Fast and robust quantification of uncertainty in non-linear diffusion MRI models.

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. We investigate the Fisher Information Matrix (FIM) and uncertainty propagation as a generally applicable method for quantifying the parameter uncertainties in linear and non-linear diffusion MRI models. In direct comparison with Markov Chain Monte Carlo (MCMC) sampling, the FIM produces similar uncertainty estimates at much lower computational cost. Using acquired and simulated data, we then list several characteristics that influence the parameter variances, including data complexity and signal-to-noise ratio. For practical purposes we investigate a possible use of uncertainty estimates in decreasing intra-group variance in group statistics by uncertainty-weighted group estimates. This has potential use cases for detection and suppression of imaging artifacts.

Ultra-high resolution and multi-shell diffusion MRI of intact ex vivo human brains using kT-dSTEAM at 9.4T.

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.

High resolution anatomical and quantitative MRI of the entire human occipital lobe ex vivo at 9.4T.

Several magnetic resonance imaging (MRI) contrasts are sensitive to myelin content in gray matter in vivo which has ignited ambitions of MRI-based in vivo cortical histology. Ultra-high field (UHF) MRI, at fields of 7T and beyond, is crucial to provide the resolution and contrast needed to sample contrasts over the depth of the cortex and get closer to layer resolved imaging. Ex vivo MRI of human post mortem samples is an important stepping stone to investigate MRI contrast in the cortex, validate it against histology techniques applied in situ to the same tissue, and investigate the resolutions needed to translate ex vivo findings to in vivo UHF MRI. Here, we investigate key technology to extend such UHF studies to large human brain samples while maintaining high resolution, which allows investigation of the layered architecture of several cortical areas over their entire 3D extent and their complete borders where architecture changes. A 16 channel cylindrical phased array radiofrequency (RF) receive coil was constructed to image a large post mortem occipital lobe sample (~80×80×80mm3) in a wide-bore 9.4T human scanner with the aim of achieving high-resolution anatomical and quantitative MR images. Compared with a human head coil at 9.4T, the maximum Signal-to-Noise ratio (SNR) was increased by a factor of about five in the peripheral cortex. Although the transmit profile with a circularly polarized transmit mode at 9.4T is relatively inhomogeneous over the large sample, this challenge was successfully resolved with parallel transmit using the kT-points method. Using this setup, we achieved 60µm anatomical images for the entire occipital lobe showing increased spatial definition of cortical details compared to lower resolutions. In addition, we were able to achieve sufficient control over SNR, B0 and B1 homogeneity and multi-contrast sampling to perform quantitative T2* mapping over the same volume at 200µm. Markov Chain Monte Carlo sampling provided maximum posterior estimates of quantitative T2* and their uncertainty, allowing delineation of the stria of Gennari over the entire length and width of the calcarine sulcus. We discuss how custom RF receive coil arrays built to specific large post mortem sample sizes can provide a platform for UHF cortical layer-specific quantitative MRI over large fields of view.

Robust and fast nonlinear optimization of diffusion MRI microstructure models.

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.

Sonographic characteristics of linear nevus sebaceous sequence.

Linear nevus sebaceous is a hamartomatous lesion most commonly seen on the face and head of infants and diagnosed after birth. We describe a patient with sonographic findings of linear nevus sebaceous seen initially at 30 weeks' gestation. Other associated sonographic findings include macrocephaly and polyhydramnios. When associated with a midline soft tissue mass, these findings are highly suggestive of the presence of congenital linear nevus sebaceous sequence.

Performance of commercial laying hens when six percent corn oil is added to the diet at various ages and with different levels of tryptophan and protein.

Three experiments were conducted to evaluate the use of corn oil in the diet of commercial layers as a method of increasing egg weight. In the first experiment, the performance of commercial layers receiving 6% added corn oil beginning at 18 to 30 wk at 2-wk intervals was evaluated. In the second experiment, comparisons were made between performance of young and old commercial layers when 6% corn oil was added to the diet. The third experiment was conducted to evaluate the effects upon commercial layers when 6% corn oil was added to diets varying in Trp content. In experiment 1, egg weights increased during the first 2 wk that corn oil was added to the diet. During this time, the intake of Trp was greater than or equal to the hen requirements. However, during the last 2 wk of the experiment, when Trp intakes were low, egg weights decreased when corn oil was added to the diet. In experiment 2, egg weights from young and old hens increased during the first 2 wk after corn oil was added to the diet. During the last 2 wk, egg weights from young hens decreased, whereas egg weights from old hens increased. In experiment 3, egg weight was not affected when the diet contained 0.166 or 0.176% Trp. However, egg weights significantly increased when corn oil was added to the diet containing 0.193% Trp. The data in these experiments indicate that the diet of a laying hen must contain a high level of Trp to get an increase in egg weight from the addition of corn oil to the diet. Also the need for other amino acids must be met. Therefore, the hen eats to meet her energy requirement for maximum egg production, and her amino acid intake determines the egg weight.

Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8 degrees C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.

Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency.

Phosphomannose isomerase (PMI) deficiency (CDG-Ib) is a newly recognized disorder of mannose and glycoprotein metabolism. PMI deficiency manifests itself mainly as a gastrointestinal disorder with protein-losing enteropathy and life-threatening intestinal bleeding. Hypoglycaemia is an additional prominent symptom. In contrast to phosphomannomutase deficiency (CDG-Ia), there are no neurological symptoms. PMI deficiency blocks the endogenous mannose formation from glucose. Exogenous oral mannose supply bypasses the enzymatic block and leads to the disappearance of all symptoms in the patient. The striking ultrastructural abnormalities of the rough endoplasmatic reticulum of the duodenal epithelial cells completely normalize and the hypoglycosylation disappears, as evidenced by the normal isoelectric focusing pattern of serum transferrin, the standard diagnostic procedure for recognition of CDG. This paper includes a detailed description of the clinical symptomatology of the first-ever diagnosed and treated patient with PMI deficiency and a 5-y follow-up study of mannose therapy.

Identifying respiratory events and artifacts using oscillatory impedance measurement in aPAP therapy.

Constant positive airway pressure (cPAP) is the predominant noninvasive therapy for the obstructive sleep apnea syndrome (OSAS). The average pressure thereby applied can be reduced by online-identification of respiratory events. Oscillatory impedance measurement as an indicator for airway patency can identify central and obstructive apneas and hypopneas. Our goal was to reduce the sensors needed, to auto-calibrate the signals to each individual patient and to rule out patient induced artifacts.

Threonine requirement of commercial laying hens fed a corn-soybean meal diet.

Two experiments were conducted with Hy-Line W36 hens to evaluate their Thr requirement in a corn-soybean meal diet. Eight experimental diets were used in Experiment 1 with graded levels of Thr: 0.53,0.50, 0.48, 0.45, 0.42, 0.40, 0.37, and 0.35%. Seven experimental diets were used in Experiment 2 with graded levels of Thr: 0.58, 0.53, 0.50, 0.48, 0.45, 0.42, and 0.40%. Supplemental amino acids (AA) were added to all diets to ensure that Thr was the first-limiting AA. Egg production (EP), egg mass (EM), and daily Thr intake were significantly increased with increasing dietary Thr levels. Broken-line regression indicated a daily Thr requirement of 439.0 and 462.1 mg per hen per d in Experiment 1 and of 393.9 and 447.1 mg per hen per d in Experiment 2 for EP and EM, respectively. The Thr requirements to produce 1 g of EM were 8.76 and 9.44 mg in Experiments 1 and 2, respectively.

Betaine does not improve performance of laying hens when the diet contains adequate choline.

An experiment was conducted with Hy-Line W36 hens to determine possible benefits from adding betaine to the diet of commercial laying hens. There was no benefit from the substitution of betaine for choline as measured by egg production, egg weight, egg content, or weight gain.

Re-evaluation of the isoleucine requirement of the commercial layer.

An experiment was conducted with Hy-Line W36 hens to re-evaluate their Ile requirements from a corn-soybean meal diet. Eight experimental diets were fed with Ile levels of 0.60, 0.57, 0.54, 0.51, 0.48, 0.45, 0.42, and 0.39%. Supplemental amino acids (AA) were added to ensure that ILe was the first-limiting AA. Increasing levels of Ile above 0.51% significantly increased egg production (EP), egg weight (EW), and egg mass (EM). Egg production, EW, and EM decreased each time the Ile content of the diet was decreased. Feed consumption (FC) and energy intake were not significantly decreased until the diet contained 0.45% Ile, and, at this time, BW was significantly reduced. Broken-line regression indicated a daily Ile requirement of 449.8, 497.0, and 469.0 mg/d for EP, EW, and EM, respectively, which indicated a requirement of 9.30 mg Ile/g EM.

Evaluation of valine requirement of the commercial layer using a corn-soybean meal basal diet.

An experiment was conducted with Hy-Line W-36 hens to evaluate the Val requirement in a corn-soybean meal diet. Eight experimental diets were fed with Val levels of 0.700, 0.665, 0.630, 0.595, 0.560, and 0.525%. A positive control (0.765% Val) was fed. Egg production (EP) was increased by addition of Val to 0.630%. Egg weight (EW) was increased by addition of Val to 0.655%. Broken-line regression indicated a daily Val requirement of 592.5, 677.7, and 619.0 mg/hen per d for EP, EW, and egg contents (EC), respectively. This requirement was 13.1 mg/g of EC.

Cloning and expression of homospermidine synthase from Senecio vulgaris: a revision.

