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.

A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We report on a novel nonsense mutation that leads to exon skipping and the activation of a cryptic exon. Screening of genomic DNA from 700 German patients with CF uncovered four cases with the nonsense mutation E92X, a G-->T transversion that creates a termination codon and affects the first base of exon 4 of the CFTR gene. Lymphocyte RNA of two CF patients heterozygous for E92X was found to contain the wild type sequence and a differentially spliced isoform lacking exon 4. In RNA derived from nasal epithelial cells of E92X patients, a third fragment of longer size was observed. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It is flanked by acceptor and donor splice sites. We conclude that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis.

Venous air embolism. Life-threatening complication of orogenital sex during pregnancy.

Vaginal insufflation in pregnant women leading to acute venous air embolism has been appreciated by obstetricians and pathologists for several decades. Initially described as a complication of powder insufflation for treatment of trichomonal vaginitis, insufflation-induced air embolism has been more recently associated with orogenital sex. The case herein illustrates a typical history that is almost pathognomonic. Clinical and laboratory abnormalities as well as treatment measures are briefly described. Familiarity with this syndrome is essential if prompt and appropriate therapy is to be rendered.

Selected neurologic complications of pregnancy.

Many neurologic disorders, such as eclampsia, pseudotumor cerebri, stroke, obstetric nerve palsies, subarachnoid hemorrhage, pituitary tumors, and choriocarcinoma, can develop in the pregnant patient. Maternal mortality from eclampsia, which ranges from 0 to 14%, can be due to intracerebral hemorrhage, pulmonary edema, disseminated intravascular coagulation, abruptio placentae, or failure of the liver or kidneys. Associated fetal mortality ranges from 10 to 28% and is directly related to decreased placental perfusion. Pseudotumor cerebri can be associated with serious visual complications; thus, the therapeutic goal is to prevent loss of vision. The risk of stroke in the pregnant patient is 13 times the risk in the nonpregnant patient of the same age. The major causes of stroke in pregnant patients are arterial occlusion and cerebral venous thrombosis. Lumbar disk prolapse is common in pregnant patients, and lumbosacral plexus injuries can occur during labor or delivery. In addition, peripheral nerve compression or entrapment syndromes are thought to be caused by the retention of fluid during pregnancy. The incidence of subarachnoid hemorrhage during pregnancy is 1 in every 10,000 patients, a rate 5 times higher than in nonpregnant women. Because of a proliferation of prolactin-secreting cells, the pituitary gland can enlarge dramatically during pregnancy, a change that can disclose a previously unknown tumor or cause a known pituitary tumor to become symptomatic. The incidence of choriocarcinoma is 1 in 50,000 full-term pregnancies but 1 in 30 molar pregnancies. This malignant tumor has a high rate of cerebral metastatic lesions. In addition to these disorders that develop during pregnancy, the pregnant state can affect numerous preexisting neurologic conditions, including epilepsy, headaches, multiple sclerosis, myasthenia gravis, spinal cord injury, and brain tumors. We discuss advice for patients with such conditions who wish to become pregnant, recommendations for medical and surgical management, and surgical considerations for neurologic complications during pregnancy.

CA-125 levels in endometriosis.

CA-125 is a cellular antigen detected in many patients with ovarian cancer, but it has also been detected in patients with endometriosis. Preoperative CA-125 levels were drawn from 113 patients before they underwent laparoscopy. Patients were categorized into diagnostic groups on the basis of pathologic findings. CA-125 levels in patients with evidence of intraabdominal adhesions were not statistically different from those in patients with normal pelvic anatomy. However, patients with advanced endometriosis had significantly elevated levels of CA-125 when compared with patients with normal pelvic anatomy (P less than 0.05). The clinical and immunologic implications of elevated CA-125 levels in patients with advanced endometriosis are discussed.

Effect of serum source on human fertilization and embryonic growth parameters in vitro.

A total of 100 mature oocytes from 13 consecutive patients were randomly assigned from each patient to one of two treatment groups (n = 53 for group 1, n = 47 for group 2). Group 1 oocytes were incubated throughout the culture periods in medium supplemented with 7.5% homologous patient serum. Group 2 oocytes were treated similarly, except the serum supplement was of fetal cord origin. End points for examination included fertilization frequency, normality of fertilization, stage of embryonic development at two time periods, and quality of embryonic development at two time periods. None of the end points examined revealed significant differences between patient serum and fetal cord serum.

