Faculty Bibliography

Parametric maximum likelihood (ML) estimators of probability density functions (pdfs) are widely used today because they are efficient to compute and have several nice properties such as consistency, fast convergence rates, and asymptotic normality. However, data is often complex making parametrization of the pdf difficult, and nonparametric estimation is required. Popular nonparametric methods, such as kernel density estimation (KDE), produce consistent estimators but are not ML and have slower convergence rates than parametric ML estimators. Further, these nonparametric methods do not share the other desirable properties of parametric ML estimators. This paper introduces a nonparametric ML estimator that assumes that the square-root of the underlying pdf is band-limited (BL) and hence "smooth". The BLML estimator is computed and shown to be consistent. Although convergence rates are not theoretically derived, the BLML estimator exhibits faster convergence rates than state-of-the-art nonparametric methods in simulations. Further, algorithms to compute the BLML estimator with lesser computational complexity than that of KDE methods are presented. The efficacy of the BLML estimator is shown by applying it to (i) density tail estimation and (ii) density estimation of complex neuronal receptive fields where it outperforms state-of-the-art methods used in neuroscience.

BACKGROUND: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. METHODS: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. RESULTS: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 mum (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 microm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. CONCLUSION: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

IN BRIEF Dietary guidelines for patients with diabetes extend beyond glycemic management to include recommendations for mitigating chronic disease risk. This review summarizes the literature suggesting that excess dietary phosphorus intake may increase the risk of skeletal and cardiovascular disease in patients who are in the early stages of chronic kidney disease (CKD) despite having normal serum phosphorus concentrations. It explores strategies for limiting dietary phosphorus, emphasizing that food additives, as a major source of highly bioavailable dietary phosphorus, may be a suitable target. Although the evidence for restricting phosphorus-based food additives in early CKD is limited, diabetes clinicians should monitor ongoing research aimed at assessing its efficacy.

Introduction: Slow wave sleep (SWS) is thought to benefit spatial memory consolidation. This study investigates whether disrupting SWS via sleep-stage specific OSA affects spatial memory consolidation and how sleep fragmentation and intermittent hypoxia differentially impact this effect. Methods: We recruited 5 subjects with severe OSA who are well treated and compliant with CPAP. Individual subjects spent 3 different nights in the lab and performed timed trials before and after sleep on unique but equally difficult 3D spatial mazes. The 3 conditions included: 1) consolidated sleep with treated OSA 2) CPAP withdrawn exclusively in SWS (SWS-OSA) and 3) CPAP withdrawn exclusively in SWS with simultaneous addition of supplemental oxygen (SWS-OSA+O2). Results: CPAP withdrawal in SWS both decreased %SWS (21% +/- 11% during consolidated sleep vs. 13% +/- 7% with SWS-OSA), and fragmented remaining SWS (SWS apnea hypopnea index with 3% oxygen desaturation or arousal (AHI3A) = 0.5/hour +/- 1 during consolidated sleep vs. 36/hour +/- 12 with SWS-OSA). During SWSOSA+ O2, SWS was also reduced (11% +/ 8%) and respiratory events continued (AHI3A 31/hour +/- 20), however indices of oxygen desaturation were minimized (%time below 90% in SWS = 4.3% +/- 1.7% during SWS-OSA vs 0.5% +/- 0.9% during SWS-OSA+O2; average oxygen saturation during respiratory event = 88.7% +/- 3.3% during SWS-OSA vs. 94% +/- 1.4% during SWS-OSA+O2). During consolidated sleep, median completion time improved from 180 sec pre-sleep (range 86 to 248 sec) to 111 sec post-sleep (range 87 to 412 sec) (38%). During SWS-OSA median completion time improved from 138 sec pre-sleep (range 116 to 272 sec) to 133 sec post-sleep (range 73 to 453 sec) (4%) and during SWS-OSA+O2 median completion time improved from 172 sec pre-sleep (range 61 to 339 sec) to 161 sec postsleep (range 51 to 306 sec) (6%). Conclusion: CPAP withdrawal during SWS in subjects with severe OSA reduces and fragments SWS. The addition of supplemental oxygen during CPAP withdrawal minimizes the associated intermittent hypoxia. Early evidence suggests a greater benefit of consolidated sleep on overnight change in spatial navigation performance than sleep with SWS disruption either with or without intermittent hypoxia

Introduction: Sleep may play a role in AD pathogenesis, but the timing, role, and extent to which sleep disturbances in late-life are associated with increasing burden of AD neuropathology remains unclear. Sleep spindles have been implicated in sleep quality. Wakefulness is mediated by an arousal system beginning in the brainstem and continuing on to the diencephalon and innervating the thalamus, the region where sleep spindle oscillations are generated. In AD pathology, hyperphosphorylated tau (P-Tau) protein accumulates in the brainstem, from where it spreads to the entorhinal cortices, hippocampi and other brain regions. These tau aggregates may interfere with the sleep-wake cycle resulting in down-regulation of sleep spindles and associated sleep disruption. Increased CSF P-tau and T-tau levels are likely related to the formation of neurofibrillary tangles in the brainstem and limbic system (Braak stages I-IV). Methods: 49 cognitively normal (CDR=0) elderly (66.95 +/- 7.76 years) subjects completed a structural MRI, lumbar puncture (LP) and nocturnal polysomnography (NPSG) within 4.65 +/- 6.81 months of the LP. From the NPSG, spindle frequency and density were analyzed for stages NREM1, NREM2 and NREM3, using an automated optimization algorithm which decomposes the EEG as a sum of transient and oscillatory components. This was used to detect the spindles and a Fourier analysis was performed to evaluate the spindle frequency in Hz. Results: Spindle frequency and density in NREM2 sleep were inversely associated with CSF P-tau (r= -0.355, p<0.05; r=-0.476, p<0.05) and CSF T-tau (r=-0.405, p<.05; r=-0.542, p<.05) using partial correlation controlling for age and ApoE4 allele. There were no associations between spindle frequency or density and CSF P-tau or CSF T-tau in stages NREM1, NREM3. Conclusion: The association of spindle frequency and density in NREM2 to CSF P-tau and CSF T-tau in cognitively normal elderly suggest either that tau pathology may produce an early downstream effect on sleep spindles, or that changes in sleep spindles can identify a process relating to tau pathology. Whether the association of tau to spindles is a non-specific effect of tau on increasing sleep fragmentation in general remains an area of active investigation

Sleep is an ancient animal behavior that is regulated similarly in species ranging from flies to humans. Various genes that regulate sleep have been identified in invertebrates, but whether the functions of these genes are conserved in mammals remains poorly explored. Drosophila insomniac (inc) mutants exhibit severely shortened and fragmented sleep. Inc protein physically associates with the Cullin-3 (Cul3) ubiquitin ligase, and neuronal depletion of Inc or Cul3 strongly curtails sleep, suggesting that Inc is a Cul3 adaptor that directs the ubiquitination of neuronal substrates that impact sleep. Three proteins similar to Inc exist in vertebrates-KCTD2, KCTD5, and KCTD17-but are uncharacterized within the nervous system and their functional conservation with Inc has not been addressed. Here we show that Inc and its mouse orthologs exhibit striking biochemical and functional interchangeability within Cul3 complexes. Remarkably, KCTD2 and KCTD5 restore sleep to inc mutants, indicating that they can substitute for Inc in vivo and engage its neuronal targets relevant to sleep. Inc and its orthologs localize similarly within fly and mammalian neurons and can traffic to synapses, suggesting that their substrates may include synaptic proteins. Consistent with such a mechanism, inc mutants exhibit defects in synaptic structure and physiology, indicating that Inc is essential for both sleep and synaptic function. Our findings reveal that molecular functions of Inc are conserved through ~600 million years of evolution and support the hypothesis that Inc and its orthologs participate in an evolutionarily conserved ubiquitination pathway that links synaptic function and sleep regulation.

Introduction Radiation Therapy (RT) for Head and Neck Cancer (HNC) can cause significant oral complications. However, modern techniques such as Intensity Modulated RT (IMRT) may reduce their incidence/severity. Objectives To assess severity of oral complications 6 months after modern RT for HNC. Methods OraRad is an ongoing 6-center prospective cohort study. Oral outcomes are evaluated before start of RT (baseline), and 6, 12, 18, 24 months after RT. For this analysis, we compared baseline vs. 6 month data using mixed linear models for continuous measures and generalized estimating equations for categorical measures. Data are presented as outcome mean (SD, number of subjects), unless otherwise stated. Results Stimulated whole salivary flow declined from 1.09 ml/min (0.67, 354) at baseline to 0.47 (0.47, 216) at 6 months (p < 0.0001). Maximal mouth opening reduced from 45.58 mm (10.40, 371) to 42.53 (9.52, 208) (p < 0.0001). 17 of 203 subjects (8.4%) had persistent oral mucositis at 6 months. Overall oral health-related quality of life score (1-4 scale) worsened from 1.48 (0.42, 371) to 1.86 (0.47, 211) (p < 0.0001). Contributing to this decline were subject-reported negative changes related to swallowing solid food, choking when swallowing, opening the mouth wide, dry mouth, sticky saliva, smell, and taste (p < 0.0001). At 6 months, there was greater frequency of using dental floss, and greater proportion using supplemental fluoride (p < 0.0001). Conclusions Despite use of IMRT, HNC patients continue to suffer significant oral complications of cancer therapy, with negative impact on oral health, function, and quality of life