Faculty Bibliography

CONTEXT.: Approximately 30% of women report pain in the affected breast prior to breast cancer surgery. OBJECTIVES: The purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain. METHODS: Differences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time. RESULTS: Between-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast prior to surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. LME modeling revealed significant group effects for the majority of outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain. CONCLUSION: Investigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high risk group, are needed.

There exist many challenges hampering the discovery and development of effective interventions to prevent dementia. Three major trends have now intersected to influence the emerging interest in disease modifying therapies that may delay or halt dementia. The three crucial factors shaping this current focus are: (1) the emergence of the longevity revolution and the impact of a aging society, (2) the effects of the US Federal investment in research in advancing knowledge about the neurobiology of aging and dementia, and (3) the problem of US legislators and health policy makers to balance the allocation of evermore scarce research funding resources. The purpose of this essay is to provide a survey of the politics of science and to describe efforts to correctly manage the high level of expectations of both the patient and research communities. The perspective offered reviews the history and evolution of the ideas to treat or prevent dementia and Alzheimer's disease as a national strategic goal. The aim is to evaluate the interplay between science and formulation of public policy for setting research priority. We use the history of developing US National Institute of Aging's extramural research programs on brain aging and Alzheimer's disease (Khachaturian, 2006; 2007) as an initial case study.

BACKGROUND: Non-Gaussian diffusion imaging by using diffusional kurtosis imaging (DKI) allows assessment of isotropic tissue as of gray matter (GM), an important limitation of diffusion tensor imaging (DTI). OBJECTIVE: In this study, we describe DKI and DTI metrics of GM in multiple sclerosis (MS) patients and their association with cognitive deficits. METHODS: Thirty-four patients with relapsing-remitting MS and 17 controls underwent MRI on a 3T scanner including a sequence for DKI with 30 diffusion directions and 3b values for each direction. Mean kurtosis (MK), mean diffusivity and fractional anisotropy (FA) of cortical and subcortical GM were measured using histogram analysis. Spearman rank correlations were used to characterize associations among imaging measures and clinical/neuropsychological scores. RESULTS: In cortical GM, a significant decrease of MK (0.68 vs. 0.73; p < 0.001) and increase of FA (0.16 vs. 0.13; p < 0.001) was found in patients compared to controls. Decreased cortical MK was correlated with poor performance on the Delis-Kaplan Executive Function System test (r = 0.66, p = 0.01). CONCLUSION: Mean kurtosis is sensitive to abnormality in GM of MS patients and can provide information that is complementary to that of conventional DTI-derived metrics. The association between MK and cognitive deficits suggests that DKI might serve as a clinically relevant biomarker for cortical injury.

Objective: To assess group-differences in movement measures in published studies contrasting Attention-Deficit/Hyperactivity Disorder (ADHD) vs. controls. Background: ADHD diagnoses continue to be completely based on clinical history, which is subjective and subject to recall bias. In response, investigators have proposed incorporating objective measures such as locomotor activity which can be measured with actigraphy or with a high spatial and temporal resolution infrared camera. In May 2014, the United States Food and Drug Administration cleared an example of the latter, the Qb-Test, as a device to be used in supporting the diagnosis of ADHD. A review of the literature did not reveal any prior meta-analyses of such data. Methods: We performed a systematic review and meta-analysis of published studies on motion measures contrasting individuals diagnosed with ADHD and healthy controls. Two authors reviewed a total of 89 abstracts culled from an initial search of 356. After applying inclusion and exclusion criteria, 13 papers were included in our analyses of actigraphy and five papers in analyses of motion tracking systems. Results: The combined sample sizes were 406 patients with ADHD versus 359 controls with actigraphy data and 164 patients with ADHD versus 156 controls with motion tracking system data. Meta-analyses revealed medium effect sizes for actigraphy (standardized mean difference [SMD]: 0.64, 95 % CI: 0.43, 0.85) and large effects for motion tracking systems (SMD: 0.92, 95 % CI: 0.65, 1.20) in differentiating individuals with ADHD from controls. Conclusions: When measured objectively, locomotor hyperactivity robustly differentiates groups of patients with ADHD from healthy controls. Inclusion of objective locomotion measures is likely to be useful in circumstances in which ancillary information is not available, such as when evaluating adults with possible ADHD. However, even the relatively large effect sizes reported to date are unlikely to yield clinically actionable information for individual patients on their own. How to best incorporate such objective data in the diagnostic process remains unclear

Independent evolution has resulted in a vast diversity of eyes. Despite the lack of a common Bauplan or ancestral structure, similar developmental strategies are used. For instance, different classes of photoreceptor cells (PRs) are distributed stochastically and/or localized in different regions of the retina. Here, we focus on recent progress made towards understanding the molecular principles behind patterning retinal mosaics of insects, one of the most diverse groups of animals adapted to life on land, in the air, under water, or on the water surface. Morphological, physiological, and behavioral studies from many species provide detailed descriptions of the vast variation in retinal design and function. By integrating this knowledge with recent progress in the characterization of insect Rhodopsins as well as insight from the model organism Drosophila melanogaster, we seek to identify the molecular logic behind the adaptation of retinal mosaics to the habitat and way of life of an animal.

Small ubiquitin-like modifier-1 (SUMO1) plays a number of roles in cellular events and recent evidence has given momentum for its contributions to neuronal development and function. Here, we have generated a SUMO1 transgenic mouse model with exclusive overexpression in neurons in an effort to identify in vivo conjugation targets and the functional consequences of their SUMOylation. A high-expressing line was examined which displayed elevated levels of mono-SUMO1 and increased high molecular weight conjugates in all brain regions. Immunoprecipitation of SUMOylated proteins from total brain extract and proteomic analysis revealed ~95 candidate proteins from a variety of functional classes, including a number of synaptic and cytoskeletal proteins. SUMO1 modification of synaptotagmin-1 was found to be elevated as compared to non-transgenic mice. This observation was associated with an age-dependent reduction in basal synaptic transmission and impaired presynaptic function as shown by altered paired pulse facilitation, as well as a decrease in spine density. The changes in neuronal function and morphology were also associated with a specific impairment in learning and memory while other behavioral features remained unchanged. These findings point to a significant contribution of SUMO1 modification on neuronal function which may have implications for mechanisms involved in mental retardation and neurodegeneration.

Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17∼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17∼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17∼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17∼92 responsible for LMC-MN degeneration. Additionally, mir-17∼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival.

Fatty acids (FAs) are not only essential components of cellular energy storage and structure, but play crucial roles in signalling. Here we present a toolkit of photoswitchable FA analogues (FAAzos) that incorporate an azobenzene photoswitch along the FA chain. By modifying the FAAzos to resemble capsaicin, we prepare a series of photolipids targeting the Vanilloid Receptor 1 (TRPV1), a non-selective cation channel known for its role in nociception. Several azo-capsaicin derivatives (AzCAs) emerge as photoswitchable agonists of TRPV1 that are relatively inactive in the dark and become active on irradiation with ultraviolet-A light. This effect can be rapidly reversed by irradiation with blue light and permits the robust optical control of dorsal root ganglion neurons and C-fibre nociceptors with precision timing and kinetics not available with any other technique. More generally, we expect that photolipids will find many applications in controlling biological pathways that rely on protein-lipid interactions.

Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal alpha7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans.