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Based on published results of experiments on low-temperature, low-pressure frictional sliding and creep at higher temperature and pressure, theoretical curves of yield strength versus depth corresponding to maximum crustal stresses (STRESSMAX) are calculated. These curves are compared to the frequency-depth distribution of earthquakes (DEFREQ) in several tectonic areas. Both sets of curves have a very similar form and show a prominent peak. From the similarity it is concluded that it is basically the temperature and the water content of the entire crust, not the properties of a particular layer, which determine the shape of maxima of the DEFREQ curves. The peaks of DEFREQ curves are generally at 5- to l0-km depth and agree with STRESSMAX peaks of wet upper crust only. At this depth range the high stresses provide an increased 'cracking potential', resulting in an increased number and an increased stress drop of earthquakes. More and stronger barriers/asperities seem to exist at these depths, causing large earthquakes to nucleate in this high-strength region. The stresses required to overcome the strength maximum are built up from below by ductile creep. The lower crust is considered to be a stress and viscosity minimum; in orogenic zones, strong interaction with plumes from the mantle may take place, and lateral movements are probable. [ABSTRACT FROM AUTHOR]

Deals with a study which evaluated basiliximab in children undergoing renal transplantation and compared it with conventional immunosupression using cyclosporine and prednisolone. Methodology used in the study; Results and conclusion.

In a retrospective analysis of paediatric renal-transplant recipients receiving basiliximab, we noted significantly increased blood concentrations of cyclosporin, early cyclosporin toxicity, and a lower dose requirement within the first 10 days compared with controls. As the CD25 saturation fades at days 28-50, cyclosporin concentrations decline and 20% higher doses are required to maintain adequate trough concentrations. We suggest that an interleukin-2 receptor-mediated alteration of the cytochrome P450 system causes this systemic drug interaction and propose that the initial ciclosporin dose should be limited to 400 mg/m2 if used in combination with basiliximab. [ABSTRACT FROM AUTHOR]

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

A novel method based on liquid-liquid extraction with subsequent gas chromatography separation and mass spectrometric detection (GC-MS) for the quantification of organic carbonates in cell culture materials is presented. Method parameters including the choice of extraction solvent, of extraction method and of extraction time were optimised and the method was validated. The setup allowed for determination within a linear range of more than two orders of magnitude. The limits of detection (LODs) were between 0.0002 and 0.002 mmol/L and the repeatability precisions were in the range of 1.5-12.9%. It could be shown that no matrix effects were present and recovery rates between 98 and 104% were achieved. The methodology was applied to cell culture models incubated with commercial lithium ion battery (LIB) electrolytes to gain more insight into the potential toxic effects of these compounds. The stability of the organic carbonates in cell culture medium after incubation was studied. In a porcine model of the blood-cerebrospinal fluid (CSF) barrier, it could be shown that a transfer of organic carbonates into the brain facing compartment took place. Graphical abstract Schematic setup for the investigation of toxicity of lithium ion battery electrolytes.

Background and Objectives: No large, randomized, double-blind trials in children with proteinuria treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported., Design, Setting, Participants, & Measurements: This 12-week, double-blind, multinational study investigated the effects of losartan 0.7 to 1.4 mg/kg per day compared with placebo (normotensive stratum) or amlodipine 0.1 to 0.2 mg/kg per day up to 5 mg/d (hypertensive stratum) on proteinuria (morning-void urinary protein-creatinine ratio, baseline > or =0.3 g/g) in 306 children up to 17 years of age., Results: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with amlodipine/placebo: losartan -35.8% (95% confidence interval: -27.6% to -43.1%) versus amlodipine/placebo 1.4% (95% confidence interval: -10.3% to 14.5%), P < or = 0.001. Significance remained after adjustment for differences across treatment groups in change in BP (losartan produced incremental systolic and diastolic BP reductions versus amlodipine of 5.4 and 4.6 mmHg, respectively; and versus placebo of 3.8 and 4.0 mmHg, respectively). Proteinuria reduction was consistently observed in the normotensive (-34.4% losartan; 2.6% placebo) and hypertensive (-41.5% losartan; 2.4% amlodipine) strata, and in all prespecified subgroups, including age, gender, race, Tanner stage, weight, prior therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, as well as among the most common etiologies of proteinuria. Adverse event incidence was low and comparable in all groups., Conclusions: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks in children aged 1 to 17 years with proteinuria with or without hypertension, a population that has not previously been rigorously studied.

