Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:The persistent rise in kidney stone prevalence in recent decades has prompted much speculation as to the causes. There has been some discussion about the effect of heat on nephrolithiasis. Here, we review recent data and postulate that heat may play a role in stone formation on a large scale and among African-Americans in particular. RECENT FINDINGS/RESULTS:African-Americans are the race/ancestry group with faster rates of increasing incidence and prevalence of kidney stones. We make the observation that urban heat islands in the United States have resulted in part from the effects of redlining, a practice of systematic segregation and racism in housing that led to the development of neighborhoods with substantial disparities in environmental conditions. SUMMARY/CONCLUSIONS:In this thought experiment, we propose that the disproportionate rise in the prevalence of nephrolithiasis in minoritized populations correlates with increased temperatures specifically in neighborhoods adversely affected by the practice of redlining. We discuss phenomena in support of this hypothesis and ongoing work to test this theory.

Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

Modern medical imaging techniques, such as ultrasound (US) and cardiac magnetic resonance (MR) imaging, have enabled the evaluation of myocardial deformation directly from an image sequence. While many traditional cardiac motion tracking methods have been developed for the automated estimation of the myocardial wall deformation, they are not widely used in clinical diagnosis, due to their lack of accuracy and efficiency. In this paper, we propose a novel deep learning-based fully unsupervised method, SequenceMorph, for in vivo motion tracking in cardiac image sequences. In our method, we introduce the concept of motion decomposition and recomposition. We first estimate the inter-frame (INF) motion field between any two consecutive frames, by a bi-directional generative diffeomorphic registration neural network. Using this result, we then estimate the Lagrangian motion field between the reference frame and any other frame, through a differentiable composition layer. Our framework can be extended to incorporate another registration network, to further reduce the accumulated errors introduced in the INF motion tracking step, and to refine the Lagrangian motion estimation. By utilizing temporal information to perform reasonable estimations of spatio-temporal motion fields, this novel method provides a useful solution for image sequence motion tracking. Our method has been applied to US (echocardiographic) and cardiac MR (untagged and tagged cine) image sequences; the results show that SequenceMorph is significantly superior to conventional motion tracking methods, in terms of the cardiac motion tracking accuracy and inference efficiency. Code will be available at <uri>https://github.com/DeepTag/SequenceMorph</uri>.

In neonatal brain development there is a period of normal apoptotic cell death that regulates adult neuron number. At approximately the same period, ethanol exposure can cause a dramatic spike in apoptotic cell death. While ethanol-induced apoptosis has been shown to reduce adult neuron number, questions remain about the regional selectivity of the ethanol effect, and whether the brain might have some capacity to overcome the initial neuron loss. The present study used stereological cell counting to compare cumulative neuron loss 8 h after postnatal day 7 (P7) ethanol treatment to that of animals left to mature to adulthood (P70). Across several brain regions we found that the reduction of total neuron number after 8 h was as large as that of adult animals. Comparison between regions revealed that some areas are more vulnerable, with neuron loss in the anterior thalamic nuclei > the medial septum/vertical diagonal band, dorsal subiculum, and dorsal lateral geniculate nucleus > the mammillary bodies and cingulate cortex > whole neocortex. In contrast to estimates of total neuron number, estimates of apoptotic cell number in Nissl-stained sections at 8 h after ethanol treatment provided a less reliable predictor of adult neuron loss. The findings show that ethanol-induced neonatal apoptosis often causes immediate neuron deficits that persist in adulthood, and furthermore suggests that the brain may have limited capacity to compensate for ethanol-induced neuron loss.

Introduction: Transitions between sleep and waking and sleep-dependent cortical oscillations are heavily dependent on GABAergic neurons. Importantly, GABAergic neurons are especially sensitive to developmental ethanol exposure, suggesting a potential unique vulnerability of sleep circuits to early ethanol. In fact, developmental ethanol exposure can produce long-lasting impairments in sleep, including increased sleep fragmentation and decreased delta wave amplitude. Here, we assessed the efficacy of optogenetic manipulations of somatostatin (SST) GABAergic neurons in the neocortex of adult mice exposed to saline or ethanol on P7, to modulate cortical slow-wave physiology. Methods: SST-cre × Ai32 mice, which selectively express channel rhodopsin in SST neurons, were exposed to ethanol or saline on P7. This line expressed similar developmental ethanol induced loss of SST cortical neurons and sleep impairments as C57BL/6By mice. As adults, optical fibers were implanted targeting the prefrontal cortex (PFC) and telemetry electrodes were implanted in the neocortex to monitor slow-wave activity and sleep-wake states. Results: Optical stimulation of PFC SST neurons evoked slow-wave potentials and long-latency single-unit excitation in saline treated mice but not in ethanol mice. Closed-loop optogenetic stimulation of PFC SST neuron activation on spontaneous slow-waves enhanced cortical delta oscillations, and this manipulation was more effective in saline mice than P7 ethanol mice. Discussion: Together, these results suggest that SST cortical neurons may contribute to slow-wave impairment after developmental ethanol.

Background and Objectives: Perioperative ketamine has been shown to reduce opioid consumption and pain after surgery. Ketamine is most often given as an infusion, but an alternative is single-dose ketamine. Single-dose ketamine at up to 1 mg/kg has been shown to reduce symptoms of depression, and a wide range of dosages has been used for pain in the emergency department. However, limited data exists on the tolerability and efficacy of a single-dose of ketamine at 0.6 mg/kg for pain when administered immediately after surgery. We conducted a pilot study of single-dose ketamine in patients undergoing mastectomy with reconstruction, hypothesizing that a single-dose of ketamine is well tolerated and can relieve postoperative pain and improve mood and recovery. Methods: This is a randomized, single-blind, placebo-controlled, two-arm parallel, single-center study. Thirty adult women undergoing mastectomy with reconstruction for oncologic indication received a single-dose of ketamine (0.6mg/kg) or placebo after surgery in the post-anesthesia care unit (PACU). Patients were followed through postoperative day (POD) 7. The primary outcome was postoperative pain measured by the Brief Pain Inventory (BPI) pain subscale on POD 1 and 2. Secondary outcomes include effects on opioid use, PROMIS fatigue and sleep, mood, Quality of Recovery-15, and the Breast Cancer Pain Questionnaire. Results: Side effects were minor and not significantly different in frequency between groups. The ketamine group reported lower scores on the BPI pain severity subscale, especially at POD 7; however, the difference was not statistically significant. There were no statistically significant differences between ketamine and placebo groups for the secondary outcomes. Conclusion: A single-dose of ketamine at 0.6mg/kg administered postoperatively in the PACU is well tolerated in women undergoing mastectomy and may confer better pain control up to one week after surgery. Future studies with larger sample sizes are necessary to adequately characterize the effect of postoperative single-dose ketamine on pain control in this population.

Diseases are manifestations of complex changes in protein-protein interaction (PPI) networks whereby stressors, genetic, environmental, and combinations thereof, alter molecular interactions and perturb the individual from the level of cells and tissues to the entire organism. Targeting stressor-induced dysfunctions in PPI networks has therefore become a promising but technically challenging frontier in therapeutics discovery. This opinion provides a new framework based upon disrupting epichaperomes - pathological entities that enable dysfunctional rewiring of PPI networks - as a mechanism to revert context-specific PPI network dysfunction to a normative state. We speculate on the implications of recent research in this area for a precision medicine approach to detecting and treating complex diseases, including cancer and neurodegenerative disorders.