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.

Correlation of IgE antibody titer to Aspergillus fumigatus with decreased lung function in cystic fibrosis.

Obstructive pulmonary disease is a typical feature of cystic fibrosis (CF) and is often associated with bronchial hyperreactivity. Positive skin-test reactions to Aspergillus fumigatus antigens are frequently seen even in nonatopic patients with CF. Full-fledged allergic bronchopulmonary aspergillosis (ABPA) has been estimated to occur in 10% of patients with CF. The relationship between lung function and presence of IgE antibodies to Aspergillus antigens in patients without ABPA is not clear. In 148 outpatients with CF (aged 6-34 years) specific immunoglobulin E (IgE) to Aspergillus fumigatus antigens, basic lung-function parameters, and bronchial response to salbutamol were measured. Multiple regression was performed for age, weight as percentile for actual height (indicating general condition), and Aspergillus RAST. Aspergillus IgE was present in 46% of patients; 19% had RAST class 3 or 4. Independent negative correlations of Aspergillus RAST with FEV1, FEF50%, FEF25%, RV, Chrispin Norman score, and sRaw (P less than 0.05) were found. Bronchodilator sensitivity did not correlate significantly with age and weight percentile. However, Aspergillus RAST did correlate significantly with bronchodilator response measured by sRaw (P less than 0.05). High titers of Aspergillus RAST might serve as a selective criterion for patients to be included in future studies evaluating broncholytic or antiphlogistic therapies.

The Wisconsin wrestling minimum weight project: a model for weight control among high school wrestlers.

In 1989, the Wisconsin Interscholastic Athletic Association implemented a project including new rules and an educational program, consistent with ACSM and AMA guidelines, to curtail "weight cutting" among high-school wrestlers. The project included skinfold estimates of body fatness to determine a minimum competitive weight, a limit on weekly weight loss, and presentation of nutrition education information to help wrestlers diet effectively. Implementation of the project has overcome a variety of obstacles and has received widespread endorsement from parents, teachers, wrestlers, and coaches. The success of this project offers a model for other states to emulate and should encourage clinicians in other sports to initiate interventions addressing these unhealthy weight loss behaviors.

Calculated T1 images derived from a partial saturation-inversion recovery pulse sequence with adiabatic fast passage.

Calculated T1 images of the head and abdomen have been obtained using an alternating partial saturation-inversion recovery pulse sequence. Timing parameters were adjusted to yield optimum T1 contrast-to-noise ratio for this sequence for the range of T1 studied. Adiabatic fast passage (AFP) was implemented for the nonselective inverting pulse, to reduce the sensitivity of the measurement to RF and static field inhomogeneity. A nonlinear frequency sweep was used to improve the efficiency of the AFP pulse. The effect on the T1 calculation of slice selection during the pi/2 pulses was also determined and corrected for in the image reconstruction algorithm. The T1's determined by this method show a standard deviation of less than 10%, and good agreement with the literature.

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.

Renal function and renotropic effects of secretin in cystic fibrosis.

In ten cystic fibrosis patients and nine age-matched controls, renal function was determined before and after infusion of secretin. Under baseline conditions creatinine excretion and clearance were significantly elevated, exclusively due to those patients who were homozygous for the DF508 mutation (153 vs 132 ml/min*1.73m2), whereas the glomerular filtration rate, measured by inulin clearance showed no difference. Renal plasma flow and the fractional reabsorption rates of electrolytes were similar in patients and controls. During secretin infusion renal plasma flow increased and the fractional reabsorption rates of electrolytes decreased in both groups. The patients had a increased metabolic clearance (2900 vs 1660 ml/min*m2) and endogenous production rate (9,9 vs 2,5 pmol/min*m2) of of secretin. In conclusion global renal function and electrolyte handling, in particular chloride permeability, are unchanged in cystic fibrosis. Individuals expressing the DF508 genotype showed a selective elevation of creatinine excretion and clearance. The secretion and metabolic clearance of secretin are increased in cystic fibrosis.

Aortic atherosclerosis in nonlaying hens with fatty liver syndrome.

