Martyn Klein and Wilfred Rivera (both social workers) speak to press following defeat of Intro 2

General note: Title and date provided by Bettye Lane.

Autosomal recessive ataxias: 20 types, and counting

More than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in Neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.

Distortion product otoacoustic emissions in children at school entry: A comparison with pure tone screening and tympanometry results

This study examined the test performance of distortion product otoacoustic emissions (DPOAEs) when used as a screening tool in the school setting. A total of 1003 children (mean age 6.2 years, SD = 0.4) were tested with pure-tone screening, tympanometry, and DPOAE assessment. Optimal DPOAE test performance was determined in comparison with pure-tone screening results using clinical decision analysis. The results showed hit rates of 0.86, 0.89, and 0.90, and false alarm rates of 0.52, 0.19, and 0.22 for criterion signal-to-noise ratio (SNR) values of 4, 5, and 11 dB at 1.1, 1.9, and 3.8 kHz respectively. DPOAE test performance was compromised at 1.1 kHz. In view of the different test performance characteristics across the frequencies, the use of a fixed SNR as a pass criterion for all frequencies in DPOAE assessments is not recommended. When compared to pure tone plus tympanometry results, the DPOAEs showed deterioration in test performance, suggesting that the use of DPOAEs alone might miss children with subtle middle ear dysfunction. However, when the results of a test protocol, which incorporates both DPOAEs and tympanometry, were used in comparison with the gold standard of pure-tone screening plus tympanometry, test performance was enhanced. In view of its high performance, the use of a protocol that includes both DPOAEs and tympanometry holds promise as a useful tool in the hearing screening of schoolchildren, including difficult-to-test children.

The interaction of metal ions and Marimastat with matrix metalloproteinase 9

The effect of a range of metal ions on the ability of Marimastat to inhibit matrix metalloproteinase 9 (MMP-9) was examined in a fluorescence based proteolytic assay. Whilst none of the metals examined significantly affected the inhibitory ability of Marimastat, several metal ions did have a significant effect on MMP-9 activity itself. In the absence of Marimastat, Zn(II) and Fe(II) significantly inhibited MMP-9 activity at metal ion concentrations of 10 and 100 muM, respectively. In both the absence and presence of Marimastat, Cd(II) significantly inhibited MMP-9 at 100 muM. In contrast, 1 mM Co(II) significantly upregulated MMP-9 proteolytic activity. (C) 2003 Elsevier Science Inc. All rights reserved.

Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.