Background: Chronic allograft injury induced by immunological as well as non-immunological mechanisms is still a major cause of long-term graft loss after renal transplantation. Major histocompatibility complex (MHC) incompatibilities as well as donor-specific alloantibodies are known risk factors, but the interaction of cellular and humoral mechanisms leading to allograft damage remains to be defined. The aim of this study was to analyze the impact of donor-specific post-transplant antibodies against a non-classical MHC Ib antigen apart from T-cell-dependent immune response. Therefore, we utilized a transplant rat model injecting a moAb directed against a donor MHC Ib molecule into athymic nude recipients lacking an immunocompetent T-cell system., Methods: F344 kidneys were transplanted into LEW.RNU rats. Donor and recipient differ in the RT1.C locus (MHC Ib) but are phenotypically identical for the RT1.A (MHC I) and RT1.B/D (MHC II) loci. A moAb directed against the donors RT1.C(lv1) was injected into recipients with stable graft function. A control group remained untreated after transplantation. The rats were monitored for renal function and grafts were analyzed for morphological changes, infiltrating cells and C4d deposition., Results: Antibody-infused rats developed renal impairment with massive urine albumin excretion. Histological changes consistent with antibody-mediated injury were interstitial fibrosis, tubular atrophy and severe glomerulopathy accompanied by an infiltrate of numerous macrophages. At time of death, grafts were negative for C4d at the peritubular capillaries and arterial endothelium., Conclusion: Antibodies directed against a MHC Ib antigen are able to induce allograft injury in T-cell-deficient rats. This model underlines the role of non-classical MHC disparities for long-term allograft survival and demonstrates the long-term results of antibody-induced allograft damage.

In multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), clinical disease is associated with infiltration of the central nervous system (CNS) by immune cells. Subsequent remission with remyelination has been linked to an increased occurrence of oligodendrocyte progenitor (O2A) cells. Platelet-derived growth factor (PDGF) and fibroblast growth factor-2 (FGF-2) are key growth factors for O2A cells, yet little is known about their relevance in EAE and MS. We analyzed the expression of PDGF, FGF-2, and their receptors by peripheral-blood leukocytes (PBLs) and lymphocyte subsets during MBP-induced EAE. Strong up-regulation of PDGF, but not FGF-2, was observed in PBLs, with the highest expression after the disease maximum. T, NK, and NKT cells expressed PDGF, which is a novel observation because thus far only monocytes/macrophages have been reported to express PDGF. These results extend the idea that growth factors may contribute to improved CNS tissue repair, including PDGF, which is secreted by lesion-homing immune cells. The production of PDGF by lymphocytes may have potential therapeutic value when activating or modulating T-cell responses in demyelinating diseases., ((c) 2007 Wiley-Liss, Inc.)

Background: Antigen-specific immunoadsorption combined with rituximab offers the possibility for ABO-incompatible kidney transplantation without splenectomy., Patient and Method: An 8-year-old mentally retarded girl with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis due to mitochondriopathy poorly tolerated hemodialysis. Paternal blood group A1B was incompatible with blood group B of the child. Therefore, we decided to perform the first ABO-incompatible renal transplantation in a child in Germany using antigen-specific immunoadsorption. Rituximab (1 x 375 mg/m2) was administered 2 weeks before the first immunoadsorption (Glycosorb) ABO A-column). Triple-drug immunosuppression (tacrolimus, mycophenolate mofetil and prednisolone) was simultaneously started with immunoadsorption. Initial tacrolimus levels were targeted between 15 and 20 ng/ml. Before transplantation, six immunoadsorptions were applied on days -9, -7, -4, -3, -2 and -1. Intravenous immunoglobulin (0.5 g/kg) was administered preoperatively. After transplantation, three immunoadsorptions were performed on days +4, +6 and +8., Results: Before transplantation, antibody (Ab) titers against paternal erythrocytes (20 degrees C) were reduced from 1 : 64 to 1 : 4 by six antigen-specific immunoadsorptions. After transplantation, we performed three more immunoadsorptions and the Ab titers were stable between 1 : 1 and 1 : 8. One, 2 and 8 months later we observed increases in the Ab titer up to 1 : 32 requiring no change in immunosuppressive therapy. No side effects of immunoadsorption were observed. The girl had excellent initial graft function with a serum creatinine of 55 to 70 micromol/l. Two weeks after transplantation, graft biopsy showed no signs of rejection; there was focal positivity for C4d only. Twelve months after transplantation, renal function was stable, with a serum creatinine of 117 micromol/l. Episodes of rejection or severe infections were absent., Conclusion: ABO-incompatible transplantation using antigen-specific immunoadsorption and rituximab may serve as a suitable alternative for children urgently needing renal transplantation and missing a blood group-compatible donor.

The renal arterial resistance index (RI) and the PicroSirius-Red stained cortical fractional interstitial fibrosis volume (VintFib) proved to be two independent methods that are reliable predictive factors of poor renal allograft outcome. No data have been published, which define the correlation between ultrasound assessment and quantitative morphologic changes. Renal biopsies were performed in 56 children according to increases in s-creatinine >10%. VintFib was calculated by computerized image analysis. RI was determined in two segmental arteries, 1 yr after transplantation and at the time-point of biopsy. RIs 1 yr after transplantation correlated significantly with RIs at time of biopsy (r = 0.58, p < 0.001). VintFib was higher in children with a RI = 80 than in children with a RI < 80 (mean VintFib = 9.5 +/- 3.2% vs. 5.2 +/- 5.1%, p = 0.004). In children with VintFib > 10%, the mean RI was 77 +/- 5 compared with 69 +/- 6 in patients with VintFib < 10% (p = 0.0002). The highest positive predictive value to detect the risk of decline of GFR at 2 yr after biopsy was 98% when an RI = 80% was associated with a VintFib > 10%. For VintFib > 10% or RI = 80 alone, it was 87% or 67%, respectively. The combined measurement of RI and VintFib is a reliable predictive tool for the risk of developing long-term graft dysfunction after kidney transplantation.

