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Background Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice. Case-Diagnosis Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development. Conclusions A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear., Author(s): Anna Eichinger [sup.1] , Sabine Ponsel [sup.1] , Carsten Bergmann [sup.2] , Roman Günthner [sup.3] [sup.4] , Julia Hoefele [sup.3] , Kerstin Amann [sup.5] , Bärbel Lange-Sperandio [sup.1] Author [...]

The electrochemical behavior of [trans-RuCl4L(DMSO)](super -), [trans-RuCl4L2](super -) complexes, where L=imidazole, 1,2,4-triazole and indazole, are studied by cyclic voltammetry and controlled potential electrolysis. The characterization of the complexes is reported.

The synthesis of a series of mer-[Ru(super III)Cl3L3], trans-[Ru(super III)Cl2L4]Cl, trans-[Ru(super II)Cl2L4] and [RU(super II)L6](CF3SO3)2 complexes is reported. Compounds mer-[Ru(super III)Cl3L3] and a number of trans-[Ru(super III)Cl2L4]Cl complexes exhibit one Ru(super III)/Ru(super II) reduction, followed, at a sufficiently long time scale, by metal dechlorination on solvolysis.

Abstract: Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH4) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah enu1/2 bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH4 treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH4 pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using 13C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah enu1/1 , and Pah enu1/2 mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah enu1/1 and Pah enu1/2 indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH4. In conclusion, our findings show a significant impact of the genotype on the response to BH4 in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects. [ABSTRACT FROM AUTHOR]

The electrochemical behavior of [trans-RuCl4L(DMSO)]- (A) and [trans-RuCl4L2]- (B) [L = imidazole (Him), 1,2,4triazole (Htrz), and indazole (Hind)] complexes has been studied in BMF, DMSO, and aqueous media by cyclic voltammetry and controlled potential electrolysis. They exhibit one single-electron RuIIIRuII reduction involving, at a sufficiently long time scale, metal dechlorination on solvolysis, as well as, in organic media, one single-electron reversible RuIII/RuIV oxidation. The redox potential values are interpreted on the basis of the Lever's parametrization method, and particular forms of this linear expression (that relates the redox potential with the ligand EL parameter) are proposed, for the first time, for negatively (1-) charged complexes with the RuIII/II redox couple center in aqueous phosphate buffer (pH 7) medium and for complexes with the RuIII/IV couple in organic media. The EL parameter was estimated for indazole showing that this ligand behaves as a weaker net electron donor than imidazole or triazole. The kinetics of the reductively induced stepwise replacement of chloride by DMF were studied by digital simulation of the cyclic voltammograms, and the obtained rate constants were shown to increase with the net electron donor character (decrease of EL) of the neutral ligands (DMSO < indazole < triazole < imidazole) and with the basicity of the ligated azole, factors that destabilize the RuII relative to the ReIII form of the complexes. The synthesis and characterization of some novel complexes of the A and B series are also reported, including the X-ray structural analyses of (Ph3PCH2Ph)[trans-RuCl4(Htrz)(DMSO)], [(Ph3P)2N][trans-RuCl4(Htrz)(BMSO)], (H2ind)[trans-RuCl4(Hind)(DMSO)], and [(Hind)2H][ trans-RuCl4(Hind)2]. [ABSTRACT FROM AUTHOR]

Castleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGFβ, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment., Competing Interests: Conflict of interest: The authors do not have a conflict of interest.

Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH(4)) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah(enu1/2) bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH(4) treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH(4) pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using (13)C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah(enu1/1), and Pah(enu1/2) mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah(enu1/1) and Pah(enu1/2) indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH(4). In conclusion, our findings show a significant impact of the genotype on the response to BH(4) in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A series of mixed chloro-azole ruthenium complexes with potential antitumor activity, viz., mer-[RuIIICl3(azole)3] (B), trans-[RuIIICl2(azole)4]Cl (C), trans-[RuIICl2(azole)4] (D), and [RuII(azole)6](SO3CF3)2 (E), where azole = 1-butylimidazole (1), imidazole (2), benzimidazole (3), 1-methyl-1,2,4-triazole (4), 4-methylpyrazole (5), 1,2,4-triazole (6), pyrazole (7), and indazole (8), have been prepared as a further development of anticancer drugs with the general formula [RuCl4(azole)2]- (A). These compounds were characterized by elemental analysis, IR spectroscopy, electronic spectra, electrospray mass spectrometry, and X-ray crystallography. The electrochemical behavior has been studied in detail in DMF, DMSO, and aqueous media using cyclic voltammetry, square wave voltammetry, and controlled potential electrolysis. Compounds B and a number of C complexes exhibit one RuIII/RuII reduction, followed, at a sufficiently long time scale, by metal dechlorination on solvolysis. The redox potential values in organic media agree with those predicted by Lever's parametrization method, and the yet unknown EL parameters were estimated for 1 (EL = 0.06 V), 3 (EL = 0.10 V), 4 (EL = 0.17 V), and 5 (EL = 0.18 V). The EL values for the azole ligands 1-8 correlate linearly with their basicity (pK(a) value of the corresponding azolium acid H2L+). In addition, a logarithmic dependence between the homogeneous rate constants for the reductively induced stepwise replacement of chloro ligands by solvent molecules and the RuIII/RuII redox potentials was observed. Lower E(1/2) values (higher net electron donor character of the ligands) result in enhanced kinetic rate constants of solvolysis upon reduction. The effect of the net charge on the RuIII/RuII redox potentials in water is tentatively explained by the application of the Born equation. In addition, the pH-dependent electrochemical behavior of trans-[RuCl2(1,2,4-triazole)4]Cl is discussed.

The electrochemical behavior of [trans-RuCl(4)L(DMSO)](-) (A) and [trans-RuCl(4)L(2)](-) (B) [L = imidazole (Him), 1,2,4-triazole (Htrz), and indazole (Hind)] complexes has been studied in DMF, DMSO, and aqueous media by cyclic voltammetry and controlled potential electrolysis. They exhibit one single-electron Ru(III)/Ru(II) reduction involving, at a sufficiently long time scale, metal dechlorination on solvolysis, as well as, in organic media, one single-electron reversible Ru(III)/Ru(IV) oxidation. The redox potential values are interpreted on the basis of the Lever's parametrization method, and particular forms of this linear expression (that relates the redox potential with the ligand E(L) parameter) are proposed, for the first time, for negatively (1-) charged complexes with the Ru(III/II) redox couple center in aqueous phosphate buffer (pH 7) medium and for complexes with the Ru(III/IV) couple in organic media. The E(L) parameter was estimated for indazole showing that this ligand behaves as a weaker net electron donor than imidazole or triazole. The kinetics of the reductively induced stepwise replacement of chloride by DMF were studied by digital simulation of the cyclic voltammograms, and the obtained rate constants were shown to increase with the net electron donor character (decrease of E(L)) of the neutral ligands (DMSO < indazole < triazole < imidazole) and with the basicity of the ligated azole, factors that destabilize the Ru(II) relative to the Ru(III) form of the complexes. The synthesis and characterization of some novel complexes of the A and B series are also reported, including the X-ray structural analyses of (Ph(3)PCH(2)Ph)[trans-RuCl(4)(Htrz)(DMSO)], [(Ph(3)P)(2)N][trans-RuCl(4)(Htrz)(DMSO)], (H(2)ind)[trans-RuCl(4)(Hind)(DMSO)], and [(Hind)(2)H][trans-RuCl(4)(Hind)(2)].