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1.  Natural History of the Early Repolarization Pattern in a Biracial Cohort: CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Objectives
The objective of this analysis was to determine the natural history and prospective association of cardiovascular risk factors with early repolarization (ER).
Background
ER is common and has been suggested to increase risk for cardiovascular mortality in middle-aged adults. Data are sparse regarding the natural history of ER from young adulthood to middle age.
Methods
We examined 5,069 participants (mean age 25 years at baseline; 40% black) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort over 20 years. Electrocardiograms were recorded at years 0 (Y0), 7 (Y7), and 20 (Y20) and coded as either definite, probable, possible, or no ER. Logistic regression was used to determine the association of cardiovascular risk factors with the presence of ER cross-sectionally and prospectively.
Results
A total of 941 of the 5,069 participants (18.6%) had definite ER at baseline, and only 119 of 2,505 participants (4.8%) at the Y20 examination still demonstrated the presence of ER. Younger age, black race, male sex, longer exercise duration and QRS duration, and lower body mass index (BMI), heart rate, QT index, and Cornell voltage were associated cross-sectionally with the presence of ER. Predictors of maintenance of ER from Y0 to Y20 were black race (odds ratio [OR]: 2.62; 95% CI; 1.61 to 4.25), BMI (OR: 0.62 per 1 SD; 95% CI: 0.40 to 0.94), serum triglyceride levels (OR: 0.66 per 1 SD; 95% CI: 0.45 to 0.98), and QRS duration (OR: 1.68 per 1 SD; 95% CI: 1.37 to 2.06) at baseline.
Conclusions
The prevalence of ER was significantly higher than previous estimates among asymptomatic young adults, and the majority of ER regressed by middle age. Black race, lower BMI, lower serum triglyceride levels, and longer QRS duration were independently associated with maintenance of ER over time.
doi:10.1016/j.jacc.2012.11.053
PMCID: PMC3748821  PMID: 23428218
early repolarization; electrocardiography; epidemiology
2.  In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography 
Biomedical Optics Express  2013;4(8):1305-1317.
The adaptive optics scanning light ophthalmoscope (AOSLO) allows visualization of microscopic structures of the human retina in vivo. In this work, we demonstrate its application in combination with oral and intravenous (IV) fluorescein angiography (FA) to the in vivo visualization of the human retinal microvasculature. Ten healthy subjects ages 20 to 38 years were imaged using oral (7 and/or 20 mg/kg) and/or IV (500 mg) fluorescein. In agreement with current literature, there were no adverse effects among the patients receiving oral fluorescein while one patient receiving IV fluorescein experienced some nausea and heaving. We determined that all retinal capillary beds can be imaged using clinically accepted fluorescein dosages and safe light levels according to the ANSI Z136.1-2000 maximum permissible exposure. As expected, the 20 mg/kg oral dose showed higher image intensity for a longer period of time than did the 7 mg/kg oral and the 500 mg IV doses. The increased resolution of AOSLO FA, compared to conventional FA, offers great opportunity for studying physiological and pathological vascular processes.
doi:10.1364/BOE.4.001305
PMCID: PMC3756583  PMID: 24009994
(110.1080) Active or adaptive optics; (330.5380) Physiology; (170.1610) Clinical applications; (170.3880) Medical and biological imaging; (170.4470) Ophthalmology
3.  Prevalence of Electrocardiographic Abnormalities in a Middle-Aged, Biracial Population: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Journal of electrocardiology  2010;43(5):385.e1-385.e9.
Background
Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.
Methods and Results
Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.
Conclusions
Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.
doi:10.1016/j.jelectrocard.2010.02.001
PMCID: PMC3569004  PMID: 20374967
4.  In Vivo, Transcutaneous Glucose Sensing Using Surface-Enhanced Spatially Offset Raman Spectroscopy: Multiple Rats, Improved Hypoglycemic Accuracy, Low Incident Power, and Continuous Monitoring for Greater Than 17 Days 
Analytical chemistry  2011;83(23):9146-9152.
This paper presents the latest progress on quantitative, in vivo, transcutaneous glucose sensing using surface enhanced spatially offset Raman spectroscopy (SESORS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in Sprague-Dawley rats. The glucose concentration was monitored in the interstitial fluid of six separate rats. The results demonstrated excellent accuracy and consistency. Remarkably, the root mean square error of calibration (RMSEC) (3.6 mg/dL) and the root mean square error of prediction (RMSEP) (13.7 mg/dL) for low glucose concentration (< 80 mg/dL) is lower than the current International Organization Standard (ISO/DIS 15197) requirements. None of the commercially available glucose sensing techniques can achieve enough accuracy during hypoglycemic episodes. Additionally, our sensor demonstrated functionality up 17 days after implantation, including 12 days under the laser safety level for human skin exposure with only one time calibration. Therefore, our SERS based sensor shows promise for the challenge of reliable continuous glucose sensing systems for optimal glycemic control.
doi:10.1021/ac202343e
PMCID: PMC3229825  PMID: 22007689
surface-enhanced Raman spectroscopy; SERS; in vivo glucose sensing; transcutaneous; hypoglycemic; accuracy; stability; reliability; calibration
5.  Neural stimulation with optical radiation 
Laser & photonics reviews  2010;5(1):68-80.
This paper reviews the existing research on infrared neural stimulation, a means of artificially stimulating neurons that has been proposed as an alternative to electrical stimulation. Infrared neural stimulation (INS) is defined as the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. The foremost advantage of using optical radiation for neural stimulation is its spatial resolution. Exogenously applied or trans-genetically synthesized fluorophores are not used to achieve stimulation. Here, current work on INS is presented for motor nerves, sensory nerves, central nervous system, and in vitro preparations. A discussion follows addressing the mechanism of INS and its potential use in neuroprostheses. A brief review of neural depolarization involving other optical methods is also presented. Topics covered include optical stimulation concurrent with electrical stimulation, optical stimulation using exogenous fluorophores, and optical stimulation by transgenic induction of light-gated ion channels.
doi:10.1002/lpor.200900044
PMCID: PMC3472451  PMID: 23082105
Cochlea; cochlear implants; deafening; electrical stimulation; infrared neural stimulation; laser; neuroprosthesis; optical stimulation; spatial selectivity
6.  Optical Stimulation of the Facial Nerve: A New Monitoring Technique? 
The Laryngoscope  2007;117(9):1641-1647.
Objectives/Hypothesis
One sequela of skull base surgery is iatrogenic damage to cranial nerves, which can be prevented if the nerve is identified. Devices that stimulate nerves with electric current assist in nerve identification. Contemporary devices have two main limitations: 1) the physical contact of the stimulating electrode and (2) the spread of the current through the tissue. In contrast to electrical stimulation, pulsed infrared optical radiation can be used to safely and selectively stimulate neural tissue and might be valuable for screening.
Methods
The gerbil facial nerve was exposed to 250 microsecond pulses of 2.12 μm radiation delivered via a 600-μm-diameter optical fiber at a repetition rate of 2 Hz. With use of 27 GA, 12-mm intradermal electrodes, muscle action potentials were recorded. Nerve samples were examined for possible tissue damage.
Results
Eight facial nerves were stimulated with radiant exposures between 0.71 and 1.77 J/cm2, resulting in compound muscle action potentials (CmAPs) that were simultaneously measured at the m. orbicularis oculi, m. levator nasolabialis, and m. orbicularis oris. Resulting CmAP amplitudes were 0.3 to 0.4 mV, 0.15 to 1.4 mV, and 0.3 to 2.3 mV, respectively, depending on the radial location of the optical fiber and the radiant exposure. Individual nerve branches were also stimulated, resulting in CmAP amplitudes between 0.2 and 1.6 mV. Histology revealed tissue damage at radiant exposures of 2.2 J/cm2 but no apparent damage at radiant exposures of 2.0 J/cm2.
Conclusions
The experiments showed that selective muscle action potentials can be evoked optically in the gerbil facial nerve without direct physical contact.
doi:10.1097/MLG.0b013e318074ec00
PMCID: PMC3471076  PMID: 17607145
Facial nerve; laser; optical stimulation; monitoring; parotidectomy
7.  Optical Parameter Variability in Laser Nerve Stimulation: A Study of Pulse Duration, Repetition Rate, and Wavelength 
IEEE transactions on bio-medical engineering  2007;54(6 Pt 1):1108-1114.
Pulsed lasers can evoke neural activity from motor as well as sensory neurons in vivo. Lasers allow more selective spatial resolution of stimulation than the conventional electrical stimulation. To date, few studies have examined pulsed, mid-infrared laser stimulation of nerves and very little of the available optical parameter space has been studied. In this study, a pulsed diode laser, with wavelength between 1.844–1.873 μm, was used to elicit compound action potentials (CAPs) from the auditory system of the gerbil. We found that pulse durations as short as 35 μs elicit a CAP from the cochlea. In addition, repetition rates up to 13 Hz can continually stimulate cochlear spiral ganglion cells for extended periods of time. Varying the wavelength and, therefore, the optical penetration depth, allowed different populations of neurons to be stimulated. The technology of optical stimulation could significantly improve cochlear implants, which are hampered by a lack of spatial selectivity.
doi:10.1109/TBME.2007.892925
PMCID: PMC3471085  PMID: 17554829
Auditory nerve; cochlear implant; spiral ganglion cell
8.  Optical stimulation of auditory neurons: Effects of acute and chronic deafening 
Hearing research  2008;242(1-2):42-51.
In developing neural prostheses, particular success has been realized with cochlear implants. These devices bypass damaged hair cells in the auditory system and electrically stimulate the auditory nerve directly. In contemporary cochlear implants, however, the injected electric current spreads widely along the scala tympani and across turns. Consequently, stimulation of spatially discrete spiral ganglion cell populations is difficult. In contrast to electrical stimulation, it has been shown that extremely spatially selective stimulation is possible using infrared radiation (e.g. Izzo et al., 2007a). Here, we explore the correlation between surviving spiral ganglion cells, following acute and chronic deafness induced by neomycin application into the middle ear, and neural stimulation using optical radiation and electrical current.
In vivo experiments were conducted in gerbils. Before the animals were deafened, acoustic thresholds were obtained and neurons were stimulated with optical radiation at various pulse durations, radiation exposures, and pulse repetition rates. In one group of animals, measurements were made immediately after deafening, while the other group was tested at least four weeks after deafening. Deafness was confirmed by measuring acoustically evoked compound action potentials. Optically and electrically evoked compound action potentials and auditory brainstem responses were determined for different radiation exposures and for different electrical current amplitudes, respectively. After completion of the experiments, the animals were euthanized and the cochleae were harvested for histology.
Acoustically evoked compound action potential thresholds were elevated by more than 40 dB after neomycin application in acutely deaf and more than 60 dB in chronically deaf animals. Compound action potential thresholds, which were determined with optical radiation pulses, were not significantly elevated in acutely deaf animals. However, in chronically deaf animals optically evoked CAP thresholds were elevated. Changes correlated with the number of surviving spiral ganglion cells and the optical parameters that were used for stimulation.
doi:10.1016/j.heares.2008.01.011
PMCID: PMC3431617  PMID: 18321670
cochlea; cochlear implants; deafening; optical stimulation; spatial selectivity
9.  Dynamics of Antibody Domains Studied by Solution NMR 
Information on local dynamics of antibodies is important to evaluate stability, to rationally design variants, and to clarify conformational disorders at the epitope binding sites. Such information may also be useful for improved understanding of antigen recognition. NMR can be used for characterization of local protein dynamics at the atomic level through relaxation measurements. Due to the complexity of the NMR spectra, an extensive use of this method is limited to small protein molecules, for example, antibody domains and some scFv. Here, we describe a protocol that was used to study the dynamics of an antibody domain in solution using NMR. We describe protein preparation for NMR studies, NMR sample optimization, signal assignments, and dynamics experiments.
doi:10.1007/978-1-59745-554-1_29
PMCID: PMC3423202  PMID: 19252840
NMR; relaxation; protein; dynamics; backbone; domain antibody
10.  Effects of melatonin and its receptor antagonist on retinal pigment epithelial cells against hydrogen peroxide damage 
Molecular Vision  2012;18:1640-1648.
Purpose
Recently, we reported finding that circulating melatonin levels in age-related macular degeneration patients were significantly lower than those in age-matched controls. The purpose of this study was to investigate the hypothesis that melatonin deficiency may play a role in the oxidative damage of the retinal pigment epithelium (RPE) by testing the protective effect of melatonin and its receptor antagonist on RPE cells exposed to H2O2 damage.
Methods
Cultured human RPE cells were subjected to oxidative stress induced by 0.5 mM H2O2. Cell viability was measured using the microculture tetrazoline test (MTT) assay. Cells were pretreated with or without melatonin for 24 h. Luzindole (50 μM), a melatonin membrane-receptor antagonist, was added to the culture 1 h before melatonin to distinguish direct antioxidant effects from indirect receptor-dependent effects. All tests were performed in triplicate.
