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There is an increasing interest in quantitative imaging of T1, T2 and diffusion contrast in the brain due to greater robustness against bias fields and artifacts, as well as better biophysical interpretability in terms of microstructure. However, acquisition time constraints are a challenge, particularly when multiple quantitative contrasts are desired and when extensive sampling of diffusion directions, high b-values or long diffusion times are needed for multi-compartment microstructure modeling. Although ultra-high fields of 7 T and above have desirable properties for many MR modalities, the shortening T2 and the high specific absorption rate (SAR) of inversion and refocusing pulses bring great challenges to quantitative T1, T2 and diffusion imaging. Here, we present the MESMERISED sequence (Multiplexed Echo Shifted Multiband Excited and Recalled Imaging of STEAM Encoded Diffusion). MESMERISED removes the dead time in Stimulated Echo Acquisition Mode (STEAM) imaging by an echo-shifting mechanism. The echo-shift (ES) factor is independent of multiband (MB) acceleration and allows for very high multiplicative (ESxMB) acceleration factors, particularly under moderate and long mixing times. This results in super-acceleration and high time efficiency at 7 T for quantitative T1 and diffusion imaging, while also retaining the capacity to perform quantitative T2 and B1 mapping. We demonstrate the super-acceleration of MESMERISED for whole-brain T1 relaxometry with total acceleration factors up to 36 at 1.8 mm isotropic resolution, and up to 54 at 1.25 mm resolution qT1 imaging, corresponding to a 6x and 9x speedup, respectively, compared to MB-only accelerated acquisitions. We then demonstrate highly efficient diffusion MRI with high b-values and long diffusion times in two separate cases. First, we show that super-accelerated multi-shell diffusion acquisitions with 370 whole-brain diffusion volumes over 8 b-value shells up to b = 7000 s/mm2 can be generated at 2 mm isotropic in under 8 minutes, a data rate of almost a volume per second, or at 1.8 mm isotropic in under 11 minutes, achieving up to 3.4x speedup compared to MB-only. A comparison of b = 7000 s/mm2 MESMERISED against standard MB pulsed gradient spin echo (PGSE) diffusion imaging shows 70% higher SNR efficiency and greater effectiveness in supporting complex diffusion signal modeling. Second, we demonstrate time-efficient sampling of different diffusion times with 1.8 mm isotropic diffusion data acquired at four diffusion times up to 290 ms, which supports both Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) at each diffusion time. Finally, we demonstrate how adding quantitative T2 and B1+ mapping to super-accelerated qT1 and diffusion imaging enables efficient quantitative multi-contrast mapping with the same MESMERISED sequence and the same readout train. MESMERISED extends possibilities to efficiently probe T1, T2 and diffusion contrast for multi-component modeling of tissue microstructure.

There is an increasing interest in quantitative imaging of T

There is an increasing interest in quantitative imaging of T1, T2 and diffusion contrast in the brain due to greater robustness against bias fields and artifacts, as well as better biophysical interpretability in terms of microstructure. However, acquisition time constraints are a challenge, particularly when multiple quantitative contrasts are desired and when extensive sampling of diffusion directions, high b-values or long diffusion times are needed for multi-compartment microstructure modeling. Although ultra-high fields of 7 T and above have desirable properties for many MR modalities, the shortening T2 and the high specific absorption rate (SAR) of inversion and refocusing pulses bring great challenges to quantitative T1, T2 and diffusion imaging. Here, we present the MESMERISED sequence (Multiplexed Echo Shifted Multiband Excited and Recalled Imaging of STEAM Encoded Diffusion). MESMERISED removes the dead time in Stimulated Echo Acquisition Mode (STEAM) imaging by an echo-shifting mechanism. The echo-shift (ES) factor is independent of multiband (MB) acceleration and allows for very high multiplicative (ESxMB) acceleration factors, particularly under moderate and long mixing times. This results in super-acceleration and high time efficiency at 7 T for quantitative T1 and diffusion imaging, while also retaining the capacity to perform quantitative T2 and B1 mapping. We demonstrate the super-acceleration of MESMERISED for whole-brain T1 relaxometry with total acceleration factors up to 36 at 1.8 mm isotropic resolution, and up to 54 at 1.25 mm resolution qT1 imaging, corresponding to a 6x and 9x speedup, respectively, compared to MB-only accelerated acquisitions. We then demonstrate highly efficient diffusion MRI with high b-values and long diffusion times in two separate cases. First, we show that super-accelerated multi-shell diffusion acquisitions with 370 whole-brain diffusion volumes over 8 b-value shells up to b = 7000 s/mm2 can be generated at 2 mm isotropic in under 8 minutes, a data rate of almost a volume per second, or at 1.8 mm isotropic in under 11 minutes, achieving up to 3.4x speedup compared to MB-only. A comparison of b = 7000 s/mm2 MESMERISED against standard MB pulsed gradient spin echo (PGSE) diffusion imaging shows 70% higher SNR efficiency and greater effectiveness in supporting complex diffusion signal modeling. Second, we demonstrate time-efficient sampling of different diffusion times with 1.8 mm isotropic diffusion data acquired at four diffusion times up to 290 ms, which supports both Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) at each diffusion time. Finally, we demonstrate how adding quantitative T2 and B1+ mapping to super-accelerated qT1 and diffusion imaging enables efficient quantitative multi-contrast mapping with the same MESMERISED sequence and the same readout train. MESMERISED extends possibilities to efficiently probe T1, T2 and diffusion contrast for multi-component modeling of tissue microstructure.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B1+) inhomogeneities, specially at ultra-high field (UHF, 7T and higher). To overcome these issues, it is necessary to tailor ex vivo diffusion-weighted sequences specifically for high resolution and high diffusion-weighting. Here, we present kT-dSTEAM, which achieves B1+ homogenization across whole human brain specimens using parallel transmit (pTx) on a 9.4T MR system. We use kT-dSTEAM to obtain multi-shell high b-value and high resolution diffusion-weighted data in ex vivo whole human brains. Isotropic whole brain data can be acquired at high b-value (6000-8000 s/mm2) at high resolution (1000 μm) and at moderate b-value (3000 s/mm2) at ultra-high isotropic resolution (400 μm). As an illustration of the advantages of the ultra-high resolution, tractography across the WM/GM border shows less of the unwanted gyral crown bias, and more high-curvature paths connecting the sulcal wall than at lower resolution. The kT-dSTEAM also allows for acquisition of T1 and T2 weighted images suitable for estimating quantitative T1 and T2 maps. Finally, multi-shell analysis of kT-dSTEAM data at variable mixing time (TM) is shown as an approach for ex vivo data analysis which is adapted to the strengths of STEAM diffusion-weighting. Here, we use this gain for multi-orientation modelling and crossing-fiber tractography. We show that multi-shell data allows superior multiple orientation tractography of known crossing fiber structures in the brain stem.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B

