Faculty Bibliography

Nephrolithiasis is a complex disease of worldwide prevalence that is influenced by both genetic and environmental factors. About 75% of kidney stones are predominantly composed of calcium oxalate and urinary oxalate is considered a crucial risk factor. Microorganisms may have a role in the pathogenesis and prevention of kidney stones and the involvement of the intestinal microbiome in this renal disease has been a recent area of interest. Oxalobacter formigenes is a gram negative bacteria that degrades oxalate in the gut decreasing urinary oxalate excretion. In this review, we examine the data studying the role of Oxalobacter formigenes kidney stone disease in humans and animals, the effect of antibiotics on its colonization, and the potential role of probiotics and whole microbial communities as therapeutic interventions.

STUDY OBJECTIVES: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Abeta). We thus aimed to examine relationships between concentrations of Abeta42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. METHODS: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Abeta42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Abeta42 groups to compare SWS bout length using survival analyses. RESULTS: A significant inverse correlation was found between CSF Abeta42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Abeta42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Abeta42. CONCLUSIONS: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Abeta42, suggesting that disturbed sleep might drive an increase in soluble brain Abeta levels prior to amyloid deposition.

Neural activity recorded at multiple spatiotemporal scales is dominated by arrhythmic fluctuations without a characteristic temporal periodicity. Such activity often exhibits a 1/f-type power spectrum, in which power falls off with increasing frequency following a power-law function: [Formula: see text], which is indicative of scale-free dynamics. Two extensively studied forms of scale-free neural dynamics in the human brain are slow cortical potentials (SCPs)-the low-frequency (<5 Hz) component of brain field potentials-and the amplitude fluctuations of alpha oscillations, both of which have been shown to carry important functional roles. In addition, scale-free dynamics characterize normal human physiology such as heartbeat dynamics. However, the exact relationships among these scale-free neural and physiological dynamics remain unclear. We recorded simultaneous magnetoencephalography and electrocardiography in healthy subjects in the resting state and while performing a discrimination task on scale-free dynamical auditory stimuli that followed different scale-free statistics. We observed that long-range temporal correlation (captured by the power-law exponent beta) in SCPs positively correlated with that of heartbeat dynamics across time within an individual and negatively correlated with that of alpha-amplitude fluctuations across individuals. In addition, across individuals, long-range temporal correlation of both SCP and alpha-oscillation amplitude predicted subjects' discrimination performance in the auditory task, albeit through antagonistic relationships. These findings reveal interrelations among different scale-free neural and physiological dynamics and initial evidence for the involvement of scale-free neural dynamics in the processing of natural stimuli, which often exhibit scale-free dynamics.

Functional analysis of a clinical microbiome facilitates the elucidation of mechanisms by which microbiome perturbation can cause a phenotypic change in the patient. The direct approach for the analysis of the functional capacity of the microbiome is via shotgun metagenomics. An inexpensive method to estimate the functional capacity of a microbial community is through collecting 16S rRNA gene profiles then indirectly inferring the abundance of functional genes. This inference approach has been implemented in the PICRUSt and Tax4Fun software tools. However, those tools have important limitations since they rely on outdated functional databases and uncertain phylogenetic trees and require very specific data pre-processing protocols. Here we introduce Piphillin, a straightforward algorithm independent of any proposed phylogenetic tree, leveraging contemporary functional databases and not obliged to any singular data pre-processing protocol. When all three inference tools were evaluated against actual shotgun metagenomics, Piphillin was superior in predicting gene composition in human clinical samples compared to both PICRUSt and Tax4Fun (p<0.01 and p<0.001, respectively) and Piphillin's ability to predict disease associations with specific gene orthologs exhibited a 15% increase in balanced accuracy compared to PICRUSt. From laboratory animal samples, no performance advantage was observed for any one of the tools over the others and for environmental samples all produced unsatisfactory predictions. Our results demonstrate that functional inference using the direct method implemented in Piphillin is preferable for clinical biospecimens. Piphillin is publicly available for academic use at http://secondgenome.com/Piphillin.

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 +/- 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP >/=10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.

OBJECTIVE: To examine whether childhood attention-deficit/hyperactivity disorder (ADHD) predicts homelessness in adulthood, and whether the persistence of childhood ADHD through adolescence influences the likelihood of homelessness. METHOD: A 33-year prospective, controlled, follow-up was performed of clinic-referred, 6- to 12-year-old boys of white ethnicity with ADHD (probands; mean = 8), at a mean age of 41 years (follow-up [FU] = 41). Comparisons, children without ADHD from the same medical center, were matched for age and socioeconomic status (SES). Both groups were evaluated at a mean age of 18 years (FU18). Homelessness was assessed at FU41 in 134 of 207 probands (65%) and 136 of 178 (76%) comparisons. We tested the following: the relationship between childhood ADHD and homelessness; whether adolescent dysfunctions (conduct disorder, non-alcohol substance use disorder, arrests, and school dropout) accounted for this relationship, if found; and whether ADHD that persisted through FU18 elevated probands' homelessness rate. RESULTS: Probands had significantly higher rates of homelessness than comparisons (23.7% vs. 4.4%; chi21 = 21.15, df = 1, p < .001). In a multivariate analysis, including childhood ADHD and covariates, the probands' significant elevation of homelessness remained (odds ratio [OR] = 3.60, 95% CI = 1.32-9.76, p = .01). Probands with persistent ADHD through adolescence had significantly more homelessness than remitted probands (chi21 = 12.73, p < .001), but this relationship was no longer significant when conduct disorder at FU18 was controlled (OR = 1.97, 95% CI = 0.89-4.38, p = .09). CONCLUSION: Among boys of white ethnicity who were followed into adulthood, childhood ADHD was associated with an elevated rate of homelessness. Findings point to the need for clinical monitoring of childhood ADHD through adolescence, even when ADHD does not persist, in hopes of mitigating a cascade of malfunction that includes homelessness.

Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis.

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.

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.