The role of the classical complement pathway in humoral immune responses was investigated in gene-targeted C1q-deficient mice (c1qa(-/-). Production of antigen-specific immunoglobulin (lg)g2a and Igg3 in primary and secondary responses to T cell-dependent antigen was significantly reduced, whereas Igm, Igg1, and Igg2b responses were similar in control and C1qa(-/-) mice. Despite abnormal humoral responses, B cells from C1qa(-/-) mice proliferated normally to a number of stimuli in vitro. Immune complex localization to follicular dendritic cells within splenic follicles was lacking in C1qa(-/-) mice. The precursor frequency of antigen-specific T cells was similar in C1qa(-/-) and wild-type mice. However, analysis of cytokine production by primed T cells in response to keyhole limpet hemocyanin revealed a significant reduction in interferon-γ production in C1qa(-/-) mice compared with control mice, whereas interleukin 4 secretion was equivalent. These data suggest that the classical pathway of complement may influence the cytokine profile of antigen-specific T lymphocytes and the subsequent immune response.

The extremum stack, as proposed by Koenderink, is a multiresolution image description and segmentation scheme which examines intensity extrema (minima and maxima) as they move and merge through a series of progressively isotropically diffused images known as scale space. Such a data-driven approach is attractive because it is claimed to be a generally applicable and natural method of image segmentation. The performance of the extremum stack is evaluated here using the case of neurological magnetic resonance imaging data as a specific example, and means of improving its performance proposed. It is confirmed experimentally that the extremum stack has the desirable property of being shift-, scale-, and rotation-invariant, and produces natural results for many compact regions of anatomy. It handles elongated objects poorly, however, and subsections of regions may merge prematurely before each region is represented as a single node. It is shown that this premature merging can often be avoided by the application of either a variable conductance-diffusing preprocessing step, or more effectively, the use of an adaptive variable conductance diffusion method within the extremum stack itself in place of the isotropic Gaussian diffusion proposed by Koenderink.

OBJECTIVE: The serial quantification of MRI lesion load in multiple sclerosis provides an effective tool for monitoring disease progression and this has led to its increasing use as an outcome measure in treatment trials. Segmentation techniques must display a high degree of precision and reliability if they are to be responsive to small changes over time. This study has evaluated the performance of two such techniques, the manual outlining and contour methods, in serial lesion load quantification.
METHODS: Sixteen patients with clinically definite multiple sclerosis were scanned at baseline and after two years. Scan analysis was performed twice, independently by three observers using each technique.
RESULTS: For the absolute lesion volumes the median intrarater coefficient of variation (CV) was 3.2% for the contour technique and 7.6% for the manual outlining method (p < 0.005), the interrater CVs were 3.8% and 6.1% respectively (p < 0.01) and the reliability of both techniques was very high. For the change in lesion volume the intrarater and interrater repeatability coefficients were respectively 2.6 cm3 and 2.8 cm3 for the contour technique, and 3.3 cm3 and 3.7 cm3 for the manual outlining method (lower values reflect higher precision). The values for intrarater and interrater reliability for measuring change in lesion volume were respectively, 0.945 and 0.944 for the contour technique, and 0.939 and 0.921 for the manual outline method (perfect reliability = 1.0). CONCLUSIONS: With such high values for reliability, the impact of measurement error in lesion segmentation on sample size requirements in multiple sclerosis treatment trials is minor. This study shows that a change in lesion volume can be measured with a higher level of precision and reliability with the contour technique and this supports its further application in serial studies.

The change of brain lesion load, measured on T2-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collection, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.

AIM: An approach to measuring physical quantities such as lesion load with MRI in multicentre studies is presented. METHOD: Examples are given of imperfections in current techniques: (1) a step change in a serial trial, giving an apparent (but artefactual) decrease in total lesion volume in untreated patients with multiple sclerosis; (2) inaccuracy (systematic error) in lesion volume, found by measuring a phantom with lesions of known volumes; (3) spatial non-uniformity in the radiofrequency coil sensitivity, giving gross image shading. When using the magnetic resonance imaging (MRI) scanner as a scientific instrument to measure physical quantities, accuracy (closeness to the truth, or lack of systematic error), and precision (reproducibility, or lack of random error) are the keys to success. Quality assurance procedures can utilise phantoms, normal control subjects, and stable patients, and have to be included in serial studies and trials. Between scanner agreement can perhaps be improved by attempting to replicate an inaccurate procedure at each site; but it is more preferable to seek accuracy and precision (as a perfectly accurate and precise procedure must give the same results at all sites).
CONCLUSION: Before being included in a serial study, a measurement procedure should ideally demonstrate:(1) accuracy in a phantom; (2) precision in repeated measurements on a phantom; (3) precision in repeated measurements on human subjects.

Inhomogeneity of the transmitted or received B1 field leads to intensity variations in MR images and spatial dependence in apparent concentration in MR spectra. We describe a simple method for investigating such variations. The transmitted B1 field can be measured both in vivo and in vitro which allows investigation of sample dependent effects that can not be measured on phantoms. For homogeneous regions the method also allows the received B1 field to be measured both in vivo and in vitro. Our method uses only a standard spin echo pulse sequence and simple region of interest analysis and should be implementable on any commercial scanner. The method is demonstrated using a variety of transmission and reception radiofrequency coils both in vivo and in vitro.