In der Hautklinik Linden der Medizinischen Hochschule Hannover wurden im Zeitraum 1982–1990 neunzehn Patienten mit einem Akrolentiginosen Melanom im Bereich der Finger, Zehen oder Zehenzwischenraume operativ behandelt. Neun Patienten wurden einer Amputation zugefuhrt, wahrend zehn Patienten radikal aber funktionserhaltend operiert wurden. Nach einer Nachbeobachtungszeit uber 24–107 Monate bei neun amputierten Patienten von denen 2 Patienten nach 26 bzw. 51 Monaten infolge einer generalisierten Metastasierung verstarben und nach einer Nachbeobachtungszeit uber 9–77 Monate bei zehn radikal aber funktionserhaltend operierten Patienten, von denen nach 17 Monaten ein Patient an einer generalisierten Metastasierung verstarb, scheint in Hinblick auf die Uberlebenszeit die Amputation gegenuber der radikalen funtionserhaltenden Operation nicht uberlegen zu sein.

A delayed-type hypersensitivity (DTH) reaction was induced in the skin of young pigs, by local injection of phytohaemagglutinin, and evaluation was carried out on the resulting accumulation of lymphocyte subsets and lymphocyte production by incorporation of bromodeoxyuridine in the skin and the draining lymph node. There was a rapid increase in mononuclear cells, which were found in clusters around venules. These included very few B lymphocytes, and CD8+ lymphocytes far outnumbered CD4+ cells. Underlining the importance of determining absolute numbers, the relative and absolute numbers of lymphocyte subsets showed quite different patterns during the development of the skin reaction. Lymphocytes in the normal skin incorporated the DNA precursor bromodeoxyuridine at higher rates than have been found for peripheral lymphoid organs. After intradermal phytohaemagglutinin injections, all subsets showed high proliferation rates in the skin, with kinetics which differed from the reaction in the draining lymph node. The labelling indexes of cells labelled with bromodeoxyuridine in vitro and in vivo were comparable. The phytohaemagglutinin injections also caused a marked and rapid increase in the proliferation of the cells in the basal layer of the epidermis. This model DTH-like reaction in skin with major CD8+ T-cell accumulation and proliferation locally and in the lymph nodes provides a reliable model for study of such reactions and for investigation of the regulatory role of cytokines.

Lymphocyte subsets leave the blood and appear in the thoracic duct of normal rats at different rates. The aim of the present study was to investigate their migration pattern through blood, spleen, bone marrow, mesenteric lymph nodes, and Peyer's patches in normal Lewis rats and to study the role of the spleen using splenectomized and spleen-transplanted animals. Fluorescein isothiocyanate (FITC)-labelled thoracic duct lymphocytes (TDL) were injected intravenously into rats and after 15 min, 1, 6, and 24 h the percentages of B, T, T helper (TH) and T-cytotoxic/suppressor (TC/S) lymphocytes in the FITC+ cells were determined in cell suspensions by means of monoclonal antibodies. B and T lymphocytes are preferentially localized in different organs, e.g. B cells in Peyer's patches and T cells in mesenteric lymph nodes. The migration of TH lymphocytes differed from that of TC/S lymphocytes in all the organs investigated. In the late phase after injection the migration of B and TH lymphocytes was influenced by the spleen, since after splenectomy the number of injected B lymphocytes increased and that of TH lymphocytes decreased in all organs investigated except the bone marrow. Splenic autotransplantation could not normalize the disturbed migration.

