MRI-Based Brain Volumetry at a Single Time Point Complements Clinical Evaluation of Patients With Multiple Sclerosis in an Outpatient Setting.

Purpose: Thalamic atrophy and whole brain atrophy in multiple sclerosis (MS) are associated with disease progression. The motivation of this study was to propose and evaluate a new grouping scheme which is based on MS patients' whole brain and thalamus volumes measured on MRI at a single time point. Methods: In total, 185 MS patients (128 relapsing-remitting (RRMS) and 57 secondary-progressive MS (SPMS) patients) were included from an outpatient facility. Whole brain parenchyma (BP) and regional brain volumes were derived from single time point MRI T1 images. Standard scores (z-scores) were computed by comparing individual brain volumes against corresponding volumes from healthy controls. A z-score cut-off of -1.96 was applied to separate pathologically atrophic from normal brain volumes for thalamus and whole BP (accepting a 2.5% error probability). Subgroup differences with respect to the Symbol Digit Modalities Test (SDMT) and the Expanded Disability Status Scale (EDSS) were assessed. Results: Except for two, all MS patients showed either no atrophy (group 0: 61 RRMS patients, 10 SPMS patients); thalamic but no BP atrophy (group 1: 37 RRMS patients; 18 SPMS patients) or thalamic and BP atrophy (group 2: 28 RRMS patients; 29 SPMS patients). RRMS patients without atrophy and RRMS patients with thalamic atrophy did not differ in EDSS, however, patients with thalamus and BP atrophy showed significantly higher EDSS scores than patients in the other groups. Conclusion: MRI-based brain volumetry at a single time point is able to reliably distinguish MS patients with isolated thalamus atrophy (group 1) from those without brain atrophy (group 0). MS patients with isolated thalamus atrophy might be at risk for the development of widespread atrophy and disease progression. Since RRMS patients in group 0 and 1 are clinically not distinguishable, the proposed grouping may aid identification of RRMS patients at risk of disease progression and thus complement clinical evaluation in the routine patient care.

Fully automatic detection of deep white matter T1 hypointense lesions in multiple sclerosis.

A novel method is presented for fully automatic detection of candidate white matter (WM) T1 hypointense lesions in three-dimensional high-resolution T1-weighted magnetic resonance (MR) images. By definition, T1 hypointense lesions have similar intensity as gray matter (GM) and thus appear darker than surrounding normal WM in T1-weighted images. The novel method uses a standard classification algorithm to partition T1-weighted images into GM, WM and cerebrospinal fluid (CSF). As a consequence, T1 hypointense lesions are assigned an increased GM probability by the standard classification algorithm. The GM component image of a patient is then tested voxel-by-voxel against GM component images of a normative database of healthy individuals. Clusters (≥0.1 ml) of significantly increased GM density within a predefined mask of deep WM are defined as lesions. The performance of the algorithm was assessed on voxel level by a simulation study. A maximum dice similarity coefficient of 60% was found for a typical T1 lesion pattern with contrasts ranging from WM to cortical GM, indicating substantial agreement between ground truth and automatic detection. Retrospective application to 10 patients with multiple sclerosis demonstrated that 93 out of 96 T1 hypointense lesions were detected. On average 3.6 false positive T1 hypointense lesions per patient were found. The novel method is promising to support the detection of hypointense lesions in T1-weighted images which warrants further evaluation in larger patient samples.

A delay stochastic process with applications in molecular biology.

Molecular processes of cell differentiation often involve reactions with delays. We develop a mathematical model that provides a basis for a rigorous theoretical analysis of these processes as well as for direct simulation. A discrete, stochastic approach is adopted because several molecules appear in small numbers only. Our model is a non-Markovian stochastic process. The main theoretical results include a constructive proof of the existence of the process and a derivation of the rates for initiation and completion of reactions with delays. These results guarantee that the stochastic process is a consistent and realistic description of the molecular system. They also serve as a theoretical justification of recent work on delay stochastic simulation. We apply our model to an important process in developmental biology, the formation of somites in the vertebrate embryo. Simulation of the molecular oscillator controlling this process reveals major differences between stochastic and deterministic models.

