was observed in the urinary, serological, and clinical assessment measures even at three months of treatment, and the favorable changes persisted throughout the treatment period in most of the study participants except for one. In two patients who underwent post-treatment renal biopsy, a marked histologic improvement was confirmed. No serious adverse events were observed. CONCLUSIONS: Multitarget therapy may be an attractive option for the treatment of pediatric-onset LN. Further studies involving a larger number of patients are needed.

An 8-month-old boy with congenital fibromuscular dysplasia presenting with shock caused by sudden renal hemorrhage.

Fibromuscular dysplasia (FMD) is a non-atheromatous, non-inflammatory, multifocal segmental angiopathy. FMD is the most common cause of pediatric renovascular hypertension. Aneurysmal formation of the main renal artery and distal branches is a rare complication of FMD in infancy. We report an 8-month-old boy with FMD presenting with shock caused by sudden renal hemorrhage that necessitated removal of one kidney. A diagnosis of renovascular hypertension resulting from intimal type FMD with aneurysmal formation was made on the basis of the presence of hypertension, elevation of PRA and aldosterone activity, pathological findings and the results of renal angiography. Our findings suggest that it is therefore necessary to consider FMD with aneurysmal formation as a possible cause of hypertension and renal hemorrhage in infants.

Positive association of serum levels of pigment epithelium-derived factor with high-sensitivity C-reactive protein in apparently healthy unmedicated subjects.

Pigment epithelium-derived factor (PEDF), a glycoprotein with neuronal differentiating activity, possesses anti-inflammatory properties both in cell culture and animal models. However, the relationship between serum levels of PEDF and high-sensitivity C-reactive protein (hs-CRP), one of the representative biomarkers for inflammation in humans, is largely unknown. This study investigated whether serum PEDF levels were associated with hs-CRP in 120 apparently healthy unmedicated Japanese subjects (93 males, 27 females; mean age 58.0 years). All subjects underwent a complete history and physical examination, including blood chemistries, anthropometric and metabolic variables. Multiple regression analysis found that serum hs-CRP, creatinine and triglyceride levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) and body mass index were significantly and independently associated with serum PEDF levels. It is concluded that, serum levels of PEDF are associated with serum levels of hs-CRP independently of anthropometric, metabolic and renal function variables. The results also suggest that serum PEDF levels may be elevated as a counter-system against subclinical inflammation.

Two patients with focal segmental glomerulosclerosis complicated by cyclosporine-induced reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a distinctive clinicoradiological entity observed in a variety of clinical settings. Cyclosporine (CyA)-RPLS has been reported in a few patients with focal segmental glomerulosclerosis (FSGS); however, there had been no reports on developed RPLS after the re-administration of CyA treatment. We report two patients with FSGS who developed CyA-induced RPLS and summarize the results of a literature review for similar patients. The two patients with FSGS presented here were a 4-year-old boy and a 9-year-old boy, who presented with steroid-resistant nephrotic syndrome (NS) and were treated with CyA. The first patient developed CyA-induced RPLS at the 7th day after the start of CyA treatment, and the second patient at the 16th day after the re-start of CyA treatment. The two patients complained of a visual disorder and exhibited signs of a disturbance in consciousness and hypertension. Electroencephalography (EEG) examinations revealed a generalized slow wave pattern, and magnetic resonance imaging (MRI) disclosed an area of high signal intensity in the white matter. Subsequently, CyA was discontinued and neurological symptoms improved and recrudescence of RPLS did not occur. Our findings suggest that patients with FSGS and NS who are treated with CyA should be closely monitored for the possible onset of RPLS, presenting as a disturbance in consciousness, visual disturbances and/or convulsions.

Retinoic acid-inducible gene-I (RIG-I) is induced by IFN-{gamma} in human mesangial cells in culture: possible involvement of RIG-I in the inflammation in lupus nephritis.

Interferon-gamma is a potent Th1-type cytokine and a key molecule in the pathogenesis of autoimmune diseases including lupus nephritis. Retinoic acid-inducible gene-I is a putative RNA helicase that plays an important role in immune and inflammatory reactions. We previously demonstrated the increased expression of the retinoic acid-inducible gene-I protein in the kidney tissue of patients with lupus nephritis, and the presence of a significant amount of retinoic acid-inducible gene-I mRNA in the urinary sediment of patients with this inflammatory renal disease. In the present study, interferon-gamma was found to induce the expression of retinoic acid-inducible gene-I in human mesangial cells in culture. Knockdown of retinoic acid-inducible gene-I inhibited the interferon-gamma-induced upregulation of interferon regulatory factor 7, a transcriptional factor involved in immune and inflammatory reactions. These findings suggest that retinoic acid-inducible gene-I produced by mesangial cells may be involved in the pathogenesis of lupus nephritis.

