Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and cranial nerves of a murine model of globoid cell leukodystrophy

Globoid cell leukodystrophy is an inherited neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase. In both human patients and the authentic murine Twitcher model, pathological findings include demyelination as well as axonal damage in both the central and peripheral nervous system. Diffusion tensor imaging (DTI) has emerged as a powerful noninvasive technique that is sensitive to these white matter disease processes. Increases in radial diffusivity (λ?) and decreases in axial diffusivity (λ∥) correlate with histopathological evidence of demyelination and axonal damage, respectively. Compared to age‐matched, normal littermates, DTI of optic nerve and trigeminal nerve in end‐stage Twitcher mice displayed a statistically significant increase in λ? and decrease in λ∥, consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in λ∥ was identified in both the dorsal and ventrolateral white matter, relative to normal controls. These results were consistent with immunofluorescence evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in λ? in Twitcher spinal cord white matter relative to normal controls reached statistical significance in the dorsal columns and approached statistical significance in the ventrolateral region. Correlative reduced levels of myelin basic protein were detected by immunofluorescent staining in both these white matter regions in the Twitcher spinal cord. Fractional anisotropy, a nonspecific but sensitive indicator of white matter disease, was significantly reduced in the optic nerve, trigeminal nerve, and throughout the spinal cord white matter of Twitcher mice, relative to normal controls. This first reported application of spinal cord DTI in the setting of GLD holds potential as a noninvasive, quantitative assay of therapeutic efficacy in future treatment studies. Copyright © 2009 John Wiley & Sons, Ltd.     

New radiological typing system for rhinosinusitis and comparison with existing system: Initial finding

The objective of this study was to determine whether the proposed Malan radiological sinusitis typing (RST) system facilitated a level of agreement and ease of use comparable with the Lund–Mackay (LM) system for chronic rhinosinusitis. Ten observers (one otolaryngologist and nine radiologists), in two separate centres (regional and tertiary), blinded to all clinical data, used these two systems to independently and randomly score and type 15 sets of scans, recording the time to score each film. Using unweighted kappa scores, both methods facilitated a moderate level of agreement, slightly better with the LM system. The Malan system is more time efficient. Preliminarily, this study shows that the Malan RST system is easy to apply with a comparable level of agreement. The Malan RST system is a focused attempt at classifying disease extent radiologically and correlating it to a surgical approach. It emphasizes that scoring systems are vulnerable and proves to be superior to the LM system as a surgical planning tool. To score sinus disease, a Quality‐of‐Life questionnaire in association with this typing method is more appropriate.     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

Acute renal failure in a neonate due to pelviureteric candidal bezoars successfully treated with long-term systemic fluconazole

Systemic candidiasis with renal involvement is a rare but well-recognized complication during intensive care treatment in very-low-birth-weight infants. We report a term neonate who developed anuria associated with bilateral bezoar formation in the renal pelvis and candidemia. The treatment consisted of placement of a nephrostomy tube in the left kidney, short-term irrigation with amphotericin B and iv, and later, oral administration of fluconazole.     

High mobility group proteins 1 and 2 recognize chromium-damaged DNA

Chromium (Cr) is a human carcinogen and a potent DNA damaging agent. Incubation of DNA with CrCl3 resulted in dose-dependent binding of Cr to DNA and, at concentrations >20 microM, altered the electrophoretic mobility of a 100 bp oligonucleotide. We also demonstrate that high mobility group (HMG) proteins 1 and 2 bind Cr-damaged DNA (Cr-DNA). Protein binding was lesion density-dependent, with maximal binding to DNA treated with 100 microM CrCl3. HMG2 binds to Cr-DNA with a calculated Kd of approximately 10(-9) M. These proteins also bound DNA obtained from chromate-treated cells. These results suggest that the covalent attachment of Cr to DNA induces alterations in DNA structure which are recognized by HMG1 and HMG2. Therefore, these proteins may function as Cr-damaged DNA recognition proteins in vivo and as a consequence of binding, may play a role in directing the cellular response to Cr-DNA adduct formation.