Quantitative proton magnetic resonance spectroscopy of children with adrenoleukodystrophy before and after hematopoietic stem cell transplantation

About 35-40 % of boys with X-linked adrenoleukodystrophy (ALD) develop a rapidly progressive cerebral form which leads to severe neurologic disability and death within 3-5 years after onset of clinical symptoms. Because previous proton magnetic resonance spectroscopy (MRS) studies of ALD identified metabolite patterns characteristic of demyelination, gliosis, and neuroaxonal loss, this work tested the hypothesis that MRS--apart from indicating disease progression--provides criteria for the outcome after hematopoietic stem cell transplantation (HSCT) which has been promising at an early stage of the active disease. Follow-up quantitative proton MRS was performed in frontal and occipital white matter of ALD patients (n = 12) before and up to 5 years after HSCT. The observed metabolite alterations were retrospectively correlated with the clinical outcome representing either a stable condition (n = 5), a further deterioration (n = 5), or death (n = 2). While disease progression of patients before HSCT was mainly characterized by a further increase of elevated choline-containing compounds (Cho) as an indicator of active demyelination, a positive outcome after HSCT was correlated with high N-acetylaspartate (tNAA) levels in affected white matter before HSCT yielding positive and negative predictive values for tNAA of 80 %. Although to be confirmed in a larger cohort of patients, the present findings suggest the preservation of neuroaxonal integrity as a prerequisite for an arrested course. Conversely, the combination of increased Cho with markedly reduced tNAA before HSCT apparently reflects a degree of tissue degeneration which precludes a successful therapeutic intervention.     

Using a 1 M Gd-chelate (gadobutrol) for total-body three-dimensional MR angiography: preliminary experience

PURPOSE: To determine whether higher concentrated gadolinium chelates are advantageous for the recently introduced concept of total-body magnetic resonance angiography (MRA), allowing whole-body coverage, extending from the carotid arteries to the runoff vessels, in merely 72 seconds. MATERIALS AND METHODS: Total-body three-dimensional (3D) MRA using a 1 M Gd-chelate (gadobutrol, Gadovist, Schering, Berlin, Germany) at a dosage of 0.2 mmol/kg body-weight (biphasic injection protocol: 1.3 mL/second and 0.7 mL/second) was performed on three healthy volunteers and ten consecutive patients with DSA-documented peripheral vascular disease. Separated by at least 72 hours, the three healthy volunteers also underwent the same MRA-protocol, using gadopentetate dimeglumine in equimolar dosages. RESULTS: Compared to equimolar dosages, mean signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values in the three volunteers were significantly higher (up to 32.5% for the arteries of the thighs and calves) using gadobutrol. In the ten patients, gadobutrol-based total-body MRA accurately assessed significant stenoses (luminal narrowing > 50%) with sensitivities and specificities of 96.2% (95% CI 0.83-0.97) and 95.7% (95% CI 0.84-0.96), respectively, compared to digital subtraction angiography. CONCLUSION: The MRA image quality for total-body MRA provided by the administration of gadobutrol is superior to that obtained following administration of an identical dose of gadopentetate dimeglumine, and therefore shows promise for use as a comprehensive single exam assessing the entire arterial system for the presence of atherosclerotic disease manifestations.     

Studies on the synthesis and biological properties of non-carrier-added [(125)I and (131)I]-labeled arylalkylidenebisphosphonates: potent bone-seekers for diagnosis and therapy of malignant osseous lesions

Arylalkylidenebisphosphonates labeled with nca [(125)I or (131)I] have been synthesized and their biological function investigated. The label was attached to the aromatic group in high yield and under mild conditions by means of iododesilylation. The bone affinities of the radioactive compounds were investigated in normal Balb/C mice. The compound 1-hydroxy(m-iodo[(125,131)I]-phenylethylidene)-1,1-bisphosphonate was found to possess superior bone affinity compared to others, and its in vivo deiodination was insignificant. The uptake in femur 24h after injection was 850 +/- 265% and 986 +/- 118% of injected dose per gram tissue times gram body weight in mice and rats, respectively. The therapeutic potential of the compound was investigated in two tumor models in athymic (nude) rats, one model for mixed lytic/sclerotic metastatic bone-lesions originating from breast cancer and the other model simulating osseous osteosarcoma. The effects in these models compare favorably to those observed for established treatment modalities. The experiments demonstrate that radioiodinated bisphosphonates may have a potential for diagnosis and therapy of malignant osseous lesions.     

Synthesis and biological activity of pyridinium-type acetylcholinesterase inhibitors

A novel series of bispyridinium-type acetylcholinesterase (AChE) inhibitors derived from obidoxime, being active in the lower micromolar range, has been reported recently. According to the hypothesis that shorter pyridinium compounds should exhibit higher activity, a new series of compounds was synthesized that has 2,6-dichlorobenzyl, 2-chlorobenzyl and phthalimidomethyl moieties, respectively, at one end of the molecule and that are systematically shortened from the contralateral end. The concentration inhibiting the AChE and butyrylcholinesterase (BChE) by 50% (IC50) was evaluated by means of Ellman's test. Compounds characterized by a phenylpropyl residue at the contralateral end (3) were found to have IC50 values comparable with tacrine. In addition, the affinity of 3c toward the BChE was lower, indicating a lower degree of side effects.