Background: Vascular endothelial growth factor (VEGF) exerts cytoprotective, antiapoptotic and proangiogenic effects; its synthesis is induced by hypoxia, several cytokines and histamine. The effects of histamine and the H2 receptor antagonist ranitidine on renal VEGF and IL-6 synthesis were investigated in a well-established rat model of renal ischemia/reperfusion injury., Methods: Following 7 days of pretreatment with histamine (H group; n = 12), ranitidine (R group; n = 10) or vehicle (controls; n = 13), the left vascular pedicle was clamped for 50 min in uninephrectomized male rats and survival assessed in the different treatment groups. Additionally, renal IL-6 mRNA expression, as well as VEGF mRNA and protein abundance were measured in the three treatment groups following pretreatment only, 2 and 16 h after 50 min of renal ischemia (n = 6/group/timepoint)., Results: Ranitidine significantly increased, while histamine significantly decreased survival following renal ischemia. Renal IL-6 mRNA expression increased 2 h after reperfusion in all groups and decreased thereafter, with the lowest level observed in the R group. While VEGF mRNA did not change in controls, histamine increased, whereas ranitidine decreased its expression during the follow-up. Two hours after ischemia a twofold increase in renal VEGF protein abundance was observed in controls and the H group and significantly higher values were noted in the R group at this time point. A further increase in VEGF protein was only present in the H group 16 h after reperfusion., Conclusion: These results indicate an important role of histamine in kidney damage following renal ischemia. The beneficial effects of ranitidine were partly mediated by decreased IL-6 and VEGF mRNA expression and significant early increase in renal VEGF abundance., (Copyright 2004 S. Karger AG, Basel)

Background: Mycophenolate mofetil (MMF) has been used for the treatment of chronic allograft nephropathy (CAN) in adults with inconsistent results, but data in children are rare. To evaluate its impact on advanced CAN, we studied changes in glomerular filtration rate (GFR) and the correlation of GFR changes to histology., Methods: Thirty-six children (13.1+/-3.6 years) with a progressive decline in GFR of 16.9+/-12.4 mL/min per 1.73 m2/year and biopsy confirmed CAN 4.3+/-2.9 years after transplantation were studied. MMF was added to conventional immunosuppression (IS) consisting of cyclosporine (CsA) and prednisolone (n=26) or tacrolimus (n=1) or replaced azathioprine in triple IS (n=9). Alterations of GFR were correlated to histologic guidelines according to the Banff chronic score (BCS)., Results: One year after conversion, 22 (61%) children showed a rise in GFR (7.5+/-6 mL/min per 1.73 m2), 8 (22%) remained stable, and 6 (17%) showed a further decline of GFR (7.4+/-2 mL/min per 1.73 m2). Mean CsA trough levels were 114 ng/mL before and 98 ng/mL 1 year after conversion. MMF side effects required dose reduction in 14 children. Children responding to MMF with increasing GFR showed a trend toward less fibrosis, less incidence of vasculopathy, and transplant glomerulopathy in the initial biopsy but had a similar incidence of borderline tubulitis compared with the other groups., Conclusions: Cotreatment with MMF reversed the progressive loss of GFR in approximately two thirds of children with CAN for at least 1 year. Less chronicity signs in histology seem to indicate a more favorable response to treatment.

Background: Chronic allograft nephropathy (CAN) has become the predominant limiting factor for long-term transplant survival. A cardinal histomorphologic correlate for CAN is interstitial fibrosis. Currently, no method has been established in routine use that reliably quantifies the extent of interstitial fibrosis in renal grafts. We have used staining with picrosirius red followed by computerized image analysis to study the correlation between graft fibrosis and future development of glomerular filtration rate (GFR) in a group of children with advanced CAN., Methods: Renal biopsies were performed in 56 children (mean age, 13.7+/-3.6 years) after a mean period of 4.6+/-3.1 years after transplantation because of significant increases in serum creatinine. All biopsy specimens were stained with picrosirius red. The magnitude of fibrotic tissue was calculated by computerized image analysis. Linear regression analysis was performed correlating the intensity of graft fibrosis and the changes in the GFR at the time points of renal biopsy and 2 years later., Results: There was a significant positive correlation (r=0.62, P<0.001) between the picrosirius red-stained cortical fractional interstitial fibrosis volume (V(intFib)) and the decrease of GFR within 2 years postrenal biopsy. When V(intFib) was below 5%, 82% of the patients had an increase in GFR within 2 years. Ninety-three percent of the patients with greater than 10% of fibrosis experienced a worsening renal function after 2 years. When comparing patients with stable GFR with patients having a decrease in GFR, a highly significant difference in V(intFib) was found (P=0.008)., Conclusions: The quantitative measurement of fibrosis by picrosirius red staining appears to be a useful prognostic indicator for estimating long-term graft function in CAN and may provide an easy, fast, and inexpensive tool helpful for treatment decisions in patients developing CAN.