Number of active transcription factor binding sites is essential for the Hes7 oscillator.

BACKGROUND: It is commonly accepted that embryonic segmentation of vertebrates is regulated by a segmentation clock, which is induced by the cycling genes Hes1 and Hes7. Their products form dimers that bind to the regulatory regions and thereby repress the transcription of their own encoding genes. An increase of the half-life of Hes7 protein causes irregular somite formation. This was shown in recent experiments by Hirata et al. In the same work, numerical simulations from a delay differential equations model, originally invented by Lewis, gave additional support. For a longer half-life of the Hes7 protein, these simulations exhibited strongly damped oscillations with, after few periods, severely attenuated the amplitudes. In these simulations, the Hill coefficient, a crucial model parameter, was set to 2 indicating that Hes7 has only one binding site in its promoter. On the other hand, Bessho et al. established three regulatory elements in the promoter region. RESULTS: We show that--with the same half life--the delay system is highly sensitive to changes in the Hill coefficient. A small increase changes the qualitative behaviour of the solutions drastically. There is sustained oscillation and hence the model can no longer explain the disruption of the segmentation clock. On the other hand, the Hill coefficient is correlated with the number of active binding sites, and with the way in which dimers bind to them. In this paper, we adopt response functions in order to estimate Hill coefficients for a variable number of active binding sites. It turns out that three active transcription factor binding sites increase the Hill coefficient by at least 20% as compared to one single active site. CONCLUSION: Our findings lead to the following crucial dichotomy: either Hirata's model is correct for the Hes7 oscillator, in which case at most two binding sites are active in its promoter region; or at least three binding sites are active, in which case Hirata's delay system does not explain the experimental results. Recent experiments by Chen et al. seem to support the former hypothesis, but the discussion is still open.

Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative system disorder affecting both upper and lower motor neurons. Despite supportive electrophysiological investigations, the involvement of the upper motor neuron is often difficult to assess at an early stage of disease. Diffusion tensor MRI provides an estimate of the orientation of fibre bundles in white matter on the basis of the diffusion characteristics of water. Diffusivity is generally higher in directions along fibre tracts than perpendicular to them. This degree of directionality of diffusion can be measured as fractional anisotropy. Changes in tissue structure due to degeneration of the corticospinal fibres can lead to a modification of the degree of directionality which can be detected by diffusion tensor MRI. We investigated 15 patients with ALS, six of whom had no clinical signs of upper motor neuron involvement at the time of MRI investigation, but developed pyramidal tract symptoms later in the course of their disease. These patients met the El Escorial criteria as their disease progressed. We found a decrease in fractional anisotropy in the corticospinal tract, corpus callosum and thalamus in all 15 ALS patients, including the patients without clinical signs of upper motor neuron lesion, compared with healthy controls. Regression analysis showed a negative correlation between fractional anisotropy and central motor conduction time obtained by transcranial magnetic stimulation, allowing spatial differentiation between the degenerated corticospinal tract fibres that supply the upper and lower extremities. Thus, diffusion tensor MRI can be used to assess upper motor neuron involvement in ALS patients before clinical symptoms of corticospinal tract lesion become apparent, and it may therefore contribute to earlier diagnosis of motor neuron disease.

Morbidity of harvesting of retromolar bone grafts: a prospective study.

