Jere Douglas Fellmann

The synthesis, characterization and biological studies of a dimeric W3S4 cluster complex: a new potential X-ray contrast agent

Abstract An EGTA complex of the incomplete cubane-type, trinuclear tungsten sulfur cluster, [W3S4], was prepared and investigated as a possible candidate for a new generation of X-ray contrast agents for medical diagnostic imaging. The aqua ion, [W3S4(H2O)9]4+ (I) was prepared through an improvement of the literature method to facilitate scale-up. Reaction of I with EGTA in refluxing DMF produced a mixture of (W3S4)x(EGTA)y (x,y ≥ 1) cluster complexes. A 2:3(W3S4:ligand) complex, [(W3S4)2(EGTA)3]4− (II), was isolated via size-exclusion chromatography in 25–40% yield. Cluster complex II was fully characterized by X-ray crystallography in addition to routine techniques. It is soluble in H2O and stable in the pH range 2 to 10. Animal studies of II indicated a low acute toxicity and a pharmacokinetic profile similar to that of an existing heavy metal cluster complex with a known extracellular biodistribution.

Shunting in AD slows progression of the dementia

Background The pathogenesis of Alzheimers disease (AD) may involve impaired clearance of toxic metabolites, e.g. amyloid-beta peptides (Aβ), from the brain via interstitial fluid (ISF) and cerebrospinal fluid (CSF) circulation, and the blood-brain barrier (BBB). If so, then increasing ISF and CSF circulation may improve CSF Aβ clearance and may slow the progression of AD. We tested this hypothesis in a prospective, randomized, double-blind, placebo-controlled trial of low-flow CSF shunting. Our previously reported analysis using the Generalised Estimating Equations showed no effect of CSF shunting. The present report provides post hoc analyses using linear mixedeffects models fit by maximum likelihood.

Shunting in AD increases ventricular CSF protein levels

Background Defects in CSF circulation may impair clearance of toxic metabolites (i.e. amyloid-beta peptides – Aβ), from the brain via interstitial fluid (ISF) and so contribute to pathology in Alzheimers disease (AD). On this view, constant drainage of CSF via a low-flow ventriculo-peritoneal shunt could facilitate clearance of toxic moieties from ISF and so slow disease progression. We tested this possibility in a prospective, randomized, double-blind controlled, multi-centre trial. We have reported elsewhere that patients with active shunts showed less cognitive decline than controls. Here, we analyse the effects of shunting on CSF protein concentrations in AD patients.