Local VEGF administration enhances healing of colonic anastomoses in a rabbit model.

BACKGROUND/AIMS: Many studies report the role of vascular endothelial growth factor (VEGF) in wound healing, but few describe local VEGF administration to the digestive tract. Leakage from colonic anastomoses, including those due to ischemia, represents a major complication causing increased mortality and morbidity. Angiogenesis is crucial to anastomotic healing and restoration of blood supply, and VEGF is a potent angiogenic factor showing improved healing in various models of reconstruction and anastomosis. Here, we examine the effects of local VEGF-A(165) administration on postoperative rabbit colon anastomosis. METHODS: Two colotomies per animal were made in the sinistral colon on opposite sides of the mesentery. Randomly assigned VEGF (10 microg/0.1 ml) or saline (0.1 ml) was injected into the muscularis propria on both sides of each colonic anastomosis before closing the access laparotomy using single-layer sutures. On postoperative days 3, 4 and 7, the bursting pressure of partially healed anastomoses was measured. On postoperative day 4, anastomotic tissues were examined for the following: hydroxyproline; histopathologically for inflammatory infiltrate and tissue organization and immunohistochemically for capillary proliferation and density; vessel density of midzone collaterals around anastomoses by microangiography. RESULTS: Compared to saline, VEGF administration significantly improved bursting pressure (p = 0.014, paired t test) and increased hydroxyproline (p = 0.027, paired t test) on postoperative day 4. Inflammatory cell infiltration and fibroblast proliferation were prominent, and submucosal capillary vascular counts were significantly higher for VEGF. CONCLUSIONS: Administration of VEGF to colonic anastomosis accelerates wound healing and strengthens the anastomosis by increased angiogenesis.

How many well vs. unwell days can you expect over 10 years, once you become depressed?

OBJECTIVE: Prognostic studies of major depression have mainly focused on episode remission and relapse, and only a limited number of studies have examined long-term course of depressive symptomatology at threshold and subthreshold levels. METHOD: The Group for Longitudinal Affective Disorders Study has conducted prospective serial assessments of a cohort of heretofore untreated major depressive episodes for 10 years under naturalistic conditions. RESULTS: Of the 94 patients in the cohort, the follow-up rate was 70% of the 11,280 person-months. Around 77% of the follow-up months were spent in euthymia, 16% in subthreshold depression and 7% in major depression. Duration of the index episode before reaching recovery was the only significant predictor of the ensuing well time. CONCLUSION: On average, patients with major depression starting treatment today may expect to spend three quarters of the next decade in euthymia but the remaining one quarter in subthreshold or threshold depression.

Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation.

Advanced glycation end products (AGEs) could be implicated in insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and how PEDF improves insulin resistance in AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [ (14)C]-d-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and IkappaB kinase in association with decreased IkappaB levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF. Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and IkappaB kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.

Involvement of retinoic acid-inducible gene-I in inflammation of rheumatoid fibroblast-like synoviocytes.

Interferon (IFN)-gamma is a major cytokine that regulates T helper 1-type immune reactions and serves as an important mediator in the pathogenesis of autoimmune diseases. Retinoic acid-inducible gene-I (RIG-I) is an IFN-gamma-inducible gene and known to be involved in the inflammatory and immune reactions. In the present study, we found high levels of RIG-I expression in synovial tissues of rheumatoid arthritis (RA), while the expression in osteoarthritis tissues was low. Treatment of cultured fibroblast-like synoviocytes with IFN-gamma markedly induced the expression of RIG-I. Knockdown of RIG-I in fibroblast-like synoviocytes, with specific siRNA, resulted in the inhibition of the IFN-gamma-induced expression of chemokine (C-X-C motif) ligand 10 (CXCL10)/IFN-gamma-inducible protein-10 (IP-10), a chemokine with chemotactic activity towards T cells. These findings suggest that RIG-I may play an important role in the pathogenesis of synovial inflammation in RA, at least in part, by regulating the IFN-gamma-induced expression of CXCL10/IP-10.

