Faculty Bibliography

A concise, enantioselective synthesis of lycopladine A and carinatine A is presented. Our synthetic approach hinges on the recently developed mild carbocyclization of ynones to furnish the hydrindane core of the alkaloids. Their pyridine ring was efficiently installed using the Ciufolini method. Both heterocycles of carinatine A, a rare naturally occurring nitrone, were formed in a single operation.

Study Objectives: Sudden unexpected death during sleep (SUDS) is the most common cause of death in patients with familial dysautonomia, an autosomal recessive disease characterized by sensory and autonomic dysfunction. It remains unknown what causes SUDS in these patients and who is at highest risk. We tested the hypothesis that SUDS in FD is linked to sleep-disordered breathing. Methods: We retrospectively identified patients with familial dysautonomia who died suddenly and unexpectedly during sleep and had undergone polysomnography within the 18-month period prior to death. For each case, we sampled one age-matched surviving subject with familial dysautonomia that had also undergone polysomnography within the 18-month period prior to study. Data on polysomnography, EKG, ambulatory blood pressure monitoring, arterial blood gases, blood count, and metabolic panel were analyzed. Results: Thirty-two deceased cases and 31 surviving controls were included. Autopsy was available in 6 cases. Compared with controls, subjects with SUDS were more likely to be receiving treatment with fludrocortisone (odds ratio; 95% confidence interval) (OR 29.7; 4.1-213.4), have untreated obstructive sleep apnea (OR 17.4; 1.5-193) and plasma potassium levels < 4 mEq/L (OR 19.5; 2.36-161), but less likely to use non-invasive ventilation at night (OR 0.19; 0.06-0.61). Conclusions: Initiation of non-invasive ventilation when required, and discontinuation of fludrocortisone treatment may reduce the high incidence rate of SUDS in patients with familial dysautonomia. Our findings contribute to the understanding of the link between autonomic, cardiovascular, and respiratory risk factors in sudden unexpected death during sleep.

Purkinje cells (PCs) generate two types of action potentials, called simple and complex spikes (SSs and CSs). We first investigated the CS-associated modulation of SS activity and its relationship to the zebrin status of the PC. The modulation pattern consisted of a pre-CS rise in SS activity, and then, following the CS, a pause, a rebound, and finally a late inhibition of SS activity for both zebrin positive (Z+) and negative (Z-) cells, though the amplitudes of the phases were larger in Z+ cells. Moreover, the amplitudes of the pre-CS rise with the late inhibitory phase of the modulation were correlated across PCs. In contrast, correlations between modulation phases across CSs of individual PCs were generally weak. Next, the relationship between CS spikelets and SS activity was investigated. The number of spikelets/CS correlated with the average SS firing rate only for Z+ cells. In contrast, correlations across CSs between spikelet numbers and the amplitudes of the SS modulation phases were generally weak. Division of spikelets into likely axonally propagated and non-propagated groups (based on their interspikelet interval) showed that the correlation of spikelet number with SS firing rate primarily reflected a relationship with non-propagated spikelets. In sum, the results show that both zebrin-related and non-zebrin-related physiological heterogeneity in SS-CS interactions among PCs, which suggests that the cerebellar cortex is more functionally diverse than is assumed by standard theories of cerebellar function

Acoustic trauma or inner ear disease may predominantly injure one ear, causing asymmetric sensorineural hearing loss (SNHL). While characteristic frequency (CF) map plasticity of primary auditory cortex (AI) contralateral to the injured ear has been detailed, there is no study that also evaluates ipsilateral AI to compare cortical reorganization across both hemispheres. We assess whether normal isomorphic mirror image relationship between the two hemispheres is maintained or disrupted in mild-to-moderate asymmetric SNHL of adult squirrel monkeys. At week 24 following induction of acoustic injury to the right ear, functional organization of the two hemispheres differs in direction and magnitude of interaural CF difference, percentage of recording sites with spectrally non-overlapping binaural activation, and the concurrence of peripheral and central activation thresholds. The emergence of this anisomorphic cortical reorganization of the two hemispheres is replicated by simulation based on spike-timing-dependent plasticity, where: 1) AI input from the contralateral ear is dominant, 2) reestablishment of relatively shorter contralateral ear input timing drives reorganization, and 3) only AI contralateral to the injured ear undergoes major realignment of interaural frequency maps that evolve over months. Asymmetric SNHL disrupts isomorphic organization between the two hemispheres and results in relative local hemispheric autonomy, potentially impairing performance of tasks that require binaural input alignment or interhemispheric processing.

