A report of three cases of patients with tubulointerstitial nephritis with IgM-positive plasma cells, treatment, and serum-IgM as a sensitive marker for relapse.

BACKGROUND: Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined. CASE PRESENTATION: Case 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement. Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement. Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient's serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day). CONCLUSION: We report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary ß2-microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated.

Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors.

Erythropoietin (Epo) is produced by a subpopulation of resident fibroblasts in the healthy kidney. We have previously demonstrated that, during kidney fibrosis, kidney fibroblasts including Epo-producing cells transdifferentiate into myofibroblasts and lose their Epo-producing ability. However, it remains unclear whether Epo-producing cells survive and transform into myofibroblasts during fibrosis because previous studies did not specifically label Epo-producing cells in pathophysiological conditions. Here, we generated EpoCreERT2/+ mice, a novel mouse strain that enables labeling of Epo-producing cells at desired time points and examined the behaviors of Epo-producing cells under pathophysiological conditions. Lineage-labeled cells that were producing Epo when labeled were found to be a small subpopulation of fibroblasts located in the interstitium of the kidney, and their number increased during phlebotomy-induced anemia. Around half of lineage-labeled cells expressed Epo mRNA, and this percentage was maintained even 16 weeks after recombination, supporting the idea that a distinct subpopulation of cells with Epo-producing ability makes Epo repeatedly. During fibrosis caused by ureteral obstruction, EpoCreERT2/+-labeled cells were found to transdifferentiate into myofibroblasts with concomitant loss of Epo-producing ability, and their numbers and the proportion among resident fibroblasts increased during fibrosis, indicating their high proliferative capacity. Finally, we confirmed that EpoCreERT2/+-labeled cells that lost their Epo-producing ability during fibrosis regained their ability after kidney repair due to relief of the ureteral obstruction. Thus, our analyses have revealed previously unappreciated characteristic behaviors of Epo-producing cells, which had not been clearly distinguished from those of resident fibroblasts.

Spatiotemporal ATP Dynamics during AKI Predict Renal Prognosis.

BACKGROUND: Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal in vivo ATP distribution and dynamics has hindered further analysis. METHODS: A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase. RESULTS: Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues. CONCLUSIONS: Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information.

Cluster-Fault Tolerant Routing in a Torus.

The number of Internet-connected devices grows very rapidly, with even fears of running out of available IP addresses. It is clear that the number of sensors follows this trend, thus inducing large sensor networks. It is insightful to make the comparison with the huge number of processors of modern supercomputers. In such large networks, the problem of node faults necessarily arises, with faults often happening in clusters. The tolerance to faults, and especially cluster faults, is thus critical. Furthermore, thanks to its advantageous topological properties, the torus interconnection network has been adopted by the major supercomputer manufacturers of the recent years, thus proving its applicability. Acknowledging and embracing these two technological and industrial aspects, we propose in this paper a node-to-node routing algorithm in an n-dimensional k-ary torus that is tolerant to faults. Not only is this algorithm tolerant to faulty nodes, it also tolerates faulty node clusters. The described algorithm selects a fault-free path of length at most n ( 2 k + ⌊ k / 2 ⌋ - 2 ) with an O ( n 2 k 2 | F | ) worst-case time complexity with F the set of faulty nodes induced by the faulty clusters.

Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury.

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

Torus Pairwise Disjoint-Path Routing.

Modern supercomputers include hundreds of thousands of processors and they are thus massively parallel systems. The interconnection network of a system is in charge of mutually connecting these processors. Recently, the torus has become a very popular interconnection network topology. For example, the Fujitsu K, IBM Blue Gene/L, IBM Blue Gene/P, and Cray Titan supercomputers all rely on this topology. The pairwise disjoint-path routing problem in a torus network is addressed in this paper. This fundamental problem consists of the selection of mutually vertex disjoint paths between given vertex pairs. Proposing a solution to this problem has critical implications, such as increased system dependability and more efficient data transfers, and provides concrete implementation of green and sustainable computing as well as security, privacy, and trust, for instance, for the Internet of Things (IoT). Then, the correctness and complexities of the proposed routing algorithm are formally established. Precisely, in an n-dimensional k-ary torus ( n < k , k ≥ 5 ), the proposed algorithm connects c ( c ≤ n ) vertex pairs with mutually vertex-disjoint paths of lengths at most 2 k ( c - 1 ) + n ⌊ k / 2 ⌋ , and the worst-case time complexity of the algorithm is O ( n c 4 ) . Finally, empirical evaluation of the proposed algorithm is conducted in order to inspect its practical behavior.