Homospermidine synthase. which catalyses the first pathway-specific reaction in pyrrolizidine alkaloid biosynthesis, was cloned from root cultures of Senecio vulgaris and expressed in E. coli. The open reading frame encodes a protein of 370 amino acids with a molecular mass of 40,740 Da. The enzyme is strictly dependent on spermidine as aminobutyl donor since it cannot be substituted by putrescine. The homospermidine synthase from S. vulgaris showed 97.9 and 99.3% nucleic acid identity with two HSS sequences from the closely related species Senecio vernalis. This report also revises data from a previous publication (Kaiser, A., 1999. Cloning and expression of a cDNA encoding homospermidine synthase from Senecio vulgaris (Asteraceae) in Escherichia coli. Plant J. 19. 195 201.) that is incorrect.

Evaluation of the isoleucine requirement of the commercial layer in a corn-soybean meal diet.

An experiment was conducted with Hy-Line W36 hens to evaluate their Ile requirement in a corn-soybean meal diet. Five experimental diets were fed with Ile levels of 0.61, 0.58, 0.55, 0.52, and 0.49%. Supplemental amino acids (AA) were added to ensure that Ile was the first-limiting AA. Two diets with 0.55 and 0.52% Ile were also fed with higher levels of supplemental AA. A positive control (0.67% Ile) with only Met supplementation was fed, which had previously been shown to support maximum performance. All levels of Ile addition significantly increased egg production (EP), egg weight (EW), and egg contents (EC). Broken-line regression indicated a daily Ile requirement of 589.2, 601.2, and 601.4 mg per day for EP, EW, and EC, respectively, which indicated a requirement of 12.6 mg Ile per gram of EC.

Evaluation of tryptophan requirement of the commercial layer by using a corn-soybean meal basal diet.

An experiment was conduced with Hy-Line W36 hens to evaluate the requirement for Trp in a corn-soybean meal diet. Seven experimental diets were fed with Trp levels of 0.12, 0.13, 0.14, 0.15, 0.16, 0.17 and 0.18%. Supplemental amino acids (AA) were added to all diets to ensure that Trp was the first-limiting AA. A positive control diet (0.20% Trp) with Met supplementation was fed that had previously been shown to support maximum performance. Egg production (EP), egg weight (EW), and egg content (EC) were significantly increased by the addition of Trp to the basal diet. Broken-line regression indicated the Trp requirement for EP and EC was 139.8 and 149.0 mg per hen/d, respectively, for EP and EC when hens had a daily EC of 45.4 g per hen/d.

Biliary atresia: which factors predict the success of a Kasai operation? An analysis of 36 patients.

UNLABELLED: Biliary atresia (BA) is one of the most frequent causes of neonatal cholestasis. Portoenterostomy is one therapeutic option in these patients with a success rate of 30-40%. To answer the question of therapy liver transplantation or Kasai operation - we analyzed 36 consecutive patients being followed in our center during the past 7 years. Two groups were formed: group I : patients developing cirrhosis within the first 2 years of life with the need for liver transplantation (n = 21). Group II: patients without need for transplantation within the first 2 years of life (n = 15). The two groups were compared regarding birth weight, age at diagnosis, age at Kasai-procedure, liver histology. The following biochemical parameters were analyzed at the time of diagnosis, 1 week and 5 weeks after Kasai: AST, ALT, gammaGT, and bilirubin. - RESULTS: Clinical characteristics were similar in both groups. However BA was diagnosed in group I 8.2 weeks after birth compared to 5.6 wk in group II. gammaGT, ALT, AST, and bilirubin were similar in both groups at the time of diagnosis and 1 wk after Kasai. However 5 wk after Kasai gammaGT was 276 U/l in group I compared to 72 U/l in group II (p <0.001), bilirubin was 6.3mg/dl in group I compared to 2. 3mg/dl in group II (p <0.001). - CONCLUSION: Kasai operation before the 7th wk of life increases the success rate of this technique significantly. Children with cirrhosis at the time of diagnosis should be evaluated for primary liver transplantation. gammaGT and bilirubin 5 weeks after Kasai operation may be useful markers for the success of this procedure. Patients with a gammaGT > 100 U/l and a bilirubin level >5mg/dl should be followed closely and should be evaluated for liver transplantation early.

Tryptophan requirement of the commercial hen.

An experiment was conducted to determine the Trp requirement of the commercial laying hen. A corn-soybean meal diet was used that contained gelatin, which is low in Trp. Tryptophan was the first-limiting amino acid in this diet. Methionine, Lys, Arg, Thr, Val, and Ile were added to ensure that they were not deficient. Experimental diets containing 0.0, 0.02, 0.04, 0.06, 0.08, 0.10, and 0.12% Trp were fed, and a corn-soybean meal diet served as the positive control. Egg production (EP), egg mass (EM), and egg content (EC) were significantly increased by the addition of supplemental Trp. Broken-line regression indicated that the Trp requirement for EP and EC for this experiment was 136.0 (R2 = 0.81) and 136.5 (R2 = 0.82) mg per hen per d, respectively. These hens produced 43.5 g of EC, resulting in a Trp requirement of 3.14 mg/g of EC. Therefore, assuming an output of 50 g of EC, we suggest 157 mg per hen per d as the requirement for maximum production of EC.