Faculty Bibliography

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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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.

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.

The exposome is the assembly and measure of all the exposures of an individual in a lifetime. An individual's exposures begin before birth and include insults from environmental and occupational sources. The associated field is called exposomics, which relies on the application of internal and external exposure assessment methods. Exposomics has not yet been thoroughly applied to the study of kidney stones although much is known about how diet and fluid intake affect nephrolithiasis. Some other novel exposures that may contribute to kidney stones are discussed including use of antibiotics, urbanization and migration to urban heat islands, and occupation. People whose school and jobs limit their access to fluids and adequate bathroom facilities may have higher prevalence of stones. Examples include athletes, teachers, heathcare workers, and cab drivers. Occupational kidney stones have received scant attention and may represent a neglected, and preventable, type of stone. An exposomic-oriented history would include a careful delineation of occupation and activities.

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.

In high field MRI, the spatial distribution of the radiofrequency magnetic ( B1) field is usually affected by the presence of the sample. For hardware design and to aid interpretation of experimental results, it is important both to anticipate and to accurately simulate the behavior of these fields. Fields generated by a radiofrequency surface coil were simulated using dyadic Green's functions, or experimentally measured over a range of frequencies inside an object whose electrical properties were varied to illustrate a variety of transmit [Formula: see text] and receive [Formula: see text] field patterns. In this work, we examine how changes in polarization of the field and interference of propagating waves in an object can affect the B1 spatial distribution. Results are explained conceptually using Maxwell's equations and intuitive illustrations. We demonstrate that the electrical conductivity alters the spatial distribution of distinct polarized components of the field, causing "twisted" transmit and receive field patterns, and asymmetries between [Formula: see text] and [Formula: see text]. Additionally, interference patterns due to wavelength effects are observed at high field in samples with high relative permittivity and near-zero conductivity, but are not present in lossy samples due to the attenuation of propagating EM fields. This work provides a conceptual framework for understanding B1 spatial distributions for surface coils and can provide guidance for RF engineers.

OBJECTIVES: Clinical neuroscience is increasingly turning to imaging the human brain for answers to a range of questions and challenges. To date, the majority of studies have focused on the neural basis of current psychiatric symptoms, which can facilitate the identification of neurobiological markers for diagnosis. However, the increasing availability and feasibility of using imaging modalities, such as diffusion imaging and resting-state fMRI, enable longitudinal mapping of brain development. This shift in the field is opening the possibility of identifying predictive markers of risk or prognosis, and also represents a critical missing element for efforts to promote personalized or individualized medicine in psychiatry (i.e., stratified psychiatry). METHODS: The present work provides a selective review of potentially high-yield populations for longitudinal examination with MRI, based upon our understanding of risk from epidemiologic studies and initial MRI findings. RESULTS: Our discussion is organized into three topic areas: (1) practical considerations for establishing temporal precedence in psychiatric research; (2) readiness of the field for conducting longitudinal MRI, particularly for neurodevelopmental questions; and (3) illustrations of high-yield populations and time windows for examination that can be used to rapidly generate meaningful and useful data. Particular emphasis is placed on the implementation of time-appropriate, developmentally informed longitudinal designs, capable of facilitating the identification of biomarkers predictive of risk and prognosis. CONCLUSIONS: Strategic longitudinal examination of the brain at-risk has the potential to bring the concepts of early intervention and prevention to psychiatry. (JINS, 2016, 22, 164-179).

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.

Oxalobacter formigenes, a member of the human colonic microbiota that plays a major role in net colonic oxalate transport and secretion, is protective against formation of calcium oxalate kidney stones. We now describe the prevalence, relative abundance and stability of O. formigenes in healthy young adults in the United States, as revealed by Human Microbiome Project (HMP) data from fecal samples from 242 healthy young adults who had 1-3 study visits. Samples underwent whole-genomic shotgun (WGS) sequencing, and/or 16S rRNA sequencing. Three datasets available from the processed sequence data were studied: WGS metagenomic analysis by alignment to reference genomes (HMSCP) or using MetaPhlAn, or QIIME analysis of the V1-3 or V3-5 16S sequences. O. formigenes was detected in fecal samples using both the WGS and 16S rRNA data. Analysis of the WGS dataset, using HMSCP, showed that 29 (31%) of 94 subjects were O. formigenes-positive while the V1-3 and V3-5 analyses were less sensitive for O. formigenes detection. When present, O. formigenes relative abundance varied over 3 log10, and was normally distributed. For 66 samples studied by all three methods, all assays agreed in 58 (88%). Of 14 subjects who were O. formigenes-positive at baseline, 13 (93%) were positive on follow-up visit, indicating the stability of colonization. O. formigenes appears to be stably present in fewer than half of healthy young USA adults and is most sensitively detected by WGS.