Regiodivergent kinetic resolution of terminal and internal rac-aziridines with malonates under dinuclear Schiff base catalysis.

Regiodivergent parallel kinetic resolution of aziridines with malonates was achieved under dinuclear Schiff base catalysis. The regiodivergent reaction proceeded under catalyst-control irrespective of the substituents on the aziridines, and 2.5-10 mol % of a Y(OTf)3/La(OiPr)3/a dinucleating Schiff base = 1:1:1 mixture gave versatile γ-amino acid derivatives in 96 → >99.5% ee. Not only terminal but also internal racemic aziridines reacted smoothly under suitably combined Lewis acid/Brønsted base catalysis.

Core-shell catalysts consisting of nanoporous cores for oxygen reduction reaction.

A comprehensive experimental study was conducted on the dealloying of PdNi6 nanoparticles under various conditions. A two-stage dealloying protocol was developed to leach >95% of Ni while minimizing the dissolution of Pd. The final structure of the dealloyed particle was strongly dependent on the acid used and temperature. When H2SO4 and HNO3 solutions were used in the first stage of dealloying, solid and porous particles were generated, respectively. The porous particles have a 3-fold higher electrochemical surface area per Pd mass than the solid ones. The dealloyed PdNi6 nanoparticles were then used as a core material for the synthesis of core-shell catalysts. These catalysts were synthesized in gram-size batches and involved Pt displacement of an underpotentially deposited (UPD) Cu monolayer. The resulting materials were characterized by scanning transmission electron microscopy (STEM) and in situ X-ray diffraction (XRD). The oxygen reduction reaction (ORR) activity of the core-shell catalysts is 7-fold higher than the state-of-the-art Pt/C. The high activity was confirmed by a more than 40 mV improvement in fuel cell performance with a Pt loading of 0.1 mg cm(-2) by using the core-shell catalysts.

An IT-based self-checking system of spreadsheet exercises for learners with visual impairments.

PURPOSE: In vocational education and training of computer literacy as part of vocational rehabilitation, learners often work on problem-solving exercises as self-study assignments, and check if their answers are correct. Sighted learners can get information on their incorrect answers by comparing their answers with the correct answers. However, learners with visual impairments largely depend on their teachers for getting this feedback. To remove this dependence, we designed a self-checking system for learners with visual impairments to verify the correctness of their answers. In this paper, we report the results of a usability study to evaluate whether learners with visual impairments can self-check spreadsheet problem-solving exercises using our system in a teacherless environment. METHODS: Usability evaluation experiment was conducted using 2 × 2 crossover design with people with visual impairments (n = 11). The participants checked their answers (detected and corrected errors) after working on problem-solving exercises in two ways: (i) manually; and (ii) using our system. The system usability was evaluated by measuring Detection-And-Correction (DAC) ratio as effectiveness, time taken and the number of steps required for DAC as efficiency, and System Usability Scale score as satisfaction. RESULTS AND CONCLUSIONS: The results show that all the participants could complete the DAC task by using our system, and the time required for DAC task was significantly reduced by using our system as compared to by checking manually. Our system enables learners with visual impairments to self-check problem-solving exercises answers. However, to increase the user satisfaction, the number of required keystrokes needs to be decreased.