20 retromolar bone grafts were harvested in outpatients for augmentation of the implant site from January to June 2000 (10 female, 10 male, 40.9 +/- 12.8 years, minimum 17 years, maximum 66 years). The aim of the study was to assess typical complications of this procedure in a prospective manner. For the determination of the superficial sensory function of the inferior alveolar and the lingual nerve, an objective method was used. The bone grafts were harvested for single tooth reconstruction. In 14 cases a ridge augmentation and in 6 cases an endoscopically controlled crestal sinus floor elevation was performed. Preoperatively, the height of bone above the cranial aspect of the inferior alveolar nerve in the retromolar region was assessed radiologically with known markers. The maximum mouth opening was determined. The superficial sensory function of the inferior alveolar and the lingual nerve was assessed with the Pointed-Blunt Test, the Two-Point-Discrimination Test and the objective method of the 'Pain and Thermal Sensitivity' Test (PATH Test). Moreover, the pulp sensitivity of the teeth of the donor site was determined by cold vitality testing. All tests were repeated 1 week postoperatively. Intraoperatively, the width of the retromolar region was measured with a caliper. The patients rated the operative strain on a visual analogue scale. The height of bone above the inferior alveolar nerve in the retromolar region was 11.0 +/- 2.2 mm. The width of the retromolar area was 14.2 +/- 1.9 mm. Postoperatively, the maximal mouth opening changed significantly (40.8 +/- 3.5 mm preoperatively, 38.9 +/- 3.7 mm postoperatively, P = 0.006). However, the reduction was not relevant clinically. A direct injury of the inferior alveolar or lingual nerve did not occur. A sensitivity impairment could not be detected for either of the nerves by the different test methods 1 week postoperatively. The operative strain related to the donor site was significantly less than the strain generated by the implant placement (rating on a visual analogue scale 2.8 +/- 1.0 and 4.1 +/- 2.0, respectively, P = 0.027). Retromolar bone grafts are a viable method for augmentation of the implant site in conjunction with single tooth reconstruction with low strain on the patient and minimal risk of complications.

Mutation of the myosin converter domain alters cross-bridge elasticity.

Elastic distortion of a structural element of the actomyosin complex is fundamental to the ability of myosin to generate motile forces. An elastic element allows strain to develop within the actomyosin complex (cross-bridge) before movement. Relief of this strain then drives filament sliding, or more generally, movement of a cargo. Even with the known crystal structure of the myosin head, however, the structural element of the actomyosin complex in which elastic distortion occurs remained unclear. To assign functional relevance to various structural elements of the myosin head, e.g., to identify the elastic element within the cross-bridge, we studied mechanical properties of muscle fibers from patients with familial hypertrophic cardiomyopathy with point mutations in the head domain of the beta-myosin heavy chain. We found that the Arg-719 --> Trp (Arg719Trp) mutation, which is located in the converter domain of the myosin head fragment, causes an increase in force generation and fiber stiffness under isometric conditions by 48-59%. Under rigor and relaxing conditions, fiber stiffness was 45-47% higher than in control fibers. Yet, kinetics of active cross-bridge cycling were unchanged. These findings, especially the increase in fiber stiffness under rigor conditions, indicate that cross-bridges with the Arg719Trp mutation are more resistant to elastic distortion. The data presented here strongly suggest that the converter domain that forms the junction between the catalytic and the light-chain-binding domain of the myosin head is not only essential for elastic distortion of the cross-bridge, but that the main elastic distortion may even occur within the converter domain itself.

Untersuchungen über die Höhlenimmigration von Micropterna nycterobia (Trichoptera, Limnephilidae).

The adults of Micropterna spp. estivate in caves, but there are considerable differences in abundance and species composition among different caves. Marking-recapture experiments were carried out with M. nycterobia near and in the Eisenstein cave in Lower Austria. Individuals released in early summer in distances up to 3 km from the cave returned and were recaptured there at rates of only 1-5%, but more or less independent of the distance from place of release and of the individual date of emergence. Later in the summer released Micropterna no longer immigrated. It is supposed that the migration of the adults of this species is not exclusively directed to caves, and that high abundance in a given cave depends mainly on mass occurrence of the larval stages in a nearby running stream. By exposure to light-sensitive material it was demonstrated that the caddis flies rest in the cave only in the region of weak illumination. They avoid total darkness. Therefore, we have not excluded that the development of their gonads depends, as is usual in insects, on day length.