Advances in biophysical multi-compartment modeling for diffusion MRI (dMRI) have gained popularity because of greater specificity than DTI in relating the dMRI signal to underlying cellular microstructure. A large range of these diffusion microstructure models have been developed and each of the popular models comes with its own, often different, optimization algorithm, noise model and initialization strategy to estimate its parameter maps. Since data fit, accuracy and precision is hard to verify, this creates additional challenges to comparability and generalization of results from diffusion microstructure models. In addition, non-linear optimization is computationally expensive leading to very long run times, which can be prohibitive in large group or population studies. In this technical note we investigate the performance of several optimization algorithms and initialization strategies over a few of the most popular diffusion microstructure models, including NODDI and CHARMED. We evaluate whether a single well performing optimization approach exists that could be applied to many models and would equate both run time and fit aspects. All models, algorithms and strategies were implemented on the Graphics Processing Unit (GPU) to remove run time constraints, with which we achieve whole brain dataset fits in seconds to minutes. We then evaluated fit, accuracy, precision and run time for different models of differing complexity against three common optimization algorithms and three parameter initialization strategies. Variability of the achieved quality of fit in actual data was evaluated on ten subjects of each of two population studies with a different acquisition protocol. We find that optimization algorithms and multi-step optimization approaches have a considerable influence on performance and stability over subjects and over acquisition protocols. The gradient-free Powell conjugate-direction algorithm was found to outperform other common algorithms in terms of run time, fit, accuracy and precision. Parameter initialization approaches were found to be relevant especially for more complex models, such as those involving several fiber orientations per voxel. For these, a fitting cascade initializing or fixing parameter values in a later optimization step from simpler models in an earlier optimization step further improved run time, fit, accuracy and precision compared to a single step fit. This establishes and makes available standards by which robust fit and accuracy can be achieved in shorter run times. This is especially relevant for the use of diffusion microstructure modeling in large group or population studies and in combining microstructure parameter maps with tractography results., Highlights • Evaluate robustness of fit, accuracy, precision for diffusion microstructure models • Test three optimization algorithms and three parameter initialization strategies • GPU implementation removes run time constraints; whole brain fit within minutes • Powell conjugate-direction algorithm has superior fit, accuracy, precision • Initialization approaches are important for crossing fiber microstructure models

The development of the number, size, structure and proliferative capacity of Peyer's patches (PP) in the jejunum and ileum has been studied during the early postnatal period of conventional and germ-free pigs. A mean of 15 discrete PP in the jejunum and upper ileum (jejPP) were counted at birth, and the number increased only gradually. A continuous PP is located in the terminal ileum (ileal PP). The length of both jejPP and ileal PP increased with age due to the increase in follicle size and in the number of follicles in the ileal PP. In older pigs, only the ileal PP regressed to small scattered follicles. In germ-free piglets at 39 and 59 days of age, longer PP were found than in normal new-born piglets, but they were significantly shorter than in age-matched controls. Lymphocyte production was studied by the metaphase-arrest technique using vincristine. Lymphocyte production in follicles increased dramatically with age, while in other compartments, such as the inter-follicular and dome area, a low age-independent production of lymphocytes was found. There were no differences in lymphocytopoiesis between jejPP and ileal PP. The present data show major differences in the development, structure and function of PP in pigs in comparison to other species. These species-specific aspects are important for future studies on the immunological function of PP.

The gut-associated lymphoid tissue consists of intraepithelial and lamina propria lymphocytes and organized lymphoid tissue, the Peyer’s patches (PP). In pigs there are two types of PP, discrete ones in the jejunum (jejPP) and a continuous PP in the ileum (ilPP). Their role in the pig’s lymphoid system is not known: probably antigen from the gut lumen crossing the epithelium of the PP stimulates their lymphocytopoiesis.

Diffusion MRI (dMRI) allows for non-invasive investigation of brain tissue microstructure. By fitting a model to the dMRI signal, various quantitative measures can be derived from the data, such as fractional anisotropy, neurite density and axonal radii maps. The uncertainty in these dMRI measures is often ignored, while previous work in functional MRI has shown that incorporating uncertainty estimates can lead to group statistics with a higher statistical power. We propose the Fisher Information Matrix (FIM) as a generally applicable method for quantifying the parameter uncertainties in non-linear diffusion MRI models. In direct comparison with Markov Chain Monte Carlo sampling, the FIM produces similar uncertainty estimates at lower computational cost. Using acquired and simulated data, we then list several characteristics that influence the parameter variances, like data complexity and signal-to-noise ratio. In individual subjects, the parameter standard deviations can help in detecting white matter artifacts as patches of relatively large standard deviations. In group statistics, we recommend using the parameter standard deviations by means of variance weighted averaging. Doing so can reduce the overall variance in group statistics and reduce the effect of data artifacts without discarding data from the analysis. Both these effects can lead to a higher statistical power in group studies.