A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

PLA2R-positive membranous nephropathy in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory disease that affects multiple organs, including the pancreas, lacrimal glands, salivary glands, periaortic/retroperitoneum, and kidney. Interstitial nephritis is a typical renal disorder associated with IgG4-RD, but membranous nephropathy is also seen in some cases. CASE PRESENTATION: Herein we report on the case of a 77-year-old male patient with nephrotic syndrome and IgG4-related lung disease. His serum phospholipase A2 receptor (PLA2R) antibody was positive. His renal biopsy specimen was also positive for PLA2R. The renal biopsy specimen showed membranous nephropathy with equal IgG3 and IgG4 immunofluorescence staining and no interstitial nephritis, suggesting IgG4-RD manifesting as membranous nephropathy. CONCLUSIONS: Nephrotic syndrome caused by membranous nephropathy is sometimes associated with IgG4-RD. In such cases, even if serum PLA2R antibody is positive, it should be considered that the membranous nephropathy may be secondary to IgG4-RD.

Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases.

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4-82] years; BMI, 16.0 ± 2.9 [13.0-22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases.

Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis.

Glomerular parietal epithelial cell (PEC) activation, as revealed by de novo expression of CD44 and cell migration toward the injured filtration barrier, is a hallmark of podocyte injury-driven focal segmental glomerulosclerosis (FSGS). However, the signaling pathway that mediates activation of PECs in response to podocyte injury is unknown. The present study focused on CD44 signaling, particularly the roles of two CD44-related chemokines, migration inhibitory factor (MIF) and stromal cell-derived factor 1 (SDF1), and their common receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), in the NEP25/LMB2 mouse podocyte-toxin model of FSGS. In the early phase of the disease, CD44-positive PECs were locally evident on the opposite side of the intact glomerular tuft and subsequently increased in the vicinity of synechiae with podocyte loss. Expression of MIF and SDF1 was first increased in injured podocytes and subsequently transferred to activated PECs expressing CD44 and CXCR4. In an immortalized mouse PEC (mPEC) line, recombinant MIF and SDF1 (rMIF and rSDF1, respectively) individually increased CD44 and CXCR4 mRNA and protein levels. rMIF and rSDF1 stimulated endogenous MIF and SDF1 production. rMIF- and rSDF1-induced mPEC migration was suppressed by CD44 siRNA. However, MIF and SDF1 inhibitors failed to show any impact on proteinuria, podocyte number, and CD44 expression in NEP25/LMB2 mice. Our data suggest that injured podocytes upregulate MIF and SDF1 that stimulate CD44 expression and CD44-mediated migration, which is enhanced by endogenous MIF and SDF1 in PECs. This biphasic expression pattern of the chemokine-CD44 axis in podocytes and PECs may be a novel mechanism of "podocyte-PEC cross-talk" signaling underlying podocyte injury-driven FSGS.

Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood.

Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent studies have suggested that alterations in the gut microbiota, referred to as dysbiosis, are associated with MS. However, it is still largely unknown how gut dysbiosis affects the onset and progression of CNS autoimmunity. In this study, we investigated the effects of age and gut dysbiosis on the development of CNS autoimmunity in humanized transgenic mice expressing the MS-associated MHC class II (MHC-II) gene, HLA-DR2a, and T-cell receptor (TCR) genes specific for MBP87-99/DR2a that were derived from an MS patient. We show here that the induction of gut dysbiosis triggers the development of spontaneous experimental autoimmune encephalomyelitis (EAE) during adolescence and early young adulthood, while an increase in immunological tolerance with aging suppresses disease onset after late young adulthood in mice. Furthermore, gut dysbiosis induces the expression of complement C3 and production of the anaphylatoxin C3a, and down-regulates the expression of the Foxp3 gene and anergy-related E3 ubiquitin ligase genes. Consequently, gut dysbiosis was able to trigger the development of encephalitogenic T cells and promote the induction of EAE during the age window of young adulthood.

Characterization of FLOWERING LOCUS C Homologs in Apple as a Model for Fruit Trees.

