The p53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis and Influences Cerebellar Foliation

Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2puro), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1+/− mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis

Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population

Parathyroidectomy in Chronic Kidney Disease

Chronic Kidney Disease (CKD) associates with disturbed modulation of hormones involved in calcium and phosphate homeostasis, with development of secondary hyperparathyroidism (SHPT). SHPT includes not only divalent ions derangements, but also renal bone disease (high turnover, low turnover and/or osteomalacia) and accelerated vascular and ectopic calcifications. In this way, SHPT resembles a true clinical syndrome named CKD-MBD, which is a recognized risk factor of all-causeand cardiovascular death. Long lasting stimulation of parathyroid hormone synthesis and secretion, as observed in CKD, causes specific and progressive histological changes responsible for the development of nodular hyperplastic glands unresponsive to physiologic inhibitors and thus characterized by hypercalcemia, elevated PTH levels and resistance to the available medical therapies. In these cases, surgicalparathyroidectomy (PTX) becomes the only therapeutic option. In this chapter we review current evidence on indications, types and clinical outcomes of PTX from a practical and clinical point of view

The nuclear taboo, Battlestar Galactica

The nuclear age has been characterized by an emerging and now well-established norm of nuclear non-use, the 'nuclear taboo'. In the realistic and naturalistic setting of the science-fiction TV series Battlestar Galactica, however, nuclear weapons are used frequently and at times massively. Claiming that science fiction can function as an illuminating 'mirror' for international relations scholarship and that we can learn something from 'second-order' (fictional) worlds, this article explores potential in-show reasons that render the absence of a nuclear taboo plausible within the universe of Battlestar Galactica. We turn to the central pillars of the nuclear taboo in the real world and find them reversed in the show: nuclear weapons are (depicted as) 'clean', international institutions are absent, and the enemy is socially constructed as a 'radical other', thus rendering the possibility, if not likelihood, of nuclear war plausible. With these insights, we return to our world and argue that, particularly during the years of the George W Bush presidency, the erosion tendencies of the nuclear taboo were indeed quite serious: technological progress and growing political inclination expedited plans to develop usable nuclear weapons, arms control regimes came under considerable strain, and opponents were portrayed as 'unjust enemies' or 'rogues'