Faculty Bibliography

PURPOSE OF REVIEW: Current magnetic resonance imaging systems allow the visualization of normal and diseased kidney, with exquisite resolution of renal structures. Dynamic contrast magnetic resonance imaging has the potential, unique among all noninvasive modalities, to differentiate diseases that affect different portions of the vascular-nephron system. This article reviews the most important recently published studies in selected topics chosen because of their clinical relevance or potential for technical developments. RECENT FINDINGS: Magnetic resonance imaging is used increasingly to evaluate renal masses, the prenatal genitourinary system, urinary obstruction and infection, renal vasculature, and the kidneys of transplant donors and recipients. Dynamic contrast magnetic resonance renography based on gadolinium chelated to diethylenetriamine pentaacetic acid, a safe (non-nephrotoxic) paramagnetic agent, emerges as the functional renal imaging modality of choice. Both perfusion and filtration rates can be assessed in individual kidney. SUMMARY: Magnetic resonance imaging has the potential to provide a complete anatomic, physiologic, kidney-specific evaluation. With future advances in automated image analysis methods we can expect functional renal magnetic resonance imaging to play an influential role in management of renal disease

Biological therapy for the inner ear has the potential to revolutionise the treatment of sensorineural hearing loss, the most common form of deafness. Progress in the molecular understanding of hearing and hearing loss, combined with advances in the fields of both gene and cellular therapy for the inner ear, is providing a robust foundation from which clinical translation is plausible. Potential areas of interest in gene therapy and its preclinical application to deafness are reviewed, and experimental progress that has occurred in cellular therapy for the inner ear is examined

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low-frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction theta=0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding gene POU4F3 yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region of POU4F3 it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI

Mutations within three genes, SDHB, SDHC, and SDHD, encoding distinct subunits of a hetero-oligomeric protein known as the mitochondrial complex II, a component of the mitochondrial electron transport chain and the Krebs cycle have been implicated in the pathogenesis of hereditary paraganglioma (PGL). This study describes a mutation screen of SDHB, SDHC, and SDHD in blood and tumor samples of 14 sporadic and three familial cases of head and neck PGL (HNP). Germline mutations in SDHB and SDHD were identified in two of the three affected individuals with familial HNP. The SDHB mutation was a novel 3 base pair, in-frame deletion of AGC at nucleotide 583-585 encoding serine (delS195). The SDHD mutation was a C to T transition within codon 81 causing substitution of proline with leucine (P81L). In contrast to familial cases, no germline or somatic mutations were identified in the 14 sporadic cases of HNP. The presence of mutations within SDHB and SDHD in two of the three samples of familial PGLs and absence of mutations in sporadic cases is consistent with the significant contribution of these genes to familial but not sporadic PGL. The etiology of sporadic PGL remains to be elucidated.

Increasing evidence implicates reactive oxygen species, particularly hydrogen peroxide (H2O2), as intracellular and intercellular messengers in the brain. This raises the question of how the antioxidant network in the brain can be sufficiently permissive to allow messages to be conveyed yet, at the same time, provide adequate protection against oxidative damage. Here we present evidence that this is accomplished in part by differential antioxidant compartmentalization between glia and neurons. Based on the rationale that the glia-to-neuron ratio is higher in guinea-pig brain than in rat brain, we examined the neuroprotective role of the glial antioxidant network by comparing the consequences of elevated H2O2 in guinea-pig and rat brain slices. The effects of exogenously applied H2O2 on evoked population spikes in hippocampal slices and on edema formation in forebrain slices were assessed. In contrast to the epileptiform activity observed in rat hippocampal slices after H2O2 exposure, no pathophysiology was seen in guinea-pig hippocampal slices. Similarly, elevated H2O2 caused edema in rat brain slices, whereas this did not occur in guinea-pig brain tissue. The resistance of guinea-pig brain tissue to H2O2 challenge was lost, however, when glutathione (GSH) synthesis was inhibited (by buthionine sulfoximine), GSH peroxidase activity was inhibited (by mercaptosuccinate), or catalase was inhibited (by 3-amino-1,2,4,-triazole). Strikingly, exogenously applied ascorbate, a predominantly neuronal antioxidant, was able to compensate for loss of any other single component of the antioxidant network. Together, these data imply significant roles for glial antioxidants and neuronal ascorbate in the prevention of pathophysiological consequences of the endogenous neuromodulator, H2O2

The Notch and fibroblast growth factor (FGF) pathways both regulate cell fate specification during mammalian neural development. We have shown previously that Notch1 activation in the murine forebrain promotes radial glial identity. This result, together with recent evidence that radial glia can be progenitors, suggested that Notch1 signaling might promote progenitor and radial glial character simultaneously. Consistent with this idea, we found that in addition to promoting radial glial character in vivo, activated Notch1 (ActN1) increased the frequency of embryonic day 14.5 (E14.5) ganglionic eminence (GE) progenitors that grew into neurospheres in FGF2. Constitutive activation of C-promoter binding factor (CBF1), a Notch pathway effector, also increased neurosphere frequency in FGF2, suggesting that the effect of Notch1 on FGF responsiveness is mediated by CBF1. The observation that ActN1 promoted FGF responsiveness in telencephalic progenitors prompted us to examine the effect of FGF pathway activation in vivo. We focused on FGFR2 because it is expressed in radial glia in the GEs where ActN1 increases FGF2 neurosphere frequency, but not in the septum where it does not. Like ActN1, activated FGFR2 (ActFGFR2) promoted radial glial character in vivo. However, unlike ActN1, ActFGFR2 did not enhance neurosphere frequency at E14.5. Additional analysis demonstrated that, unexpectedly, neither ActFGFR2 nor ActFGFR1 could replace the need for ligand in promoting neurosphere proliferation. This study suggests that telencephalic progenitors with radial glial morphology are maintained by interactions between the Notch and FGF pathways, and that the mechanisms by which FGF signaling promotes radial glial character in vivo and progenitor proliferation in vitro can be uncoupled