To elucidate the molecular mechanism of juvenility and annual flowering of fruit trees, FLOWERING LOCUS C (FLC), an integrator of flowering signals, was investigated in apple as a model. We performed sequence and expression analyses and transgenic experiments related to juvenility with annual flowering to characterize the apple FLC homologs MdFLC. The phylogenetic tree analysis, which included other MADS-box genes, showed that both MdFLC1 and MdFLC3 belong to the same FLC group. MdFLC1c from one of the MdFLC1 splice variants and MdFLC3 contain the four conserved motives of an MIKC-type MADS protein. The mRNA of variants MdFLC1a and MdFLC1b contain intron sequences, and their deduced amino acid sequences lack K- and C-domains. The expression levels of MdFLC1a, MdFLC1b, and MdFLC1c decreased during the flowering induction period in a seasonal expression pattern in the adult trees, whereas the expression level of MdFLC3 did not decrease during that period. This suggests that MdFLC1 is involved in flowering induction in the annual growth cycle of adult trees. In apple seedlings, because phase change can be observed in individuals, seedlings can be used for analysis of expression during phase transition. The expression levels of MdFLC1b, MdFLC1c, and MdFLC3 were high during the juvenile phase and low during the transitional and adult phases. Because the expression pattern of MdFLC3 suggests that it plays a specific role in juvenility, MdFLC3 was subjected to functional analysis by transformation of Arabidopsis. The results revealed the function of MdFLC3 as a floral repressor. In addition, MdFT had CArG box-like sequences, putative targets for the suppression of flowering by MdFLC binding, in the introns and promoter regions. These results indicate that apple homologs of FLC, which might play a role upstream of the flowering signals, could be involved in juvenility as well as in annual flowering. Apples with sufficient genome-related information are useful as a model for studying phenomena unique to woody plants such as juvenility and annual flowering.

Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome.

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.

[The status of glycemic control and hypoglycemia in elderly patients visiting the outpatient department specializing in diabetes].

AIM: The Japan Diabetes Society (JDS)/Japan Geriatrics Society (JGS) Joint Committee reported 'Glycemic Targets for Elderly Patients with Diabetes' in 2016. Based on this recommendation, we aimed to clarify 1) the achievement status of glycemic targets in the elderly and 2) the presence of hypoglycemia in real life among elderly individuals with an HbA1c below the lower limit. SUBJECTS AND METHODS: [Analysis I] In 326 elderly with diabetes ≥65 years of age visiting the outpatient department specializing in diabetes, the proportions of patients with HbA1c values below the lower limit and the use of drugs potentially associated with severe hypoglycemia (e.g. insulin formulations, sulfonylureas, glinides) were investigated. [Analysis II] Of the patients with HbA1c values below the lower limit, seven were tested for hypoglycemia in real life using a continuous glucose monitoring system (CGM). RESULTS: [Analysis I] Among the 326 subjects, 235 (72.1%) were using drugs potentially associated with severe hypoglycemia, and 63 (19.3%) had an HbA1c value below the lower limit. [Analysis II] In the seven patients examined using CGM, hypoglycemia was detected in five, all of whom were unaware. CONCLUSIONS: A considerable number of elderly patients were taking drugs associated with hypoglycemic risks and had an HbA1c value below the lower limit, some of whom actually had hypoglycemia as detected by CGM. Using tools such as CGM, preventive measures against hypoglycemia should be taken.

Erratum to: C3 glomerulopathy and current dilemmas.

The article, "C3 glomerulopathy and current dilemmas", written by Naoko Ito, Ryuji Ohashi and Michio Nagata was originally published electronically on the publisher's internet portal (currently SpringerLink) on November 23, 2016 without open access.

C3 glomerulopathy and current dilemmas.

C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components. Because laboratory detection of complement dysregulation is still uncommon in practice, "dominant C3 deposition by two orders greater than that of immunoglobulins in the glomeruli by immunofluorescence", as stated in the consensus report, defines C3G. However, this morphological definition possibly includes the cases with glomerular diseases of different mechanisms such as post-infectious glomerulonephritis. In addition, the differential diagnosis between DDD and C3GN is often difficult because the distinction between these two diseases is based solely on electron microscopic features. Recent molecular and genetic advances provide information to characterize C3G. Some C3G cases are found with genetic abnormalities in complement regulatory factors, but majority of cases seem to be associated with acquired factors that dysregulate the alternative complement pathway. Because clinical courses and prognoses among glomerular diseases with dominant C3 deposition differ, further understanding the background mechanism, particularly complement dysregulation in C3G, is needed. This may resolve current dilemmas in practice and shed light on novel targeted therapies to remedy the dysregulated alternative complement pathway in C3G.