Importance: The lack of prospective randomized clinical trials demonstrating that full-body skin examination (FBSE) reduces melanoma morbidity or mortality has prompted an "I" rating from the United States Preventive Services Task Force for population-based skin cancer screening. More data on these screening programs are needed. Objectives: To describe a skin cancer screening quality initiative in a large health care system and to determine if the intervention was associated with screening of a demographically higher-risk population than previous screening programs and if melanoma incidence and thickness differed in screened vs unscreened patients. Design, Setting, and Participants: This observational evaluation of a prospectively implemented quality initiative was conducted in a large health care system in western Pennsylvania (University of Pittsburgh Medical Center, UPMC) among adults seen in an office visit by a UPMC-employed primary care physician (PCP) in 2014. Interventions: Implementation of a campaign promoting annual skin cancer screening by FBSE, including training of PCPs, promotion of the initiative to physicians and patients, and modification of the electronic health record (EHR) to include FBSE as a recommended preventive service for patients 35 years or older. Main Outcomes and Measures: Characteristics of screened and unscreened patients and melanomas detected among them. Results: Of 333735 adult patients seen in an office visit by PCPs in 2014, 53196 patients (15.9% of the screen-eligible population) received an FBSE, and 280539 did not. Screened patients were slightly older (median age, 60 vs 57 years; P < .001) but did not differ significantly by sex (43.2% vs 43.1% men; P = .49) from the unscreened population. Fifty melanomas were diagnosed in screened patients and 104 melanomas were diagnosed in unscreened patients. Screened patients were more likely than unscreened patients to be diagnosed with melanoma (adjusted risk ratio [RR], 2.4; 95% CI, 1.7-3.4; P < .001) and to have a thinner invasive melanoma (median thickness, 0.37 mm vs 0.65 mm; P < .001). The incidence of melanoma lesions 1 mm or thicker was similar in screened vs unscreened patients (adjusted RR, 0.7; 95% CI, 02.-2.2; P = .52). Conclusions and Relevance: Large-scale screening for melanoma within a United States health care system is feasible and can result in increased detection of thinner melanomas. This intervention also resulted in screening of a higher proportion of men and an older patient population than previous screening interventions in which younger individuals and women predominated.

PURPOSE: Conventional fat/water separation techniques require that patients hold breath during abdominal acquisitions, which often fails and limits the achievable spatial resolution and anatomic coverage. This work presents a novel approach for free-breathing volumetric fat/water separation. METHODS: Multiecho data are acquired using a motion-robust radial stack-of-stars three-dimensional GRE sequence with bipolar readout. To obtain fat/water maps, a model-based reconstruction is used that accounts for the off-resonant blurring of fat and integrates both compressed sensing and parallel imaging. The approach additionally enables generation of respiration-resolved fat/water maps by detecting motion from k-space data and reconstructing different respiration states. Furthermore, an extension is described for dynamic contrast-enhanced fat-water-separated measurements. RESULTS: Uniform and robust fat/water separation is demonstrated in several clinical applications, including free-breathing noncontrast abdominal examination of adults and a pediatric subject with both motion-averaged and motion-resolved reconstructions, as well as in a noncontrast breast exam. Furthermore, dynamic contrast-enhanced fat/water imaging with high temporal resolution is demonstrated in the abdomen and breast. CONCLUSION: The described framework provides a viable approach for motion-robust fat/water separation and promises particular value for clinical applications that are currently limited by the breath-holding capacity or cooperation of patients. Magn Reson Med, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine.

Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n = 10), pre-lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre-lesional tissue had higher Cr and Cho, while compared with lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady-state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

It has been reported that cross-frequency interactions may play an important role in local processing within thalamus and neocortex, as well as information transfer between subcortical and cortico-cortical brain regions. Strong commonalities in rhythmic network properties have been observed across recording techniques and task demands, but strong neuroscientific theories to situate such observations within a unified framework with direct relevance to explain neuropathologies remain scarce. Based on a comprehensive review of animal and human literature, we probe and introduce a neurophysiological framework to explain how coordinated cross-frequency and interregional oscillatory cortical dynamics underlie typical and atypical brain activation, and the formation of distributed functional ensembles supporting cortical networks underpinning perception and cognition. We propose that local regional activation by an external stimulus via a sensory pathway entails (1) attenuated alpha (8-14 Hz) and increased theta (4-8 Hz) and gamma (30-50 Hz) oscillatory activity, and (2) increased interactions among theta and gamma rhythms. These local dynamics also mediate the integration of activated neural populations into large-scale functional assemblies through neuronal synchronization. This comprehensive perspective into the animal and human literature indicates a further thinking beyond synchrony and connectivity and the readiness for more hypothesis-driven research and modeling toward unified principles of thalamo-cortical processing. We further introduced such a possible framework: "The ATG switch". We also discussed evidence that alpha-theta-gamma dynamics emerging from thalamocortical interactions may be implicated and disrupted in numerous neurological and neuropsychiatric conditions.