Ten laying hens with low plasma cholesterol levels and no signs of fatty liver syndrome were examined at necropsy. Liver coloration and deposition of body fat were not abnormal in such hens. Eleven nonlaying hens had signs of fatty liver syndrome. They were out of production for 1 to 3 months and had elevate plasma cholesterol levels. At necropsy, such hens had yellow livers, heavy deposits of body fat, and several involuted egg yolks, which were dark yellow. Intimal plaques were observed by light microscopy in the abdominal aortas of hens with low plasma cholesterol levels; the plaques contained little or no lipid and were composed of three or four rows of modified smooth-muscle cells. Aortic intimal plaques of hens with high plasma cholesterol levels were composed of 16 to 18 rows of modified smooth-muscle cells when examined by light microscopy. The plaques contained intracellular and extracellular lipid, indicating aortic atherosclerosis. Electron-microscopic observations of the abdominal aortas of both groups of hens were similar to light-microscopic observations, except that lipid, including cholesterol clefts, was seen both intracellularly and extracellularly in the thickened tunica intima of hens with high plasma cholesterol values. Thus, the presence of aortic atherosclerosis was confirmed by electron microscopy. It is suggested that the endogenous hypercholesterolemia and cessation of egg production, characteristic of severe fatty liver syndrome, originated from the reabsorption of involuted egg yolks and that such reabsorption caused the development of aortic atherosclerosis and deposition of excess body fat.

Relationship between delayed onset of egg production and involution of the bursa of Fabricius in White Leghorn chickens.

The relationship between delayed onset of oviposition and involution of the bursa of Fabricius is described. Chickens studied were 26 weeks of age and had not come into production. The bursae of nonlaying chickens were compared with those of age-matched chickens that had laid the first egg 1, 9 to 11, or 24 days before. The bursae from the nonlaying chickens were similar in weight and morphology to the functional bursae of immature pullets. Bursae of laying chickens, even on the day of the first egg, were markedly involuted. Age of the chicken was not a factor in determining bursal involution. The onset of egg production was directly related to bursal involution.

Portal vein thrombosis associated with pregnancy. A case report.

This report illustrates a case of portal vein thrombosis that developed in the second trimester of pregnancy. The patient did not have any of the known associations or predisposing factors for portal vein thrombosis or any past medical history of thrombosis or bleeding disorders. Antepartum and postpartum laboratory studies showed no evidence of a coagulation disorder; therefore, it seems that the sole cause of this thrombotic event was the hypercoagulable state of pregnancy.

Incidence of postpartum depression in Olmsted County, Minnesota. A population-based, retrospective study.

OBJECTIVE: To provide population-based data on the recognition of postpartum depression by reviewing diagnostic and treatment practices of all physicians caring for pregnant and postpartum women in Olmsted County, Minnesota. STUDY DESIGN: We reviewed the medical charts of a random sample of 403 Olmsted County women who gave birth in 1993. Using outpatient and hospital medical records, we recorded all documented symptoms and diagnoses of depression, drug therapy for depression and variables that were previously associated with postpartum depression, during pregnancy and for one year postpartum. RESULTS: Fifteen (3.7%) of the women were identified as having postpartum depression during the year following delivery. Two (0.5%) other women had preexisting depression that did not remit before delivery. We found significant associations between postpartum depression and young maternal age, single marital status, hyperemesis gravidarum, tobacco or illegal drug use during pregnancy, history of substance abuse, high utilization of emergency department services and previous affective disorder. Using multivariate analysis with stepwise logistic regression, only single marital status, previous affective disorder and high utilization of emergency services remained associated with postpartum depression. CONCLUSION: The incidence of postpartum depression was significantly below incidences seen in prospective studies. Systematic screening for postpartum depression may be appropriate in this population.

[Ulcerative colitis in childhood and its differential diagnosis]. / Die Colitis ulcerosa im Kindesalter und ihre Differentialdiagnose.

Ulcerative colitis occurs before the age of 15 years in 20% and before 20 years in 40% of all patients involved. The frequency of this disease in patients at the University Children's Hospital of Munich has clearly risen over the past years. In many patients we found characteristic differences in history, clinical picture and laboratory results as compared with Crohn's disease. The most important diagnostic procedure is endoscopy of the entire colon. The histological examination of the biopsies taken during colonoscopy differentiated less clearly between these two entities than the macroscopic judgement by the endoscopist. The development of carcinoma must be considered even in children when the disease has lasted for seven years or longer. Ulcerative colitis must be differentiated from infectious diseases of the bowel by direct search for the relevant microorganisms and by serological testing.