Pigment epithelium-derived factor inhibits vascular endothelial growth factor-induced vascular hyperpermeability both in vitro and in vivo.

Administration of pigment epithelium-derived factor (PEDF) inhibits advanced glycation end products-elicited retinal vascular hyperpermeability, as well as cold injury-induced brain oedema in rats. However, the underlying molecular mechanism by which PEDF blocks the hyperpermeability in vivo is not fully understood. This study investigated whether PEDF could inhibit vascular endothelial growth factor (VEGF)-induced vascular hyperpermeability both in vitro and in vivo. The Miles assay revealed that, after intradermal injection of VEGF in nude mice, simultaneous administration of PEDF inhibited vascular hyperpermeability in a dose-dependent manner. The in vitro permeability assay also showed that PEDF blocked the VEGF-induced barrier dysfunction in endothelial cells. These results demonstrated that PEDF could inhibit the VEGF-induced vascular hyperpermeability both in vitro and in vivo, and suggest that PEGF may be suitable to be considered as a novel therapeutic agent for various vasopermeable disorders in which VEGF is involved.

Serum level of advanced glycation end-products (AGEs) is an independent determinant of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic general population.

Glucose can react nonenzymatically with amino groups of proteins to form senescent macroprotein derivatives termed advanced glycation end-products (AGEs). Recently, AGEs have been shown to play an important role in atherosclerosis even in nondiabetic subjects. However, the molecular mechanism underlying this is not fully understood. We have now investigated whether serum AGE level was an independent determinant of plasminogen activator inhibitor-1 (PAI-1), a major physiological inhibitor of fibrinolysis, in nondiabetic general population. One-hundred and eighty-six nondiabetic Japanese subjects underwent a complete history and physical examination, determination of blood chemistries, PAI-1, and AGEs. Uni- and multivariate analyses were applied for the determinants of PAI-1 levels. The average PAI-1 levels were 29.7+/-23.8 ng/ml in males and 21.8+/-17.1 ng/ml in females, respectively. Univariate regression analysis showed that PAI-1 levels were associated with age (inversely, p=0.003), male (p=0.003), body mass index (BMI) (p<0.001), HDL-cholesterol (inversely, p<0.001), triglycerides (p<0.001), fasting plasma glucose (p<0.001), insulin (p<0.001), uric acids (p<0.001), AGEs (p=0.037), and alcohol intake (p<0.001). By the use of multiple regression analyses, BMI (p<0.001), male (p=0.003), fasting plasma glucose (p=0.005), age (inversely, p=0.017), and AGEs (p=0.034) remained significant. The present study is the first demonstration that serum AGE level was one of the independent determinants of PAI-1 in nondiabetic general population. The AGE-associated thrombogenic abnormality may be involved in atherogenesis in nondiabetic subjects.

Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation.

Interaction between advanced glycation end-products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy pathogenesis. Pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II (Ang II) is also involved in this disease. This study investigated the role of proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity on inhibition of monocyte chemoattractant protein (MCP-1) expression. Telmisartan, an Ang II type 1 receptor blocker, downregulated RAGE mRNA and inhibited superoxide generation and MCP-1 gene expression in mesangial cells; these processes were blocked by GW9662, a PPAR-gamma inhibitor. Candesartan, an Ang II type 1 receptor blocker, did not suppress AGEs-induced superoxide generation. Telmisartan and the antioxidant, N-acetylcysteine, completely inhibited AGEs-induced MCP-1 overproduction by mesangial cells. These results suggest that telmisartan inhibits AGEs-signalling to MCP-1 expression in mesangial cells by downregulating RAGE gene expression and subsequent oxidative stress generation via PPAR-gamma activation. This study has demonstrated a unique benefit of telmisartan in that it may function as an anti-inflammatory agent against AGEs via PPAR-gamma activation and may play a protective role in diabetic nephropathy.

Hydrogen peroxide stimulates pigment epithelium-derived factor gene and protein expression in the human hepatocyte cell line OUMS-29.