The effect of expiratory muscle strength training on the oral and respiratory functions of community-dwelling older people: An analysis using the swallowing, oral, phonatory, and respiratory muscle function indices.

PURPOSE: This study was performed to determine the effects of expiratory muscle strength training (EMST) on the oral and respiratory functions of community-dwelling older people. METHODS: Older people using a visiting-rehabilitation center were divided into an intervention group of 31 subjects and a control group of 15 subjects. Those in the intervention group were assigned home training for 8 weeks, which included 5 sets of 5 breaths per day with a 75% load of the maximum expiratory pressure using an EMST device. The outcome indices included (1) oral functions, evaluated by the cumulative time spent swallowing three times and the maximum phonation time (MPT) and (2) respiratory functions, evaluated by the maximum expiratory pressure and maximum inspiratory pressure (MEP/MIP). An independent t-test and paired t-test were used to analyze the data. RESULTS: The cumulative time spent swallowing three times was lower in the intervention group than in the control group. This difference remained significant even after adjusting for sex, age, and baseline values. The MPT was 2.1 seconds higher than baseline in the intervention group but 0.4 seconds lower than baseline in the control group. An average increase of 5.7 cmH2O in the PEmax was observed in the intervention group compared with an average decrease of 4.6 cmH2O in the control group, indicating a significant difference. CONCLUSION: These results suggest that EMST improves the oral and respiratory functions of community elderly subjects. This may be explained by the fact that the pathway for swallowing is partially shared with that for phonation, which contributes to a shortened swallowing time by repeated suprahyoid muscle contractions.

Efficacy and safety of eculizumab in childhood atypical hemolytic uremic syndrome in Japan.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease with frequent progression to end-stage renal disease (ESRD). Eculizumab, a humanized anti-C5 monoclonal antibody targeting the activated complement pathway, has recently been introduced as a novel therapy against aHUS. We, therefore, investigated the efficacy and safety of eculizumab in Japanese pediatric patients. METHODS: We retrospectively analyzed clinical course and laboratory data of the first ten children with aHUS treated with eculizumab nationwide. RESULTS: Seven patients were resistant to plasma therapy and three were dependent on it. Causative gene mutations were found in five patients. Two patients had anti-complement factor H autoantibody. Three patients had a family history of thrombotic microangiopathy (TMA). After initiation of eculizumab, all patients immediately achieved hematological remission and could successfully discontinue plasma therapy. The median periods to normalization of platelet count, lactate dehydrogenase levels and disappearance of schistocytes were 5.5, 17 and 12 days, respectively. Nine patients recovered their renal function and the median period to terminate renal replacement therapy (RRT) was 3 days. However, two patients progressed to ESRD and required chronic RRT at the last observation. No patients had a relapse of TMA under regular eculizumab therapy. No serious adverse events occurred during the follow-up period. CONCLUSIONS: Eculizumab is efficacious and well-tolerated therapy for children with aHUS. Although pathogenic mutations could not be detected in five patients, all patients showed immediate normalization of hematological abnormalities, strongly suggesting complement-related aHUS. This prompt hematological amelioration can become an indicator for therapeutic efficacy of eculizumab. However, appropriate indications and optimal duration of the treatment remain unclear.

Multimodal imaging of a case of peripheral cone dystrophy.

PURPOSE: To characterize the peripheral cones in the images obtained by spectral-domain optical coherence tomography (OCT), swept source OCT, and adaptive optics fundus camera in a patient with peripheral cone dystrophy. METHODS: A 28-year-old Japanese man underwent detailed ophthalmic evaluations including high-resolution imaging of the fundus of both eyes. RESULTS: The decimal best-corrected visual acuity was 1.2 in both eyes. The results of slit-lamp biomicroscopy and ophthalmoscopy were essentially normal. Fluorescein and indocyanine green angiographies did not show any hyper- or hypofluorescent areas of the retina. Goldmann perimetry showed full peripheral visual fields but relative central scotomas within the central 20°. The results of the Humphrey Visual Field Analyzer showed a limited preservation of the central sensitivity. Color vision tests showed no errors in both eyes. Spectral-domain OCT showed attenuation of both the ellipsoid and interdigitation zones throughout the macular region except the center of the fovea. The scotopic full-field ERGs were normal, but the photopic ERGs were markedly reduced. Regular cone mosaics were not observed especially more than 450 µm radius from the fovea in the adaptive optics retinal images. The parafoveal cone densities were severely decreased in both eyes. CONCLUSIONS: Our findings indicate that the peripheral cone dystrophy diagnosed by full-field ERGs and perimetry is due to a reduction in the density of parafoveal and peripheral cones.

Influenza A H1N1 pdm09-associated myocarditis during zanamivir therapy.

A 9-year-old girl developed influenza A H1N1 pdm09-associated myocarditis and pericarditis 2 days after starting zanamivir therapy. The virus was detected in the respiratory tract but not in the serum or pericardial effusion. The virus sampled from the respiratory tract had normal susceptibility to neuraminidase inhibitors. Although no differences in interferon-γ, interleukin (IL)-1ß, and tumor necrosis factor-α were observed between the plasma and pericardial effusion, some inflammatory cytokines or chemokines (IL-6 and IL-8) and vascular endothelial growth factor were remarkably elevated in the pericardial effusion compared with the plasma. This suggested that the influenza virus, after infecting the respiratory tract, affected the myocardium, causing myocarditis to gradually develop, which might have been followed by an autoreactive pericarditis causing increased pericardial effusion. Therefore, influenza-associated myocarditis should be considered when influenza patients have respiratory and cardiac involvement, even during treatment with a neuraminidase inhibitor.

Comfort with motherhood in late pregnancy facilitates maternal role attainment in early postpartum.

Quality of life, comfort, and wellbeing during pregnancy are essential for every country in the world. Pregnancy is considered a preparation period for becoming a mother. Maternal role development, including confidence and satisfaction as a mother, is important in the transition to motherhood. Negative psychosocial affect, such as increased anxiety and distress, during pregnancy adversely influences the childbirth experience and childcare, which contributes to postpartum depression. However, the impact of positive feelings on the maternal role development remains unclear. Therefore, the study purpose was to clarify the relationship between comfort in late pregnancy and maternal role attainment and childcare during early postpartum. We designed a descriptive, longitudinal, correlational study by using the Prenatal Comfort Scale, the Postpartum Maternal Role Confidence Scale, and the Postpartum Maternal Satisfaction Scale. Among 339 participants who had received care at a university hospital located in Sendai city in Japan, 215 subjects completed the longitudinal study by answering a questionnaire for the respective Scale late in their pregnancy or during early postpartum. The subjects consisted of 114 primipara (32.0 ± 5.4 years) and 101 multipara (33.4 ± 4.9 years). In primipara, comfort with motherhood was significantly correlated with maternal confidence regarding knowledge and childcare skills and maternal satisfaction. In multipara, comfort in late pregnancy was related to maternal confidence and satisfaction. Positive affect was related to maternal confidence and maternal satisfaction in early postpartum. Therefore, a prenatal nursing intervention helps women become more comfortable with impending motherhood, thereby promoting maternal role attainment after delivery.

Myelin basic protein-specific TCR/HLA-DRB5*01:01 transgenic mice support the etiologic role of DRB5*01:01 in multiple sclerosis.

Genetic susceptibility to multiple sclerosis (MS) has been linked to the HLA-DR15 haplotype consisting of DRB1*15:01(DR2b) and DRB5*01:01(DR2a) alleles. Given almost complete linkage disequilibrium of the two alleles, recent studies suggested differential roles in susceptibility (DR2b) or protection from MS (DR2a). Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease etiology, we created DR2a humanized transgenic (Tg) mice and subsequently crossed them to Tg mice expressing TL3A6, an MS patient-derived myelin basic protein 83-99-specific TCR. In TL3A6/DR2a Tg mice, CD4 Tg T cells escape thymic and peripheral deletion and initiate spontaneous experimental autoimmune encephalomyelitis (EAE) at low rates, depending on the level of DR2a expression. The ability to induce active EAE was also increased in animals expressing higher levels of DR2a. Inflammatory infiltrates and neuronal damage were present throughout the spinal cord, consistent with a classical ascending EAE phenotype with minor involvement of the cerebellum, brainstem, and peripheral nerve roots in spontaneous, as well as actively induced, disease. These studies emphasize the pathologic contribution of the DR2a allele to the development of autoimmunity when expressed as the sole MHC class II molecule, as well as strongly argue for DR2a as a contributor to the CNS autoimmunity in MS.

Pharmacokinetics of darbepoetin alfa after single, intravenous or subcutaneous administration in Japanese pediatric patients with chronic kidney disease.

BACKGROUND: Darbepoetin alfa (DA) is beneficial for pediatric patients for its less injection frequency and greater maximum dose compared to recombinant human erythropoietin. Here, we evaluated pharmacokinetics of DA in Japanese pediatric patients with chronic kidney disease (CKD). METHODS: CKD patients (2-18 years old, n = 8 each) received a single dose of body weight adjusted DA either intravenously or subcutaneously. RESULTS: When administered intravenously, the area under the concentration-time curve from time zero to infinity (AUC0-∞), clearance (CL) and terminal half-life (t 1/2) of DA were 263.7 ng · h/mL, 1.77 mL/h/kg and 26.25 h, respectively (mean). In patients under 12 years old, AUC0-∞, CL and t 1/2 were 219.1 ng · h/mL, 2.19 mL/h/kg, 23.62 h, respectively. These values were mostly similar to those of Japanese adult CKD patients, though AUC0-∞ tended to be lower and CL tended to be higher in the subjects under 12 years old. When administered subcutaneously, time to reach maximum concentration (t max) and maximum concentration (C max) were 24.47 h and 1.704 ng/mL, and AUC0-∞, apparent clearance (CL/F) and t 1/2 were 141.1 ng · h/mL, 3.23 mL/h/kg and 46.73 h, respectively. In patients under 12 years old, t max and C max were 7.50 h and 2.053 ng/mL, and AUC0-∞, CL/F and t 1/2 were 136.7 ng · h/mL, 3.29 mL/h/kg and 37.75 h, respectively, which was higher in C max, faster in t max and shorter t 1/2 compared to adult CKD patients, while AUC was not obviously different. CONCLUSION: The pharmacokinetics of DA in pediatric CKD patients is not obviously different from those in adult.

Efficacy and safety of darbepoetin alfa for anemia in children with chronic kidney disease: a multicenter prospective study in Japan.

BACKGROUND: We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND). METHODS: A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 µg DA for 200 IU rHuEPO. The initial DA dose for naïve patients was determined by body weight, and intended not to exceed 0.5 µg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks. RESULTS: Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA. CONCLUSION: These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD.

Analysis of pancreatic endocrine function in patients with IgG4-related diseases, in whom autoimmune pancreatitis was ruled out by diagnostic imaging.

IgG4-related disease (IgG4RD) is a newly recognized systemic disease characterized by the elevation of serum IgG4 levels and abundant IgG4-positive plasma cell infiltration into the involved organs. Few data exist regarding the relationship between diabetes or glucose intolerance and IgG4RD in the absence of obvious type 1 autoimmune pancreatitis (AIP). Therefore, we are characterizing pancreatic endocrine function in IgG4RD patients with no signs of type 1 AIP. 28 patients (12 men, mean age 62.1 years old) were diagnosed as having IgG4RD from serum IgG4 levels, histopathology and images. Diagnostic imaging ruled out obvious type 1AIP. We used 75g oral glucose tolerance tests (OGTT) and arginine tolerance tests (ATT) to evaluate pancreatic endocrine function. Patients' serum IgG4 and HbA1c levels were 603±437 mg/dL and 6.6±1.0%, respectively. The results of OGTT on 23 patients showed that 12 patients had diabetes, 4 had impaired glucose tolerance, and 7 had normal glucose tolerance. Interestingly, insulin secretion was preserved in most of the patients, even in diabetic patients, on OGTT and ATT. Glucagon hyperreactivity was observed in 10 of the 19 patients who underwent ATT. Twenty-three patients were treated for IgG4RD with glucocorticoids. Their HbA1c levels were significantly elevated during the first six months of treatment, but improved after twelve months in parallel with glucocorticoid therapy. These results demonstrate the high frequency of pancreatic endocrine dysfunction in IgG4RD even when there is no indication of AIP, thus revealing that pancreatic endocrine dysfunction frequently occurs in IgG4RD without obvious type 1 AIP.

MLL2 and KDM6A mutations in patients with Kabuki syndrome.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.