Dietary control of the renal reabsorption and excretion of α2u-globulin

Dietary protein supply is a factor in controlling the excretion of proteins in the urine. As early as 1926, Addis, Mackay, and Mackay observed that male rats on a 69% protein diet excreted more urinary proteins than did those on a 17% diet [1]. Protein deficiency had the opposite effect, resulting in a suppression of the proteinuria [2]. Of the total urinary proteins excreted by the adult male rat, approximately 30% is a sex-dependent globulin called α2u [3,4], which is synthesized by the liver [5] and controlled synergistically by androgens and glucocorticoids [6]. Dietary protein supply also had a profound influence on the excretion of α2u [4]. On a 0% casein diet, the excretion was reduced to approximately 1 mg/24 hours compared with a normal of 10 to 15mg. On a 50% casein diet, rats excreted 30 to 50 mg/24 hours, an increase of more than 100% above the normal [4].Early studies also suggested that high protein diets exaggerated the leakage of plasma proteins caused by a spontaneous nephrotic syndrome observed in male rats [7, 8]. Rats previously castrated did not exhibit an increased excretion of urinary protein on a 50% casein diet, whereas supplementation with testosterone restored the augmented proteinuria [9]. This suggested that the elevated excretion of urinary protein was dependent on the presence of androgens. It is now known that a high-protein diet caused an increased excretion of α2u without at the same time leading to a compensatory, stimulated hepatic biosynthesis. Conceivably, the increased excretion of α2u was the consequence of an altered state of renal reabsorption [4]. The purpose of the present communication was to compare the degree of renal reabsorption under three different dietary conditions and to determine whether the kidneys controlled the urinary excretion of α2u by altering its reabsorption

The economics of debt clearing mechanisms

We examine the evolution of decentralized clearinghouse mechanisms from the 13th to the 18th century; in particular, we explore the clearing of non- or limitedtradable debts like bills of exchange. We construct a theoretical model of these clearinghouse mechanisms, similar to the models in the theoretical matching literature, and show that specific decentralized multilateral clearing algorithms known as rescontre, skontrieren or virement des parties used by merchants were efficient in specific historical contexts. We can explain both the evolutionary self-organizing emergence of late medieval and early modern fairs, and its robustness during the 17th and 18th century

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy

Background Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.Methods In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing.Results For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found.Conclusions The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC

Biochemistry

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