Pigment epithelium-derived factor (PEDF) may have a protective role in atherosclerosis and is associated with the presence of components of the metabolic syndrome. Since oxidative stress has been postulated to play an important role in the pathogenesis of vascular injury in the metabolic syndrome, this study investigated the effects of hydrogen peroxide (H2O2) on PEDF in the immortalized human hepatocyte cell line OUMS-29. PEDF gene expression was measured using quantitative real-time reverse transcription-polymerase chain reaction and PEDF protein expression was analysed by Western blot. H2O2 upregulated PEDF mRNA levels and increased PEDF protein production in OUMS-29 cells in time- and dose-dependent manners. The anti-oxidant N-acetylcysteine significantly blocked H2O2-induced PEDF overexpression in OUMS-29 cells. These results suggest that hepatic PEDF levels may be elevated to counteract the effects of oxidative stress. H2O2-induced PEDF overproduction in the liver may act as a negative feedback system against vascular damage in the metabolic syndrome.

Role of postprandial hyperglycaemia in cardiovascular disease in diabetes.

Diabetes is associated with a marked increase in the risk of atherosclerotic vascular disorders, including coronary, cerebrovascular and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidaemia, hypertension, smoking, obesity, lack of exercise and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in diabetic population. Therefore, specific diabetes-related risk factors should be involved in the excess risk in diabetic patients. In this paper, we review the molecular mechanisms for accelerated atherosclerosis in diabetes, especially focusing on postprandial hyperglycaemia. We also discuss here the potential therapeutic strategy that specifically targets CVD in patients with diabetes.

Acarbose, an alpha-glucosidase inhibitor, decreases aortic gene expression and serum levels of monocyte chemoattractant protein-1 in fructose-fed rats.

Insulin resistance is one of the determinants of post-prandial hyperglycaemia. Recently, acarbose, an alpha-glucosidase inhibitor that delays the absorption of carbohydrates from the small intestine, has been found to reduce the incidence of cardiovascular disease in patients with impaired glucose tolerance or diabetes. However, the molecular mechanism by which acarbose inhibits cardiovascular events remains unknown. In this study, we examined whether oral administration of acarbose could suppress expression of monocyte chemoattractant protein-1 (MCP-1) in fructose-fed rats, a widely used animal model of insulin resistance. Serum MCP-1 levels were elevated in fructose-fed rats after 4 weeks. Acarbose treatment for 4 weeks reduced the fructose-induced elevation of serum MCP-1 levels. Acarbose treatment for 8 weeks decreased MCP-1 mRNA levels in the aortae of fructose-fed rats. These results suggest that the cardioprotective effects of acarbose could be due, at least in part, to the suppression of MCP-1 expression.

Retinoic acid-inducible gene-I is induced in gingival fibroblasts by lipopolysaccharide or poly IC: possible roles in interleukin-1beta, -6 and -8 expression.

Retinoic acid-inducible gene-I (RIG-I) is a member of the DExH family of proteins, and little is known of its biological function in the oral region. We previously reported that interleukin 1beta (IL-1beta) induced RIG-I expression in gingival fibroblasts. In this study, we studied the mechanism of RIG-I expression induced by lipopolysaccharide (LPS) or double-stranded RNA (dsRNA) in gingival fibroblasts. We also addressed the role of RIG-I in the expression of IL-1beta, IL-6 and IL-8 in gingival fibroblasts stimulated with LPS or dsRNA. We stimulated cultured human gingival fibroblasts with LPS or dsRNA, and examined the expression of RIG-I mRNA and protein. The effect of cycloheximide, a protein synthesis inhibitor, on RIG-I induction by these stimuli was examined. The expression of IL-1beta, IL-6 and IL-8 in gingival fibroblasts transfected with RIG-I cDNA stimulated with LPS or dsRNA was examined. LPS or dsRNA induced the expression of mRNA and protein for RIG-I in concentration- and time-dependent manners. We also examined the localization of RIG-I, and found that it was expressed in cytoplasm. Cycloheximide did not suppress the LPS or dsRNA-induced RIG-I expression. Introduction of RIG-I cDNA into gingival fibroblasts resulted in enhanced expression of IL-1beta, IL-6 and IL-8; moreover, overexpression of RIG-I stimulated with LPS or dsRNA synergistically increased expression of IL-1beta, IL-6 and IL-8. RIG-I may have important roles in the innate immune response in the regulation of IL-1beta, IL-6 and IL-8 expression in gingival fibroblasts in response to LPS and dsRNA.