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The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. Multi-center, double-blind, randomized, placebocontrolled study in a subset of the 1052 patients of the Alphase study. 51 vMRI investigative sites in the United States and Canada. A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

Objective: To determine the presenting features of brain tumours in children. Design: Retrospective case note review. Setting: Paediatric and neurosurgical services at the Wessex Neurology Centre and Southampton General Hospital, UK. Patients: 200 patients presenting with a CNS tumour between 1988 and 2001. Results: The commonest first presenting symptoms were headache (41%), vomiting (12%), unsteadiness (11%), visual difficulties (10%), educational or behavioural problems (10%), and seizures (9%). The commonest symptoms occurring at any time were headache (56%), vomiting (51%), educational or behavioural problems (44%), unsteadiness (40%), and visual difficulties (38%). Neurological signs were present at diagnosis in 88%: 38% had papilloedema, 49% cranial nerve abnormalities, 48% cerebellar signs, 27% long tract signs, 11% somatosensory abnormalities, and 12% a reduced level of consciousness. The median symptom interval was 2.5 months (range 1 day to 120 months). A short symptom interval was significantly associated with high grade tumours and patient age of 3 years or younger. Conclusions: The well known predominance of headache in children with CNS tumours is confirmed. Visual, behavioural, and educational symptoms were also prominent. With the exception of seizures, every initial symptom was accompanied by other symptoms or signs by the time of diagnosis. Questions about visual symptoms and educational or behavioural difficulties, as well as the more widely recognised symptoms of raised intracranial pressure and motor dysfunction, are important in the diagnosis of brain tumours, as are vision assessment and the appropriate plotting of growth and head size.

When incorporated into lipid vesicles, the purified inositol 1,4,5-triphosphate (IP3) receptor protein mediates45Ca2+flux. We observe a potent, selective allosteric regulation by ATP of IP3actions on Ca2+flux. The action of ATP is selective for adenine nucleotides with ADP and AMP less potent and GTP inactive. At 1-10 μM, ATP increases maximal IP3-induced flux by 50% with no change in IP3potency. The enhancing effect of ATP diminishes between 0.1 and 1 mM. Concentration-response curves are steep for both the increasing and the decreasing effects of ATP on IP3actions, suggesting a physiological regulatory role of ATP in IP3-induced Ca2+release. Diminishing local ATP concentrations coincident with filling of Ca2+stores by the Ca2+-ATPase may enhance IP3release of Ca2+, an effect that would decline as ATP returns to physiological levels. ATP regulation of Ca2+release may also play a role in oscillations of intracellular Ca2+concentration.

The results of theory/experiment correlative studies at subsonic and supersonic Mach numbers are presented in this paper. These studies were conducted by using theoretical design tools consisting of the Method of Characteristics, newly-developed integral compressible boundary-layer methods for infinitely swept wings, namely, laminar boundary layer with suction, prediction of neutral instability and transition due to amplification of Tollmien-Schlichting (T.S.) waves and crossflow (C.F.), and a method for predicting separating turbulent boundary-layer characteristics. Results of correlations have indicated that the present integral boundary layer methods are quite successful in predicting transition phenomenon both at transonic and supersonic speeds. Correlations performed at subsonic and transonic Mach numbers have indicated that results of computations by the present methods for wings with sweep angles in the range of 0° to 50°, Reynolds number range of 1 to 30 million, and with and without boundary-layer suction, are in good agreement with experimental data. For supersonic freestream conditions correlative studies have been performed by the present methods for flat plate, biconvex airfoils, and bodies of revolution, and these results have also been found very encouraging.