Matthew S. Markert

Nanostructured surface modification of ceramic-based microelectrodes to enhance biocompatibility for a direct brain-machine interface

Many different types of microelectrodes have been developed for use as a direct Brain-Machine Interface (BMI) to chronically recording single neuron action potentials from ensembles of neurons. Unfortunately, the recordings from these microelectrode devices are not consistent and often last for only a few weeks. For most microelectrode types, the loss of these recordings is not due to failure of the electrodes but most likely due to damage to surrounding tissue that results in the formation of nonconductive glial-scar. Since the extracellular matrix consists of nanostructured microtubules, we have postulated that neurons may prefer a more complex surface structure than the smooth surface typical of thin-film microelectrodes. We, therefore, investigated the suitability of a nano-porous silicon surface layer to increase the biocompatibility of our thin film ceramic-insulated multisite electrodes. In-vitro testing demonstrated, for the first time, decreased adhesion of astrocytes and increased extension of neurites from pheochromocytoma cells on porous silicon surfaces compared to smooth silicon surfaces. Moreover, nano-porous surfaces were more biocompatible than macroporous surfaces. Collectively, these results support our hypothesis that nano-porous silicon may be an ideal material to improve biocompatibility of chronically implanted microelectrodes. We next developed a method to apply nano-porous surfaces to ceramic insulated, thin-film, microelectrodes and tested them in vivo. Chronic testing demonstrated that the nano-porous surface modification did not alter the electrical properties of the recording sites and did not interfere with proper functioning of the microelectrodes in vivo.

Ethnic Differences in Carotid Artery Diameter and Stiffness: The Northern Manhattan Study

OBJECTIVE Race/ethnic differences in carotid arterial function and structure exist among those with cerebrovascular disease, but whether differences persist among healthy populations is unknown. Our objective was to investigate differences in carotid artery diameter and stiffness between race/ethnic groups, and examine whether these race/ethnic differences were age-dependent. METHODS Carotid diameters were assessed by B-mode ultrasound among 1536 participants from the Northern Manhattan Study (NOMAS), and carotid stiffness metrics were calculated. We used multivariable linear regression models to determine the relationship between race/ethnicity and both carotid arterial stiffness and carotid diastolic diameter. RESULTS Mean participant age was 70 ± 9 years (Hispanics = 68 ± 8, blacks = 72 ± 9, and whites = 74 ± 9, p < 0.0001). Mean DDIAM was 6.2 ± 1.0mm (Hispanics = 6.2 ± 0.9 mm, blacks = 6.3 ± 1.0 mm, and whites = 6.3 ± 1.0 mm, p < 0.005) and mean STIFF was 8.7 ± 6.3 (Hispanics = 8.5 ± 5.7, blacks = 9.2 ± 6.2 and whites = 8.9 ± 6.9, p < 0.02). In a model that adjusted for sociodemographics and vascular risk factors including hypertension, diabetes, dislipidemia, renal function, physical acticity and a history of known coronary artery diseases; age was positively associated with greater DDIAM in Hispanics (p < 0.0001) but not among blacks or whites. Older age was associated with greater stiffness among Hispanics (p < 0.0001) and blacks (p < 0.003), but not among whites. CONCLUSIONS We found race/ethnic differences in the association between age and arterial stiffness and diameter, including age-dependent arterial dilation observed in Hispanics that was not observed among blacks or whites.

Primary and Secondary Lacrimal Canaliculitis: A Review of Literature

Canaliculitis is an uncommon inflammation of the proximal lacrimal drainage system that is frequently misdiagnosed. It classically presents with symptoms of unilateral conjunctivitis, mucopurulent discharge, medial canthal inflammation, epiphora, and a red, pouting punctum. We summarize the literature on canaliculitis published from antiquity to the modern era and explore therapeutic options.

Relationship between carotid arterial properties and cerebral white matter hyperintensities

Objective: Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants. Methods: Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors. Results: In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (β = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race–ethnicity, STRAIN (β = −1.78, p = 0.002) and DD (β = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants. Conclusions: Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These associations suggest a potential important pathophysiologic role of extracranial large artery remodeling in the burden of WMH.

Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities: The Northern Manhattan Study

Background and Purpose— Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort. Methods— We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors. Results— In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21–0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (&bgr;=0.046 per SD cIMT; P=0.04). Age and race/ethnicity were significant modifiers (P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (&bgr;=0.088 per SD cIMT; P=0.01) and among Hispanics (&bgr;=0.084 per SD cIMT; P=0.003). Conclusions— Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline.

Relationship between sirtuin and mitochondrial uncoupling protein genes and carotid artery stiffness.

Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD+)–dependent deacetylases,1 and mitochondrial Uncoupling Proteins (UCPs) are a family of inner mitochondrial membrane proteins capable of driving the ATP-synthase pathway via regulation of the proton electrochemical gradient 2. SIRTs and UCPs have been implicated in slowing vascular aging by reducing ROS.3 Previously we demonstrated a significant association between single nucleotide polymorphisms (SNPs) in SIRT/UCP and risk for carotid plaque (CP), number of plaques,4 and carotid intima media thickness (cIMT)5 as well as risk modification of these associations by vascular risk factors (RFs). Carotid stiffness (STIFF) is a measure of the vessel wall’s tendency to resist deformation by systolic blood pressure (BP) during the cardiac cycle, and is considered a biologically and genetically distinct phenotypes of atherosclerosis compared with CP and cIMT.6, 7 A previous genetic study on carotid atherosclerosis conducted among 3,300 American Indian participants, reported as the genetic linkage seen for different phenotypes of atherosclerosis was not replicated for STIFF, suggesting a different genetic influence among these functional and structural parameters.8 In the present study we investigate the association between variation in the SIRT/UCP genes and STIFF and its components, systolic (SD) and diastolic diameter (SD) in an urban and elderly multi-ethnic population. We analyzed 1,143 participants with STIFF and genotype data from the Northern Manhattan Study (NOMAS).9 All participants provided written informed consents. The study was approved by the Institutional Review Boards of Columbia University and the University of Miami and conforms to the relevant ethical guidelines for human and genetic research. STIFF was assessed by B-mode ultrasound and derived as a dimensionless quantity that expresses the tendency of an individual’s arteries to deform from a given change in BP or [ln (SBP-DBP)]/Strain]. SBP and DBP are mean systolic and diastolic brachial BP and Strain is derived as a ratio of the amount of stress deformation relative to the unstressed state or (SD-DD)/DD).10 A total of 85 SNPs in the 11 UCP and SIRT genes were available from the AffyMetrixGenome-Wide Human SNP Array 6.0. Detailed genotyping procedures were described previously.4 To account for population stratification, we first performed principal component analysis to examine population substructure using EIGENSTRAT and included the top three principle components (PCAs) as genomic control variables in the genetic association analysis.4 To control for the potential confounders, we conducted univariate analysis to identify demographic characteristics and RFs associated with parameters of arterial function (STIFF and strain, both were log-transformed in the regression analysis to reduce skewness) and structure (carotid DD and SD) (p<0.05), in order to include them as covariates in the genetic association analysis of the UCP and SIRT variants. For single SNP-based association analyses, we examined the additive genetic effects of the UCP/SIRT variants on STIFF using linear regression models, after adjusting for the significant demographic characteristics, and RFs and the top 3 principle components. Power calculation revealed that a sample size of 1143 subjects allow 80% power to detect an additive genetic effect of β=0.12 at type 1 error rate of 0.05 given the minor allele frequency=0.25 and SD=0.9 for diameter measures. We also examined SNP-by-RFs interactions and performed stratified analyses if the interaction terms had p≤0.005. The mean age of the participants was 68±9 years, 61% were women, 71% Caribbean Hispanic, 15% Black, and 12% White. Overall, 29% had obesity, 19% had diabetes, 29% had hypercholesterolemia; 16% were current smokers, 35% former smokers, 40% moderate alcohol drinkers, and 55% had leisure-time physical activity. The mean STIFF was 8.35±5.38, mean strain was 0.08±0.14, mean DD was 6.20±0.95mm, and mean SD was 6.68±0.95mm. In univariate analysis, STIFF, strain or diameters were significantly associated with age, sex, race-ethnicity, current smoking, obesity, and diabetes, but not with moderate alcohol drinking, leisure-time physical activity and hypercholesterolemia. SNPs associated with STIFF (p 0.99), showed an association with both SD and DD, with 0.10–0.11mm increase in DD or SD per copy of minor allele of these SNPs. Similar association was found between rs1800849 in UCP3 and DD (β=0.11 per copy of A allele, p=0.046). In contrast, minor allele (A) carriers of rs5977238 in UCP5, showed a decrease in DD (β= −0.21, p=0.012) and SD (β= −0.23, p=0.007). Table 2 shows interactions between SNPs and modifiable RFs with a nominal p<0.005 and genetic effects stratified by the status of specific vascular risk factors. Mainly, SNPs of SIRT1 gene had greater effects on DD and SD in current smokers than in non-smokers. Moreover, SNPs of SIRT5 gene had greater effect on STIFF in diabetic compared to non-diabetic, with an opposite effect on Strain in the same patients (Table 2). Table 1 SNPs associated with diameters and stiffness with a p value <0.05* Table 2 SNPs showing interaction with smoking and diabetes with a p value <0.005* Current evidence suggests that STIFF fulfils the criteria for a biomarker of vascular aging as a cumulative measure of the impact of cardiovascular risk factors on the arterial wall. Based on the present study and on our previous findings4, 5, SIRT/UCP effects provide a balance between deleterious and protective atherosclerosis mechanisms. However, SNPs found to be associated with other atherosclerotic phenotypes in previous studies4,5 were not found to be associated with STIFF in this study. These findings further confirm that STIFF, plaque and cIMT are different subclinical phenotypes of atherosclerosis with different genetic mechanisms. SIRT1, the most studied sirtuin protein, extends lifespan of all tested organisms by mimicking the effects of caloric restriction.1 A reduced risk for STIFF was observed for rs7895833G/A allele carriers in SIRT1 gene. Supporting the present findings rs7895833 in SIRT1 was previously associated with variability in BP and lower BMI.11 We found an increase in STIFF among individuals with the T allele of rs10498683 in SIRT5. Previously, we found that subjects with this allele have an increased risk for CP with a specific effect-modification by a presence of diabetes and hypertension.4 SIRT5 is a mitochondrial sirtuin that is up-regulated by caloric restriction and has a similar role to SIRT1 in controlling ROS production.1 An interaction with diabetes was also observed in association between SIRT5 variants with strain and STIFF. We have recently demonstrated race-ethnic differences in changes in STIFF and carotid diameters,10 indicating that genetics may influence arterial dilatation. We previously reported significant associations between variation in UCP1 (rs1430583 and rs6818140) and cIMT.5 Similarly, in this study we found these SNPs to be associated with DD and SD. In transgenic mice, UCP1 expression in aortic smooth muscle cells has been shown to cause hypertension and increased dietary atherosclerosis without affecting cholesterol levels.12 We have previously reported a significant association between rs5977238 in UCP5 and decreased risk for CP and plaque number, particularly in subjects with hypertension.4 In this study, we found a similarly protective role involving the carotid diameters. UCP5 physiological function has not yet been fully established, although by regulating the proton gradient across the inner membrane UCP5 may be implicated in ROS formation and ATP synthesis.1 The present study reveals novel associations between UCP and SIRT genes and arterial stiffness with specific effect modifications by smoking and diabetes. Given that arterial stiffness is a potential biomarker of vascular aging and a potential predictor of vascular events, understanding of its genetic basis may be of particular importance for risk stratification and development of new therapeutic approaches specifically tailored to atherosclerotic pathways.

