Faculty Bibliography

This Matters Arising Response paper addresses the Sultan et al. (2016) Matters Arising paper, published concurrently in Neuron. Clonally related excitatory neurons maintain a coherent relationship following their specification and migration. Whether cortical interneurons behave similarly is a fundamental question in developmental neuroscience. In Mayer et al. (2015), we reported that sibling interneurons disperse over several millimeters, across functional and anatomical boundaries. This finding demonstrated that clonality is not predictive of an interneuron's ultimate circuit specificity. Comparing the distribution of interneurons published in Mayer et al. to a random computer simulation, Sultan et al. suggest that clonally related interneurons are "not randomly dispersed." We argue that this comparison provides no insight into the influence of clonality on interneuron development because the entire population of cortical interneurons is "not randomly dispersed" in vivo. We find that the majority of cortical interneurons are similarly distributed whether or not they share a lineal relationship. Thus, at present there is no compelling evidence that clonality influences the position or function of interneurons.

Ceramide is a pro-apoptotic sphingolipid with unique physical characteristics. Often viewed as a second messenger, its generation can modulate the structure of lipid rafts. We prepared three photoswitchable ceramides, ACes, which contain an azobenzene photoswitch allowing for optical control over the N-acyl chain. Using combined atomic force and confocal fluorescence microscopy, we demonstrate that the ACes enable reversible switching of lipid domains in raft-mimicking supported lipid bilayers (SLBs). In the trans-configuration, the ACes localize into the liquid-ordered (Lo) phase. Photoisomerization to the cis-form triggers a fluidification of the Lo domains, as liquid-disordered (Ld) "lakes" are formed within the rafts. Photoisomerization back to the trans-state with blue light stimulates a rigidification inside the Ld phase, as the formation of small Lo domains. These changes can be repeated over multiple cycles, enabling a dynamic spatiotemporal control of the lipid raft structure with light.

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 degrees C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 degrees C but are unexcitable at 40 degrees C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

We describe a 21-year-old woman who presented with chest pain and dyspnea on exertion and who was found to have a large pericardial mass. Multimodality imaging was instrumental in narrowing the differential diagnosis and planning surgical treatment, which included coronary artery bypass and right-sided heart reconstruction. The final pathologic diagnosis was lymphohemangioma; to our knowledge, this was the largest cardiac/pericardial vascular tumor ever to be reported in the literature.

Background/Purpose: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and European Union at 200 mg daily dose in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients unable to achieve target serum uric acid on XOI (allopurinol or febuxostat) alone. Approval of lesinurad was based on three pivotal, placebo-controlled, 12-month phase III (core) studies evaluating lesinurad 200 mg (LESU200) and 400 mg (LESU400) in combination with XOI. Patients completing core studies were eligible to enter extension studies, continuing LESU+XOI at the same dose or randomized from placebo to LESU200 or LESU400 plus XOI. Methods: Renal-related and kidney stone safety data were pooled from core studies to compare LESU200+XOI and LESU400+XOI with XOI alone and from core studies + extension studies to evaluate the impact on renal safety of extended LESU+XOI treatment. Renal-related treatment-emergent adverse events (TEAEs) were a customized list of 36 preferred terms selected from the Medical Dictionary for Regulatory Activities (MedRA) Renal and Urinary Disorders System Organ Class (SOC), the Investigations SOC and the Acute Renal Failure MedRA Standardized MedRA Query (SMQ). Descriptive statistics are provided for patients receiving >1 dose of study medication. To adjust for varying treatment duration, TEAEs are expressed as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years). Results: In the core studies, EAIRs for any renal-related TEAE, serious renal-related TEAEs, and renal-related TEAEs leading to discontinuation were similar with XOI alone and LESU200+XOI and lower than with LESU400 +XOI (Table 1). Similar results were found for kidney stone and serious kidney stone TEAEs. The most common renal-related TEAE was increased serum creatinine (sCr). EAIRs for sCr elevations >1.5x baseline were higher with LESU+XOI than XOI alone (Table 1). Overall, 75% and 84% of sCr elevations in the XOI alone and LESU+XOI groups, respectively, were resolved at last study assessment; 75% and 66% resolved without interruption of medication. Exposure to extended LESU+XOI treatment in core+extension studies did not show an increase from core studies in EAIRs for any renal-related or kidney stone adverse event category (Table 2). Conclusion: Lesinurad at the approved dose of 200 mg once-daily combined with XOI demonstrated comparable rate of adverse events to XOI alone. There was no clinically relevant increase in these adverse events with the extension of treatment beyond 1 year. (Table presented)

