IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

AZUMA, KOICHIRO, FUMINORI KATSUKAWA, SHUJI OGUCHI, MITSURU MURATA, HAJIME YAMAZAKI, AKIRA SHIMADA, AND TAKAO SARUTA. Correlation between serum resistin level and adiposity in obese individuals. Obes Res. 2003;11: 997-1001. Objective: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. Research Methods and Procedures: Sixty-four young (age 32 Ϯ 10 years), obese (BMI 32.9 Ϯ 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 Ϯ 1.3) volunteers were studied cross-sectionally. Thirty-five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75-g oral glucose tolerance test. Results: In a cross-sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 Ϯ 12.93 ng/mL; n ϭ 64 vs. 12.83 Ϯ 8.30 ng/mL; n ϭ 15; p Ͻ 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined ( ϭ 0.35, p Ͻ 0.01). Although cross-sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin ( ϭ 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p ϭ 0.02, 0.03, 0.02, Ͻ0.01, 0.02, and Ͻ0.01, respectively). Discussion: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.

Long-term follow-up for IgG4-related kidney disease, including relapse information, is sparse. To gather data on this we retrospectively examined the clinical course of 43 patients with IgG4-related kidney disease, in which most patients were treated with, and maintained on, corticosteroids. One month after the start of treatment, most of the abnormal serology and radiology parameters had improved. In 34 of the steroid-treated patients whose follow-up period was more than 12 months (median 34 months), excluding one hemodialysis patient, the estimated glomerular filtration rate (eGFR) before treatment was over 60 ml/min in 14 patients (group A) and under 60 ml/min in 20 patients (group B). In group A, there was no difference between the eGFR before therapy and at the last review. In group B, the mean eGFR before treatment (34.1 ml/min) was significantly improved after 1 month (45.0 ml/min), and renal function was maintained at a similar level through last follow-up. Among 24 evaluated patients at the last review, however, renal atrophy had developed in 2 of 9 in group A and in 9 of 15 in group B. Relapse of IgG4-related lesions occurred in 8 of 40 treated patients. Thus, the response of IgG4-related kidney disease to corticosteroids is rapid, not total, and the recovery of renal function persists for a relatively long time under low-dose maintenance. A large-scale prospective study to formulate more useful treatment strategies is necessary.

Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4-related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti-laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

OBJECTIVEOnly a few studies have evaluated the long-term effects of nonalcoholic fatty liver disease (NAFLD) on type 2 diabetes mellitus (T2DM), and none have examined whether NAFLD improvement reduces T2DM incidence. We investigated the association between NAFLD improvement and T2DM incidence. RESEARCH DESIGN AND METHODSBetween 2000 and 2012, 4,604 participants who underwent a health check twice with >10 years between were enrolled. Exclusion criteria were positive hepatitis B surface antigen, positive hepatitis C antibody, ethanol intake >20 g/day, and diabetes. The 3,074 eligible participants were divided into an NAFLD group (n = 728) and a non-NAFLD group (n = 2,346) according to ultrasonography-detected fatty liver. The NAFLD group was categorized into an improved group (n = 110) and a sustained NAFLD group (n = 618) based on fatty liver disappearance at the second visit. Incident T2DM odds ratios (ORs) were estimated by logistic regression models adjusted for age, sex, BMI, impaired fasting glucose, family history of diabetes, dyslipidemia, hypertension, and physical exercise. RESULTST2DM occurred in 117 participants (16.1%) in the NAFLD group and 72 (3.1%) in the non-NAFLD group. NAFLD at baseline was associated with T2DM incidence (multivariate OR 2.37 [95% CI 1.60-3.52]). T2DM occurred in 7 participants (6.4%) in the improved group and in 110 (17.8%) in the sustained NAFLD group. NAFLD improvement was associated with reduced T2DM incidence (multivariate OR 0.27 [95% CI 0.12-0.61]). CONCLUSIONS

The purpose of this study was to assess the adaptive effects of endurance training on autonomic function in athletes with spectral analysis of cardiovascular variability signals. Continuous ECG, arterial blood pressure (ABP), and respiratory signals were recorded from 15 athletes (VO2max > 55 mL.min-1.kg-1) and 15 nonathletes (VO2max < 45 mL.min-1.kg-1) during 10 min at sitting position. Autonomic function was assessed by low frequency power (LF power: 0.06-0.14 Hz) and high frequency power (HF power: the region of the respiratory frequency based on respiratory spectrum) obtained from the autospectra of RR interval, systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) variability signals. The spontaneous baroreflex sensitivity was evaluated by the moduli, BRSLF and BRSHF, of the transfer function between RR interval and SAP variability in LF and HF bands. The resting HR in athletes was significantly lower than that in nonathletes. The HF power, an index of parasympathetic activity, in RR interval spectra were significantly higher in athletes than in nonathletes. Meanwhile, the LF power (an indicator of sympathetic activities contributing to RR interval and of ABP variabilities) showed no significant difference between both groups, although that of athletes was slightly less than that of nonathletes. Also, BRSLF and BRSHF were not significantly different between athletes and nonathletes. These results indicate that endurance training results in the enhanced vagal activities in athletes, which may contribute in part to the resting bradycardia.

Short-type single-balloon enteroscope (short SBE)-assisted endoscopic retrograde cholangiopancreatography (ERCP) is a promising alternative treatment in postsurgical altered anatomy. However, it is technically demanding, and factors affecting its technical difficulty have not yet been clarified. This study aimed to examine the procedural success rate of short SBE-assisted ERCP and the potential factors affecting procedural failure. A total of 117 consecutive patients (203 procedures) with surgically altered anatomy underwent ERCP using prototype short SBEs. The procedural success rate of short SBE-assisted ERCP and the potential factors affecting procedural failure were examined retrospectively. The enteroscopy success rate and procedural success rate were 92.6 % (95 % confidence interval [CI] 88.1 % - 95.8 %) and 81.8 % (95 %CI 75.8 % - 86.8 %), respectively. Multivariate analyses indicated that pancreatic indication (odds ratio [OR] 4.35, 95 %CI 1.67 - 11.4), first ERCP attempt (OR 6.03, 95 %CI 2.17 - 16.8), and no transparent hood (OR 4.61, 95 %CI 1.48 - 14.3) were potential risk factors for procedural failure. Short SBE-assisted ERCP was effective in postsurgical altered anatomy. This large case series suggested the potential factors affecting procedural failure.

Megalin is the main endocytic receptor of the proximal tubule and is responsible for reabsorption of many filtered proteins. In contrast to other members of the low-density lipoprotein (LDL) receptor gene family, it is expressed on the apical plasma membrane (PM) of polarized epithelial cells. To identify megalin's apical sorting signal, we generated deletion mutants and chimeric minireceptors composed of complementary regions of megalin and LDL receptor-related protein (LRP) and assessed the distribution of the mutants in Madin-Darby canine kidney (MDCK) cells by immunofluorescence and cell surface biotinylation. Megalin and LRP minireceptors are correctly targeted to the apical and basolateral PM, respectively, of MDCK cells. We found that the information that directs apical sorting is present in the cytoplasmic tail (CT) of megalin, which contains three NPXY motifs, YXXØ, SH3, and dileucine motifs, and a PDZ-binding motif at its COOH terminus. Deletion analysis established that amino acids 107-136 of the megalin-CT containing the second NPXY-like motif are critical for apical sorting and targeting, whereas the regions containing the first and third NPXY motifs are required for efficient endocytosis. We conclude that the megalin-CT contains a novel apical sorting determinant and that cytoplasmic sorting machinery exists in MDCK cells for some apical transmembrane proteins.