Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5–2.5 µg/ml) or CsA (target trough level of 80–100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 µg⋅h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.Idiopathic nephrotic syndrome, the most common form of childhood nephrotic syndrome, is most often associated with renal biopsy findings of minimal glomerular and tubulointerstitial changes (minimal change disease). Most patients respond to therapy with corticosteroids,¹ but about 70% experience a relapsing course.² Approximately 30% develop frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS), defined as ≥4 relapses per year.³Although corticosteroids are the mainstay of therapy in pediatric patients with minimal change disease, their repeated use in FR-SSNS results in severe side effects, and other therapeutic options are needed to prevent steroid toxicity.⁴ A 2- to 3-month course of cyclophosphamide or chlorambucil has been shown to produce a longer remission period in many patients⁵; however, these drugs may have serious side effects and their long-term efficacy is limited.^6,7 Levamisole has been shown to reduce the risk of relapse in several small studies, but information is limited regarding long-term efficacy and adverse effects, and the drug is currently not available in most countries. Treatment with cyclosporin A (CsA) is highly effective in maintaining remission in patients with FR-SSNS allowing withdrawal of corticosteroids, but most patients relapse after withdrawal of CsA.⁸ Importantly, prolonged CsA therapy is accompanied by time- and dose-dependent nephrotoxicity.⁹Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a non-nephrotoxic immunosuppressive drug with inhibitory effects on T and B lymphocytes, cell-surface markers, and cytokine gene expression¹⁰ and has proven efficacy and tolerability in renal allograft recipients. Several small studies with limited statistical power have shown that MMF has steroid-sparing effects and reduces relapse rates in patients with FR-SSNS, albeit with varying efficacy.^11–18We studied efficacy and safety of MMF in patients with FR-SSNS in comparison with CsA in a prospective randomized multicenter open-label crossover trial.     

Histological confirmation and biological significance of cartilage canals demonstrated using high field MRI in swine at predilection sites of osteochondrosis

Cartilage canal vessels in epiphyseal cartilage have a pivotal role in the pathogenesis of osteochondrosis/osteochondritis dissecans. The present study aimed to validate high field magnetic resonance imaging (MRI) methods to visualize these vessels in young pigs. Osteochondral samples from the distal femur and distal humerus (predilection sites of osteochondrosis) of piglets were imaged post‐mortem: (1) using susceptibility‐weighted imaging (SWI) in an MRI scanner, followed by histological evaluation; and (2) after barium perfusion using µCT, followed by clearing techniques. In addition, both stifle joints of a 25‐day‐old piglet were imaged in vivo using SWI and gadolinium enhanced T1‐weighted MRI, after which distal femoral samples were harvested and evaluated using µCT and histology. Histological sections were compared to corresponding MRI slices, and three‐dimensional visualizations of vessels identified using MRI were compared to those obtained using µCT and to the cleared specimens. Vessels contained in cartilage canals were identified using MRI, both ex vivo and in vivo; their locations matched those observed in the histological sections, µCT images, and cleared specimens of barium‐perfused tissues. The ability to visualize cartilage canal blood vessels by MRI, without using a contrast agent, will allow future longitudinal studies to evaluate their role in developmental orthopedic disease. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:2006–2012, 2013     

TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.     

Entwicklungen und Herausforderungen der Stillpraxis in den Ländern des südlichen Afrikas

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Da es an der Überlegenheit des Stillens gegenüber anderen Formen der Säuglingsernährung keinen Zweifel mehr...     

Selbsterfahrung in der Psychodrama Ausbildung

Zeitschrift für Psychodrama und Soziometrie - In diesem Beitrag der Zeitschrift für Psychodrama und Soziometrie wird erörtert, dass Selbsterfahrung in der Ausbildung zur...     

Quantitative T2* (T2 star) relaxation times predict site specific proteoglycan content and residual mechanics of the intervertebral disc throughout degeneration

Degeneration alters the biochemical composition of the disc, affecting the mechanical integrity leading to spinal instability. Quantitative T2* MRI probes water mobility within the macromolecular network, a potentially more sensitive assessment of disc health. We determined the relationship between T2* relaxation time and proteoglycan content, collagen content, and compressive mechanics throughout the degenerative spectrum. Eighteen human cadaveric lumbar (L4–L5) discs were imaged using T2* MRI. The T2* relaxation time at five locations (nucleous pulposus or NP, anterior annulus fibrosis or AF, posterior AF, inner AF, and outer AF) was correlated with sulfated‐glycosaminoglycan (s‐GAG) content, hydroxyproline content, and residual stress and strain at each location. T2* relaxation times were significantly correlated with s‐GAG contents in all test locations and were particularly strong in the NP (r = 0.944; p < 0.001) and inner AF (r = 0.782; p < 0.001). T2* relaxation times were also significantly correlated with both residual stresses and excised strains in the NP (r = 0.857; p < 0.001: r = 0.816; p < 0.001), inner AF (r = 0.535; p = 0.022: r = 0.516; p = 0.028), and outer AF (r = 0.668; p = 0.002: r = 0.458; p = 0.041). These strong correlations highlight T2* MRI's ability to predict the biochemical and mechanical health of the disc. T2* MRI assessment of disc health is a clinically viable tool showing promise as a biomarker for distinguishing degenerative changes. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1083–1089, 2014.