Results
H2O2 at 0.5 mM decreased cell viability to 20% of control levels. Melatonin showed dose-dependent protective effects on RPE cells against H2O2. Cell viability of RPE cells pretreated with 10−10, 10−8, 10−6, and 10−4 M melatonin for 24 h was 130%, 160%, 187%, and 230% of cells treated with H2O2 alone (all p<0.05). Using cells cultured without H2O2 as the control, cell viability of cells treated with H2O2 after pretreatment with 10−10-10−4 M melatonin was still significantly lower than that of the controls, suggesting that melatonin significantly decreased but did not completely abolish the in vitro cytotoxic effects of H2O2. Luzindole completely blocked melatonin’s protective effects at low concentrations of melatonin (10−10-10−8 M) but not at high concentrations (10−6-10−4 M).
Conclusions
Melatonin has a partial protective effect on RPE cells against H2O2 damage across a wide range of concentrations (10−10-10−4 M). This protective effect occurs through the activation of melatonin membrane receptors at low concentrations (10−10-10−8 M) and through both the direct antioxidant and indirect receptor activation effects at high concentrations (10−6-10−4 M).
PMCID: PMC3388983  PMID: 22773902
11.  Transcutaneous Glucose Sensing by Surface-Enhanced Spatially Offset Raman Spectroscopy in a Rat Model 
Analytical chemistry  2010;82(20):8382-8385.
This letter presents the first quantitative, in vivo, transcutaneous glucose measurements using surface enhanced Raman spectroscopy (SERS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in a Sprague-Dawley rat. The glucose concentration was monitored in the interstitial fluid. SER spectra were collected from the sensor chip through the skin using spatially offset Raman spectroscopy (SORS). The combination of SERS and SORS is a powerful new approach to the challenging problem of in vivo metabolite and drug sensing.
doi:10.1021/ac101951j
PMCID: PMC3031996  PMID: 20845919
12.  Association of Electrocardiographic Abnormalities with Coronary Artery Calcium and Carotid Artery Intima-Media Thickness in Individuals without Clinical Coronary Heart Disease (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2009;104(8):1086-1091.
Isolated minor non-specific ST-segment and T-wave (NSSTA), minor and major electrocardiographic (ECG) abnormalities are established, independent risk markers for incident cardiovascular events. Their association with subclinical atherosclerosis has been postulated but is not clearly defined. The aim of this study is to define the association between ECG abnormalities and measures of subclinical atherosclerosis. We studied participants from MESA, a multi-ethnic sample of men and women aged 45–84 and free of clinical cardiovascular disease at enrollment. Baseline examination included measurement of traditional risk factors, resting 12-lead electrocardiograms, coronary artery calcium (CAC) measurement and common carotid intima-media thickness (CCIMT). Electrocardiograms were coded using Novacode criteria and were defined as having either minor abnormalities (e.g., minor non-specific STTA, first degree atrioventricular block, and QRS axis deviations) or major abnormalities (e.g., pathologic Q waves, major ST-segment and T-wave abnormalities, significant dysrhythmias and conduction system delays). Multivariable logistic and linear regressions were used to determine the cross-sectional associations of ECG abnormalities with CAC and common carotid-IMT. Among 6710 participants, 52.7% were women, with a mean age of 62 years. After multivariable-adjustment, isolated minor STTA, minor and major ECG abnormalities were not associated with the presence of CAC (>0) among men (OR 1.04, 95% CI 0.81–1.33; 1.10, 0.91–1.32; and 1.03, 0.81–1.31, respectively) or women (1.01, 0.82–1.24; 1.04, 0.87–1.23; and 0.94, 0.73–1.22, respectively). Lack of association remained consistent when using both log CAC and CC-IMT as continuous variables. ECG abnormalities are not associated with markers of subclinical atherosclerosis in a large multi-ethnic cohort.
doi:10.1016/j.amjcard.2009.05.060
PMCID: PMC2871277  PMID: 19801030
13.  Progress Toward an In Vivo Surface-Enhanced Raman Spectroscopy Glucose Sensor 
Abstract
Background
In this report, we detail our current work towards developing a surface-enhanced Raman spectroscopy (SERS) based sensor for in vivo glucose detection. Despite years of innovations in the development of blood glucose monitors, there remains a need for accurate continuous glucose sensors to provide care to rising numbers of diagnosed diabetes patients and mitigate secondary health complications associated with this metabolic disorder.
Methods
SERS is a highly specific and sensitive optical technique suitable for direct detection of glucose. The SERS effect is highly distance dependent, thus the glucose molecules need to be within a few nanometers or adsorbed to an SERS-active surface. In our sensor, this is achieved with a self-assembled monolayer (SAM) that facilitates reversible interactions between glucose molecules and the surface. The amount of glucose near the surface is proportional to its concentration in the surrounding environment.
Results
We determined that the SAM-functionalized surface is stable for at least 10 days and provides rapid, reversible partitioning. In vitro experiments in bovine plasma as well as in vivo experiments in rats demonstrated quantitative detection.
Conclusions
We show successful use of the SERS glucose sensor in rats, making it the first in vivo SERS sensor. Furthermore, we demonstrate free space transdermal detection of a SERS signal through the rat's skin as an initial step toward developing a transcutaneous sensor.
doi:10.1089/dia.2007.0288
PMCID: PMC2979340  PMID: 18715199
14.  Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients 
Molecular Vision  2009;15:1673-1679.
Purpose
Melatonin is a potent antioxidant and free radical scavenger. It has been reported that serum melatonin level is relevant to certain aging diseases. The purpose of this study was to investigate melatonin levels in age-related macular degeneration (AMD) patients by measurement of 6-sulfatoxymelatonin levels (aMT6s), the major metabolite of melatonin in urine, and compare it with a group of age- and gender-matched controls.
Methods
The first urine of the morning was collected from 43 AMD patients and 12 controls who did not have AMD. The level of aMT6s in specimens was measured by a commercial 6-sulfatoxymelatonin ELISA kit. The assay was performed by researchers, who were masked to the clinical information. To adjust for variation in the diluteness of urine, urinary creatinine level was measured and aMT6s levels were expressed as aMT6s/creatinine.
Results
The level of urinary aMT6s/creatinine (mean±SD) in AMD (6.24±3.45 ng aMT6s/mg creatinine) was significantly lower than that of the controls (10.40±4.51, p=0.0128). After adjustment for various factors (age, smoking, cancer, and coronary heart disease) that may influence the aMT6s level, the odds-ratio of urinary aMT6s comparing AMD patients to controls was 0.65 (95% confidence interval=0.48–0.88, p=0.0036), indicating that urinary aMT6s level in AMD patients was lower than in controls even after multivariate adjustment.
Conclusions
Urinary aMT6s level in AMD patients was 40% lower than in age- and gender-matched controls. This difference between AMD patients and controls is present after adjustment for the factors of age, smoking, and histories of cancer and coronary heart disease. The significance of this result and the role of melatonin in the occurrence of AMD require further investigation.
PMCID: PMC2730752  PMID: 19710945
15.  The Structure of Free L11 and Functional Dynamics of L11 in Free, L11-rRNA(58nt) Binary and L11-rRNA(58nt)-thiostrepton Ternary Complexes 
Journal of molecular biology  2007;367(4):1007-1022.
Summary
The L11 binding site is one of the most important functional sites in the ribosome. The N-terminal domain of L11 has been implicated as a “reversible switch” in facilitating the coordinated movements associated with EF-G–driven GTP hydrolysis. The “reversible switch” mechanism has been hypothesized to require conformational flexibility involving re-orientation and re-positioning of the two L11 domains, and warrants a close examination of the structure and dynamics of L11. Here we report the solution structure of free L11, and relaxation studies of free L11, L11complexed to its 58 nt RNA recognition site, and L11 in a ternary complex with the RNA and thiostrepton antibiotic. The binding site of thiostrepton on L11 was also defined by analysis of structural and dynamics data and chemical shift mapping. The conclusions of this work are as follows: First, the binding of L11 to RNA leads to sizable conformation changes in the regions flanking the linker and in the hinge area that links a β-sheets and a 310-helix-turn-helix element in the N-terminus. Concurrently, the change in the relative orientation may lead to re-positioning of the N-terminus, as implied by a decrease of radius of gyration from 18.5 Å to 16.2 Å. Second, the regions, which undergo large conformation changes, exhibit motions on ms-μs or ns-ps time scales. Third, binding of thiostrepton results in more rigid conformations near the linker (Thr71) and near its putative binding site (Leu12). Lastly, conformational changes in the putative thiostrepton binding site are implicated by the re-emergence of cross-correlation peaks in the spectrum of the ternary complex, which were missing in that of the binary complex. Our combined analysis of both the chemical shift perturbation and dynamics data clearly indicates that thiostrepton binds to a pocket involving residues in the 310-helix in L11.
doi:10.1016/j.jmb.2007.01.013
PMCID: PMC2045704  PMID: 17292917
ribosome protein; thiostrepton inhibition; dynamics; NMR; L11

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