Vocational rehabilitation for learners with visual impairments to improve their computer literacy is becoming increasingly important.Learners with visual impairments have the potential to acquire computer literacy in a teacherless environment by using simple assistive software like our self-checking system.Simple assistive software for learners with visual impairments like our self-checking system may have a positive effect not only on learners with visual impairments but also on sighted people.Moreover, our system reduces the teaching load of the teachers so that they can be more effective in helping learners with visual impairments.

Pt monolayer on porous Pd-Cu alloys as oxygen reduction electrocatalysts.

We demonstrate the synthesis of a core-shell catalyst consisting of a Pt monolayer as the shell and porous/hollow Pd-Cu alloy nanoparticles as the core. The porous/hollow Pd-Cu nanoparticles were fabricated by selectively dissolving a less noble metal, Cu, using an electrochemical dealloying process. The Pt mass activity for the oxygen reduction reaction of a Pt monolayer deposited on such a porous core is 3.5 times higher than that of a Pt monolayer deposited on bulk Pd nanoparticles and 14 times higher than that of state-of-the-art Pt/C electrocatalysts.

A Novel Spiro-Heterocyclic Compound Identified by the Silkworm Infection Model Inhibits Transcription in Staphylococcus aureus.

Synthetic compounds are a vital source of antimicrobial agents. To uncover therapeutically effective antimicrobial agents from a chemical library, we screened over 100,000 synthetic compounds for in vitro antimicrobial activity against methicillin-resistant Staphylococcus aureus and evaluated the in vivo therapeutic effectiveness of the hits in S. aureus-infected silkworms. Three antimicrobial agents exhibited therapeutic effects in the silkworm infection model. One of these, GPI0363, a novel spiro-heterocyclic compound, was bacteriostatic and inhibited RNA synthesis in S. aureus cells. GPI0363-resistant S. aureus strains harbored a point mutation in the gene encoding the primary sigma factor, SigA, of RNA polymerase, and this mutation was responsible for the resistance to GPI0363. We further revealed that GPI0363 could bind to SigA, inhibit promoter-specific transcription in vitro, and prolong the survival of mice infected with methicillin-resistant S. aureus. Thus, GPI0363 is an attractive candidate therapeutic agent against drug-resistant S. aureus infections.

Post-infectious acute glomerulonephritis with vasculitis and pulmonary hemorrhage.

An 84-year-old male complained of fever, cough, sputum, and appetite loss. His renal function rapidly worsened, and he had hypoalbuminemia and hypocomplementemia. His condition worsened and C-reactive protein levels were elevated. Vasculitis syndrome was suspected and he was administered 40 mg of prednisolone, although myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody tests were negative. His body temperature decreased and fatigue promptly resumed. On renal biopsy, light microscopy revealed endocapillary and extracapillary glomerulonephritis. Vasculitis was detected in interlobular arteries. Immunofluorescence studies revealed granular deposits of C3 and IgG along capillary walls. Electron microscopy revealed dome-shaped small electron-dense granular subepithelial deposits. Acute post-infectious glomerulonephritis was suspected. Although his renal function improved, he developed hemoptysis and was diagnosed with pulmonary hemorrhage. He received methylprednisolone and plasma exchange, and his respiratory status improved gradually. This is an extremely rare case and suggests the importance of considering a differential diagnosis.

Gamma 1-heavy chain deposition disease accompanied by IgG kappa in serum, urine, and bone marrow.

A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 µmol/L) to 3.46 mg/dL (305.8 µmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electron-dense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow.

Sultam synthesis via Cu-catalyzed intermolecular carboamination of alkenes with N-fluorobenzenesulfonimide.

Cu-catalyzed intermolecular carboamination of alkenes is described. The reaction of terminal alkenes and an internal alkene with N-fluorobenzenesulfonimide was promoted by 2.5 mol % of a Cu(I)-salt at 60 °C, and six-membered ring sultams were obtained in 91-44% yields.

Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents.

An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 µg ml(-1). Several derivatives of 0002-04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 µg ml(-1). Both 0002-04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 µg g(-1)) than 0002-04-KK (LD50: 100 µg g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents.