Hepatic veno-occlusive disease accompanied by thrombotic microangiopathy developed during treatment of juvenile dermatomyositis and macrophage activation syndrome: A case report.

Hepatic veno-occlusive disease (VOD) is a complication of haematopoietic stem cell transplantation. VOD is associated with the occurrence of thrombotic microangiopathy (TMA). In haematopoietic stem cell transplantation, VOD and TMA are endothelial syndromes resulting from endothelial cell activation and dysfunction. In rheumatic disease, while TMA is not rare, there are few reports of VOD. In idiopathic myositis, only one case with VOD and TMA complications has been reported, and there are no published cases in juvenile dermatomyositis (JDM). We report a case of JDM manifesting VOD and TMA complications during the treatment for myositis and macrophage activation syndrome (MAS). A 5-year-old boy diagnosed as anti-nuclear matrix protein 2 antibody-positive JDM was complicated by MAS. He received pulsed methylprednisolone, prednisolone, and tacrolimus, but JDM and MAS progressed. He was then treated with intravenous cyclophosphamide and cyclosporine A, with improvement in myositis symptoms and MAS. After initiation of cyclophosphamide and cyclosporine A, he developed haemolysis, painful hepatomegaly, liver damage, and ascites. He was diagnosed with VOD and TMA. Cyclophosphamide and cyclosporine A were discontinued, with recovery from VOD and TMA. The patient remained well on treatment with methotrexate, without any relapse of JDM and MAS to date. The presence of vasculopathy and hypercytokinaemia because of JDM and MAS exacerbated endothelial cell damage. In the present case, we suggest that the main cause of VOD was medication with CY and CsA, which had been used to treat acute exacerbation of MAS and JDM.

USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage.

Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS.

Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity.

The Role of Preoperative and Postoperative Transversus Abdominis Plane and Rectus Sheath Block in Patients Undergoing Total Laparoscopic Hysterectomy.

PURPOSE: This study was performed to assess the efficacy of a preoperative and postoperative transversus abdominis plane (TAP) and rectus sheath (RS) block compared with no TAP and RS block in patients undergoing total laparoscopic hysterectomy (TLH). DESIGN: Prospective observational cohort study. METHODS: From January 2014 to December 2017, 195 women undergoing TLH were categorized into three groups based on their perioperative analgesia: no TAP + RS block (n = 88), preoperative TAP + RS block + systemic analgesia (n = 68), and postoperative TAP + RS block + systemic analgesia (n = 39). We evaluated use of nonsteroidal anti-inflammatory drugs (NSAIDs) and NSAID consumption within the first 12 hours postoperatively and the numerical rating scale score at 0, 12, and 24 hours postoperatively. FINDINGS: Women with a preoperative TAP + RS block had a significantly lower utilization rate of NSAIDs within the first 12 hours postoperatively (54.4% vs 75.0%; P = .007), lower postoperative flurbiprofen dose (45.5 vs 62.0 mg; P = .048), and lower numerical rating scale score at 12 hours postoperatively (1.63 vs 2.20; P = .002) compared with women with no TAP + RS block. CONCLUSIONS: A preoperative TAP + RS block provided superior postoperative analgesia in patients undergoing TLH and reduced analgesic consumption during the first 12 hours postoperatively.

Refractory secondary thrombotic microangiopathy with kidney injury associated with systemic lupus erythematosus in a pediatric patient.

Thrombotic microangiopathy (TMA) is generally diagnosed through clinical features characterized as microangiopathic hemolytic anemia, thrombocytopenia, and multiple organ injury, as well as by pathological findings such as vascular damage and endothelial cell injury. Rheumatic and autoimmune diseases could be accompanied by secondary TMA; in fact, systemic lupus erythematosus (SLE) is a common disease associated with secondary TMA, and SLE complicated with TMA has been reported to have a poor prognosis. Although TMA occurs rarely in pediatric SLE patients, it often leads to severe clinical conditions. Here, we report a rare case of severe juvenile-onset SLE complicated with TMA and kidney injury. The 5-year-old patient showed renal dysfunction, thrombocytopenia, hemolytic anemia, nephrotic syndrome, hypocomplementemia, and elevation of anti-dsDNA IgG levels. Kidney biopsy revealed mesangial proliferation and endocapillary proliferation, as well as plumped endothelial cells, with full-house pattern deposits in immunofluorescence study. Combination treatment of methylprednisolone pulse therapy followed by oral prednisolone, mycophenolate mofetil, and plasma exchange was effective, whereas eculizumab did not show therapeutic effects. The patient further showed recurrent deterioration, and we initiated intravenous cyclophosphamide in addition to combination treatment and eventually succeeded in controlling the disease. Genome analysis by whole-exome sequencing revealed no particular gene mutation related to either complement disorders or type-1 interferon. Further elucidations concerning the pathogenic mechanisms causing juvenile-onset SLE are needed to establish an efficient treatment strategy for TMA with SLE.

Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis.

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

Influences of Total Laparoscopic Hysterectomy According to Body Mass Index (Underweight, Normal Weight, Overweight, or Obese).

STUDY OBJECTIVE: The aim of this study is to evaluate the effect of body mass index (BMI) on laparoscopic hysterectomy outcomes. DESIGN: This was retrospective study. SETTING: Minoh City Hospital, Japan. MATERIALS AND METHODS: Between January 1, 2014, and June 30, 2017, 183 patients underwent total laparoscopic hysterectomy (TLH) at our institution. INTERVENTION: Patients who underwent TLH were grouped according to BMI, as follows: underweight group (BMI <18.5 kg/m2), normal-weight group (18.5 ≤BMI <25 kg/m2), overweight group (25 ≤BMI <30 kg/m2), and obese group (BMI ≥30 kg/m2). MEASUREMENTS AND MAIN RESULTS: Information on patients' clinical characteristics and surgical results were collected retrospectively by medical record review. The severity of complications was graded according to the Clavien-Dindo classification. We assessed clinical characteristics, surgical results, and the perioperative complications in each BMI group. Surgical results included operation time, nonsurgical operating room time estimated blood loss, uterine weight, and postoperative hospital stay. Compared with the normal-weight group, the obese group had significantly more complications (P = 0.012) and longer operation time (P = 0.04). The underweight and overweight groups did not have significantly different surgical results than the normal-weight group. CONCLUSION: Underweight and overweight patients had no significant differences in surgical results, compared with patients of normal weight. Obese patients had significantly longer operation times and more perioperative complications than patients with normal weight. Laparoscopic hysterectomy has burdens and risks for obese patients. Our results suggest that appropriate weight control may decrease the risk of surgery for obese patients.

Diffusion-weighted Whole-body Imaging with Background Body Signal Suppression (DWIBS) as a Novel Imaging Modality for Disease Activity Assessment in Takayasu's Arteritis.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

A postzygotic KRAS mutation in a patient with Schimmelpenning syndrome presenting with lipomatosis, renovascular hypertension, and diabetes mellitus.

Schimmelpenning syndrome is a rare neurocutaneous disorder categorized as a mosaic RASopathy due to postzygotic HRAS or KRAS mutations. We report a 6-year-old girl diagnosed with Schimmelpenning syndrome due to a postzygotic KRAS G12D mutation. The patient had three atypical symptoms of Schimmelpenning syndrome: renovascular hypertension, congenital lipomatosis, and diabetes mellitus. The first two symptoms may overlap with phenotypes of other neurocutaneous syndromes or congenital lipomatous overgrowth syndrome due to mosaic RASopathies or other somatic mosaic mutations. We propose that impaired glucose tolerance was caused by KRAS mutation and a novel clinical phenotype of Schimmelpenning syndrome. Our study indicated that clinical diagnosis of Schimmelpenning syndrome or related conditions should be reorganized with genetic diagnosis of postzygotic mutation. Moreover, further accumulation of genetically proven cases with mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular-targeted therapy.

Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment.

Podocytes are highly specialized cells that line the glomerulus of the kidney and play a role in filtration. Podocyte injury plays a critical role in the development of many kidney diseases, but the underlying mechanisms remain unclear. In this study, we identified that neurofilament heavy polypeptide (NEFH), an intermediate filament component, protects podocyte from injury. We observed that NEFH was upregulated after ADRIAMYCIN(ADR)-induced podocyte injury in both mice and cultured murine podocytes. Immunofluorescence and co-immunoprecipitation analyses revealed that NEFH was colocalized with synaptopodin, a podocyte-specific marker. High NEFH expression in podocytes prevented the Adriamycin-induced reduction in synaptopodin expression. The siRNA-mediated knockdown of NEFH in podocytes reduced the number of vinculin-containing focal contacts, thereby reducing adhesion to the extracellular matrix and increasing podocyte detachment. In addition, NEFH expression was significantly increased in renal biopsy specimens from patients with focal segmental glomerulosclerosis and membranous nephropathy, but in those with minimal change disease. These findings indicate that NEFH is expressed in podocytes during the disease course and that it prevents the reduction in synaptopodin expression and detachment of podocytes.

Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis.

Rac1, a Rho family member, is ubiquitously expressed and participates in various biological processes. Rac1 expression is induced early in podocyte injury, but its role in repair is unclear. To investigate the role of Rac1 expression in podocytes under pathological conditions, we used podocyte-specific Rac1 conditional knock-out (cKO) mice administered adriamycin (ADR), which causes nephrosis and glomerulosclerosis. Larger areas of detached podocytes, more adhesion of the GBM to Bowman's capsule, and a higher ratio of sclerotic glomeruli were observed in Rac1 cKO mice than in control mice, whereas no differences were observed in glomerular podocyte numbers in both groups after ADR treatment. The mammalian target of rapamycin (mTOR) pathway, which regulates the cell size, was more strongly suppressed in the podocytes of Rac1 cKO mice than in those of control mice under pathological conditions. In accordance with this result, the volumes of podocytes in Rac1 cKO mice were significantly reduced compared with those of control mice. Experiments using in vitro ADR-administered Rac1 knockdown podocytes also supported that a reduction in Rac1 suppressed mTOR activity in injured podocytes. Taken together, these data indicate that Rac1-associated mTOR activation in podocytes plays an important role in preventing the kidneys from developing glomerulosclerosis.

Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis.

The highly conserved spalt (sal) gene family members encode proteins characterized by multiple double zinc finger motifs of the C2H2 type. Humans and mice each have four known Sal-like genes (SALL1-4 in humans and Sall1-4 in mice). Sall1 is known to have a crucial role in kidney development. To explore the significance of Sall1 in differentiated podocytes, we investigated podocyte-specific Sall1-deficient mice (Sall1 KOp°d°/p°d°) using a podocin-Cre/loxP system and siRNA Sall1 knockdown (Sall1 KD) podocytes. Under physiological conditions, Sall1 KOp°d°/p°d° mice exhibited no proteinuria during their lifetime, but foot-process effacement was detected in some of the podocytes. To elucidate the role of Sall1 in injured podocytes, we used an adriamycin (ADR)-induced model of nephrosis and glomerulosclerosis. Surprisingly, the expression of Sall1 was elevated in control mice on day 14 after ADR injection. On day 28 after ADR injection, Sall1 KOp°d°/p°d° mice exhibited significantly higher levels of proteinuria and higher numbers of sclerotic glomeruli. Differentiated Sall1 KD podocytes showed a loss of synaptopodin, suppressed stress fiber formation, and, ultimately, impaired directed cell migration. In addition, the loss of Sall1 increased the number of apoptotic podocytes following ADR treatment. These results indicated that Sall1 has a protective role in podocytes; thus, we investigated the endoplasmic reticulum stress marker GRP78. GRP78 expression was higher in ADR-treated Sall1 KOp°d°/p°d° mice than in control mice. Sall1 appeared to influence the expression of GRP78 in injured podocytes. These results suggest that Sall1 is associated with actin reorganization, endoplasmic reticulum stress, and apoptosis in injured podocytes. These protective aspects of Sall1 re-expression in injured podocytes may have the potential to reduce apoptosis and possibly glomerulosclerosis.

Sporotrichal Tenosynovitis Diagnosed Helpfully by Musculoskeletal Ultrasonography.

A 72-year-old man presented with persistent oligoarthritis and positive results for rheumatoid factor and was suspected of having rheumatoid arthritis (RA). However, the musculoskeletal ultrasonography (MSUS) findings were not consistent with those of typical RA. He had undergone surgery for carpal tunnel syndrome, which allowed both histopathological and microbiological examinations to be performed. A synovial tissue culture was positive for Sporothrix schenckii, and he was diagnosed with sporotrichal tenosynovitis. He received anti-fungal therapy, and the sporotrichal tenosynovitis resolved. This case suggests that MSUS is a useful modality, and sporotrichal tenosynovitis, though rare, should be considered in the differential diagnosis of RA.

Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.

The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin-Amphiphysin-Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.

Hemophagocytic lymphohistiocytosis with leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still's disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma. CASE PRESENTATION: A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system. CONCLUSIONS: Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation.

Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study.

OBJECTIVES: To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti-citrullinated peptide antibody (ACPA) titers. METHODS: The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti-rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year. RESULTS: The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups. CONCLUSIONS: This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers.

[Case of a 14-year-old boy with chronic tubulointerstitial nephritis first diagnosed as acute focal bacterial nephritis].

A 14-year-old boy was admitted to a general hospital because of prolonged fever of unknown origin. After Enterococcus feacalis was detected from his urine and abdominal contrast enhanced computed tomography and 99m-Tc dimercaptosuccinic acid scintigram showed multiple focal defects, he was diagnosed as acute focal bacterial nephritis (AFBN). His condition recovered as a result of Ampicillin (ABPC)and Cefotaxime infusion. There was no specific finding in voiding cystography. Six months later, his fever recurred and he was diagnosed as refractory AFBN because Enterococcus feacalis was detected in his urine again. He was treated with ABPC and Meropenem (MEPM) infusion, but the fever persisted and his renal function deteriorated. He was transferred to our hospital for intensive treatment. On admission, blood examination showed findings of inflammation (WBC 14,400/µL, CRP 3.7 mg/dL, erythrocyte sedimentation rate : 69 mm/h, IgG : 2,107 mg/dL) and renal impairment (Cr : 1.8 mg/dL, cystatin C : 2.0 mg/L). Although neither pyuria nor pathogenic bacteria were detected in his urine, Enterococcusfeacalis was detected at the hospital where he had been treated previously, hence we started treatment for AFBN with ABPC, MEPM, Levofloxacin, then Linezolid. However, the fever persisted and his renal function deteriorated (Cr 2.0 mg/dL). Kidney-specific accumulation was found in Ga scintigraphy, which suggested chronic inflammation. Clinical course and laboratory findings showed no symptoms of bacterial, viral, fungal, or tuberculous infections nor collagen disease. Although renal biopsy revealed no glomerular abnormality, tubulointerstitial edema, fibrosis and tubulitis were observed. Rupture of the tubular basal membrane and non-caseating granulomas also existed. Pathological findings did not match those of renal sarcoidosis. Ophthalmological screening negated the existence of tubulointerstitial nephritis with uveitis syndrome. After methylprednisolone pulse therapy, the fever recovered immediately and his renal impairment imroved gradually (Cr 1.49 mg/dL). He continues to undergo treatment as an outpatient. Although tubulointerstitial nephritis is rare in children, some patients have a poor renal prognosis. It is important to determine the existence of tubulointerstitial nephritis on treating a patient with renal impairment.

Dissection of the posterior wall by guide-wire during internal jugular vein catheterization.

We report a case of posterior wall hematoma formation in the internal jugular vein after the puncture of central vein. An 82-year-old woman was scheduled for laparotomy for an abdominal incisional hernia. After induction of general anesthesia, we performed central venous catheterization via the right internal jugular vein under ultrasound guidance in the short-axis view and out-of plane technique. The ultrasound view after insertion of a guide-wire revealed a hematoma-like space on the posterior wall of the vein. We removed and reinserted the guide-wire. This time, insertion of the wire and catheter was uneventful. Seven days after the surgery, no hematoma-like space was found in the vein. The malposition of the guide-wire was detected before dilation, which enabled us to avoid complications in this case. We should note that the confirmation of guide-wire placement in the vein is important during ultrasound-guided central venous catheterization.

Notch2 activation ameliorates nephrosis.

Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis. In vitro, the specific knockdown of Notch2 increases apoptosis in damaged podocytes, while Notch2 agonistic antibodies enhance activation of Akt and protect damaged podocytes from apoptosis. Treatment with triciribine, an inhibitor of Akt pathway, abolishes the protective effect of the Notch2 agonistic antibody. We find a positive linear correlation between the number of podocytes expressing activated Notch2 and the number of residual podocytes in human nephrotic specimens. Hence, specific activation of Notch2 rescues damaged podocytes and activating Notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis.