Faculty Bibliography

PURPOSE: To evaluate the performance of an edge-based registration technique in correcting for respiratory motion artifacts in magnetic resonance renographic (MRR) data and to examine the efficiency of a semiautomatic software package in processing renographic data from a cohort of clinical patients. MATERIALS AND METHODS: The developed software incorporates an image-registration algorithm based on the generalized Hough transform of edge maps. It was used to estimate glomerular filtration rate (GFR), renal plasma flow (RPF), and mean transit time (MTT) from 36 patients who underwent free-breathing MRR at 3T using saturation-recovery turbo-FLASH. The processing time required for each patient was recorded. Renal parameter estimates and model-fitting residues from the software were compared to those from a previously reported technique. Interreader variability in the software was quantified by the standard deviation of parameter estimates among three readers. GFR estimates from our software were also compared to a reference standard from nuclear medicine. RESULTS: The time taken to process one patient's data with the software averaged 12 +/- 4 minutes. The applied image registration effectively reduced motion artifacts in dynamic images by providing renal tracer-retention curves with significantly smaller fitting residues (P < 0.01) than unregistered data or data registered by the previously reported technique. Interreader variability was less than 10% for all parameters. GFR estimates from the proposed method showed greater concordance with reference values (P < 0.05). CONCLUSION: These results suggest that the proposed software can process MRR data efficiently and accurately. Its incorporated registration technique based on the generalized Hough transform effectively reduces respiratory motion artifacts in free-breathing renographic acquisitions. J. Magn. Reson. Imaging 2015.

PURPOSE: To develop a novel framework for free-breathing MRI called XD-GRASP, which sorts dynamic data into extra motion-state dimensions using the self-navigation properties of radial imaging and reconstructs the multidimensional dataset using compressed sensing. METHODS: Radial k-space data are continuously acquired using the golden-angle sampling scheme and sorted into multiple motion-states based on respiratory and/or cardiac motion signals derived directly from the data. The resulting undersampled multidimensional dataset is reconstructed using a compressed sensing approach that exploits sparsity along the new dynamic dimensions. The performance of XD-GRASP is demonstrated for free-breathing three-dimensional (3D) abdominal imaging, two-dimensional (2D) cardiac cine imaging and 3D dynamic contrast-enhanced (DCE) MRI of the liver, comparing against reconstructions without motion sorting in both healthy volunteers and patients. RESULTS: XD-GRASP separates respiratory motion from cardiac motion in cardiac imaging, and respiratory motion from contrast enhancement in liver DCE-MRI, which improves image quality and reduces motion-blurring artifacts. CONCLUSION: XD-GRASP represents a new use of sparsity for motion compensation and a novel way to handle motions in the context of a continuous acquisition paradigm. Instead of removing or correcting motion, extra motion-state dimensions are reconstructed, which improves image quality and also offers new physiological information of potential clinical value. Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.

Undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma, is a neoplasm that occurs most often in the extremities, trunk, and retroperitoneum. Rarely, UPS can occur in the cardiac chambers and great vessels. The diagnosis of UPS is difficult to establish with noninvasive imaging techniques, and these tumors may be mistaken for benign neoplasms preoperatively. Surgical excision is the standard therapy, although the extent and location of the tumor may limit the ability to perform a complete resection. Adjuvant chemotherapy and/or radiation are often used for incomplete resections. We report the case of a 57-year-old woman with a large right ventricular UPS who presented with signs of right-sided heart failure. Preoperative imaging was suggestive of a myxoma; however, histopathologic evaluation of the specimen confirmed a diagnosis of UPS. Microscopic margins of the specimen were positive, and adjuvant chemotherapy was given. We discuss diagnostic and treatment considerations for this unusual cardiac tumor. <Learning objective: The diagnosis and treatment of primary cardiac tumors are challenging. Noninvasive imaging often lacks the sensitivity and specificity to differentiate between benign and malignant neoplasms. In addition, the extent and location of tumor involvement may limit the ability to perform a complete resection. The diagnosis and treatment of right ventricular undifferentiated pleomorphic sarcoma are discussed.>.

We present long-term pulmonary function test outcomes from an ongoing, open-label, multi-center, phase 3 extension study assessing the long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio syndrome type A. In part 1 of the extension study, patients who were initially randomized to ERT in the original placebo-controlled 24-week study [1] remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two treatment regimens. During part 2, all patients received ERT 2.0 mg/kg/week. Pulmonary function was evaluated as a secondary efficacy endpoint. Changes from the original 24-week study [1] baseline to 72 and 120 weeks are presented. In the 24-week study, non-statistical increases were seen in each dosing group for forced vital capacity (FVC) and maximum voluntary ventilation (MVV) versus placebo [1] and both endpoints continued to improve for the combined patient population during the extension study for up to 120 weeks. MVV increased from baseline by a mean (SE) of 1.78 (0.74) L/min by week 72 and 1.80 (1.04) L/min or 11.04 (4.55) % by week 120. FVC increased from baseline by a mean (SE) of 0.05 (0.01) L by week 72 and 0.08 (0.02) L or 8.6 (1.8) % by week 120. In contrast, matched untreated patients from the MorCAP natural history study [2] showed mean decreases in MVV and FVC over 2 years. In conclusion, long-term ERT causes sustained improvements in pulmonary function in patients with Morquio syndrome type A. References: 1. Hendriksz CJ, Burton B, Fleming TR, et al. J Inherit Metab Dis 2014;37:979-90. 2. Harmatz P, Mengel KE, Giugliani R, et al. Mol Genet Metab 2013;109:54-61. BioMarin Pharmaceutical Inc. sponsored this study.
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Tumor necrosis factor-alpha (TNF-alpha) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-alpha expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-alpha and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-alphaglo) that could be used to conditionally overexpress TNF-alpha. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-alpha in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-alphaglo mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-alphaglo mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-alphaglo mice, we have shown that TNF-alpha expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.

Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control.

Androgens have profound effects on hippocampal structure and function, including induction of spines and spine synapses on the dendrites of CA1 pyramidal neurons, as well as alterations in long-term synaptic plasticity (LTP) and hippocampally dependent cognitive behaviors. How these effects occur remains largely unknown. Emerging evidence, however, suggests that one of the key elements in the response mechanism may be modulation of brain-derived neurotrophic factor (BDNF) in the mossy fiber (MF) system. In male rats, orchidectomy increases synaptic transmission and excitability in the MF pathway. Testosterone reverses these effects, suggesting that testosterone exerts tonic suppression on MF BDNF levels. These findings suggest that changes in hippocampal function resulting from declining androgen levels may reflect the outcome of responses mediated through normally balanced, but opposing, mechanisms: loss of androgen effects on the hippocampal circuitry may be compensated, at least in part, by an increase in BDNF-dependent MF plasticity.

The causative agent of Legionnaires' disease, Legionella pneumophila, employs the autoinducer compound LAI-1 (3-hydroxypentadecane-4-one) for cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, comprising the autoinducer synthase LqsA, the sensor kinases LqsS and LqsT, as well as the response regulator LqsR. Lqs-regulated processes include pathogen-host interactions, production of extracellular filaments and natural competence for DNA uptake. Here we show that synthetic LAI-1 promotes the motility of L. pneumophila by signalling through LqsS/LqsT and LqsR. Upon addition of LAI-1, autophosphorylation of LqsS/LqsT by [gamma-(32) P]-ATP was inhibited in a dose-dependent manner. In contrast, the Vibrio cholerae autoinducer CAI-1 (3-hydroxytridecane-4-one) promoted the phosphorylation of LqsS (but not LqsT). LAI-1 did neither affect the stability of phospho-LqsS or phospho-LqsT, nor the dephosphorylation by LqsR. Transcriptome analysis of L. pneumophila treated with LAI-1 revealed that the compound positively regulates a number of genes, including the non-coding RNAs rsmY and rsmZ, and negatively regulates the RNA-binding global regulator crsA. Accordingly, LAI-1 controls the switch from the replicative to the transmissive growth phase of L. pneumophila. In summary, the findings indicate that LAI-1 regulates motility and the biphasic life style of L. pneumophila through LqsS- and LqsT-dependent phosphorylation signalling.

The control of deep cerebellar nuclear (DCN) neuronal firing is central to cerebellar function but is not well understood. The large majority of synapses onto DCN neurons derive from Purkinje cells (PCs), suggesting that PC activity is an important determinant of DCN firing; however, PCs fire both simple and complex spikes (CSs), and little is known about how the latter's action affects DCN activity. Thus, here, we explored the effects of CSs on DCN activity. CSs were recorded from PC arrays along with individual DCN neurons. Presumed synaptically connected PC-DCN cell pairs were identified using CS-triggered correlograms of DCN activity, which also showed that CS activity was associated with a predominantly inhibitory effect on DCN activity. The strength of the CS effect varied as a function of synchrony, such that isolated CSs produced only weak inhibition of DCN activity, whereas highly synchronous CSs caused a larger drop in firing levels. Although the present findings were obtained in anesthetized animals, similar CS synchrony levels exist in awake animals, and changes in synchrony level have been observed in association with movements in awake animals. Thus, the present data suggest that synchronous CS activity may be a mechanism for shaping DCN output related to motor commands.

OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.