Introduction: Patients with afferent or efferent lesions in the arterial baroreflex pathways can have orthostatic hypotension, but only those with afferent lesions have stress-induced paroxysmal hypertension. The effect of these different abnormalities on circadian blood pressure (BP) and heart rate (HR) profiles has not been systematically compared.
Method(s): We prospectively collected 24-h ambulatory BP and HR recordings in 50 patients with afferent lesions (6 acquired and 44 developmental due to familial dysautonomia). We compared this with recordings obtained in 51 patients with efferent lesions (40 with Lewy body disorders and 11 with multiple system atrophy). A similar number of patients in both groups were taking fludrocortisone (25 %) and midodrine (37 %). Thirty-six percent of patients with afferent lesions were taking clonidine. Differences in age, medications, and diagnosis were used as co-variants.
Result(s): Patients with afferent lesions were younger, had lower average 24-h, daytime, and nighttime systolic (p<0.0001, p = 0.0002, p<0.0001) and diastolic blood pressures (p = 0.006, p = 0.085, p = 0.0001). However, with age as a covariant, these differences were not significant. HR was consistently higher in patients with afferent lesions (p<0.0001). Variability of both diastolic BP (STD 19.35.9 vs. 12.63.9 mmHg, p<0.0001) and HR (STD 11.53.5 vs. 8.54.2 bpm, p = 0.0003) were higher in patients with afferent lesions, and this was still significant with age and clonidine use as co-variants. Patients with afferent lesions had at least one diastolic hypertensive surge that was higher than those captured in patients with efferent lesions (11625 vs. 10516 mmHg, p = 0.009). Nighttime BP dipping (i.e., a fall >10 %) was present in 46 % patients with afferent lesions and only in 19 % of those with efferent lesions. Excluding patients taking clonidine did not change the significance of the results.
Conclusion(s): Patients with afferent lesions of the baroreflex have higher variability in BP and HR over a 24-h period than those with efferent lesions. Unstable blood pressure is a known risk factor for target organ damage. As these patients frequently have early onset renal disease, prospective trials to reduce blood pressure variability are warranted

Recent neuroimaging research on disorders of consciousness provides direct evidence of covert consciousness otherwise not detected clinically in a subset of severely brain-injured patients. These findings have motivated strategic development of binary communication paradigms, from which researchers interpret voluntary modulations in brain activity to glean information about patients' residual cognitive functions and emotions. The discovery of such responsiveness raises ethical and legal issues concerning the exercise of autonomy and capacity for decisionmaking on matters such as healthcare, involvement in research, and end of life. These advances have generated demands for access to the technology against a complex background of continued scientific advancement, questions about just allocation of healthcare resources, and unresolved legal issues. Interviews with professionals whose work is relevant to patients with disorders of consciousness reveal priorities concerning further basic research, legal and policy issues, and clinical considerations.

Uncertainty, which is ubiquitous in decision-making, can be fractionated into known probabilities (risk) and unknown probabilities (ambiguity). Although research has illustrated that individuals more often avoid decisions associated with ambiguity compared to risk, it remains unclear why ambiguity is perceived as more aversive. Here we examine the role of arousal in shaping the representation of value and subsequent choice under risky and ambiguous decisions. To investigate the relationship between arousal and decisions of uncertainty, we measure skin conductance response-a quantifiable measure reflecting sympathetic nervous system arousal-during choices to gamble under risk and ambiguity. To quantify the discrete influences of risk and ambiguity sensitivity and the subjective value of each option under consideration, we model fluctuating uncertainty, as well as the amount of money that can be gained by taking the gamble. Results reveal that although arousal tracks the subjective value of a lottery regardless of uncertainty type, arousal differentially contributes to the computation of value-that is, choice-depending on whether the uncertainty is risky or ambiguous: Enhanced arousal adaptively decreases risk-taking only when the lottery is highly risky but increases risk-taking when the probability of winning is ambiguous (even after controlling for subjective value). Together, this suggests that the role of arousal during decisions of uncertainty is modulatory and highly dependent on the context in which the decision is framed. (PsycINFO Database Record