Performance trends in large 10-km road running races in the United States.

Abstract Cushman, DM, Markert, M, and Rho, M. Performance trends in large 10-km road running races in the United States. J Strength Cond Res 28(4): 892–901, 2014—Our study examines the current trends of runners participating in 10-km road races in the United States. Finish times and ages of all runners participating in 10 of the largest 10-km running races in the United States between 2002–2005 and 2011 were recorded. Linear regression analysis was performed to examine the trends for age, sex, and finishing time for all participants completing the course in <1 hour. A total of 408,296 runners were analyzed. There was a significant annual decrease in the ratio of men to women finishers (p < 0.001, r2 = 0.976). The average finishing time of the top 10 (men, p ⩽ 0.05), 100 (men and women, p ⩽ 0.05), and 1,000 (men and women, p < 0.01) significantly decreased annually. The total number of subhour finishers increased annually across all races (194 men per year, r2 = 0.584, p = 0.045; 161 women per year, r2 = 0.779, p = 0.008), whereas the percentage of overall finishers completing the course in less than an hour significantly declined for men and women (p ⩽ 0.003). There was a significant trend toward younger men in all top groups except for the single fastest runner (p ⩽ 0.017). Our study demonstrates that for large 10-km U.S. races: the top men and women seem to be getting faster; there are more subhour finishers, with increasingly more women accomplishing this feat compared with men; an increasingly lower percentage of overall finishers is finishing in <1 hour; and the fastest men are also increasingly younger.

Association between carotid artery function and structure in the Northern Manhattan Study

Background and purpose Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD. Methods We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area). Results The mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm2. STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque. Conclusion Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.

Repetitive transcranial magnetic stimulation directed to a seizure focus localized by high-density EEG: A case report

We demonstrate feasibility of using high-density EEG to map a neocortical seizure focus in conjunction with delivery of magnetic therapy. Our patient had refractory seizures affecting the left leg. A five-day course of placebo stimulation followed a month later by active rTMS was directed to the mapped seizure dipole. Active rTMS resulted in reduced EEG spiking, and shortening of seizure duration compared to placebo. Seizure frequency, however, improved similarly in both placebo and active treatment stages. rTMS-evoked EEG potentials demonstrated that a negative peak at 40 ms - believed to represent GABAergic inhibition - was enhanced by stimulation.