The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (Ki) and tight junction proteins by Western immunoblot in fetal sheep at 127 days-of-gestation without ischemia, and 4-, 24-, or 48-h after ischemia. The largest increase in Ki (P<0.05) was 4-h after ischemia. Occludin and claudin-5 expressions decreased at 4-h, but returned toward control levels 24- and 48-h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between Ki and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood-brain barrier function after ischemia. We conclude that impaired blood-brain barrier function is an important component of hypoxic-ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (Ki) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4-h after ischemia and blood-brain barrier function improves early after injury because the blood-brain barrier is less permeable 24- and 48- than 4-h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood-brain barrier permeability after ischemia.

A methodology of studying of ingestive behavior by non-invasive monitoring of swallowing (deglutition) and chewing (mastication) has been developed. The target application for the developed methodology is to study the behavioral patterns of food consumption and producing volumetric and weight estimates of energy intake. Monitoring is non-invasive based on detecting swallowing by a sound sensor located over laryngopharynx or by a bone conduction microphone and detecting chewing through a below-the-ear strain sensor. Proposed sensors may be implemented in a wearable monitoring device, thus enabling monitoring of ingestive behavior in free living individuals. In this paper, the goals in the development of this methodology are two-fold. First, a system comprised of sensors, related hardware and software for multimodal data capture is designed for data collection in a controlled environment. Second, a protocol is developed for manual scoring of chewing and swallowing for use as a gold standard. The multi-modal data capture was tested by measuring chewing and swallowing in twenty one volunteers during periods of food intake and quiet sitting (no food intake). Video footage and sensor signals were manually scored by trained raters. Inter-rater reliability study for three raters conducted on the sample set of 5 subjects resulted in high average intra-class correlation coefficients of 0.996 for bites, 0.988 for chews, and 0.98 for swallows. The collected sensor signals and the resulting manual scores will be used in future research as a gold standard for further assessment of sensor design, development of automatic pattern recognition routines, and study of the relationship between swallowing/chewing and ingestive behavior.

Our understanding of etiology of obesity and overweight is incomplete due to lack of objective and accurate methods for Monitoring of Ingestive Behavior (MIB) in the free living population. Our research has shown that frequency of swallowing may serve as a predictor for detecting food intake, differentiating liquids and solids, and estimating ingested mass. This paper proposes and compares two methods of acoustical swallowing detection from sounds contaminated by motion artifacts, speech and external noise. Methods based on mel-scale Fourier spectrum, wavelet packets, and support vector machines are studied considering the effects of epoch size, level of decomposition and lagging on classification accuracy. The methodology was tested on a large dataset (64.5 hours with a total of 9,966 swallows) collected from 20 human subjects with various degrees of adiposity. Average weighted epoch recognition accuracy for intra-visit individual models was 96.8% which resulted in 84.7% average weighted accuracy in detection of swallowing events. These results suggest high efficiency of the proposed methodology in separation of swallowing sounds from artifacts that originate from respiration, intrinsic speech, head movements, food ingestion, and ambient noise. The recognition accuracy was not related to body mass index, suggesting that the methodology is suitable for obese individuals. Index Terms NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript I IntroductionThe world is still losing in the battle with the obesity epidemic. According to WHO, in 2005 there were approximately 1.6 billion overweight and at least 400 million obese adults worldwide [1]. Current trends are unsettling: 2015 projections predict 2.3 billion overweight and 700 million obese adults worldwide. Obesity is one of the risk factors for development of chronic diseases and presents a serious health problem. A recent study [2] suggested that effects of obesity on global health may be comparable to those of cancer. Though the etiology of obesity is a topic of ongoing scientific debate, regulation of food intake may be an important factor for maintaining a healthy weight [3] in the environment that provides abundance of inexpensive, highly palatable and energy dense foods, while requiring only minimal levels of physical activity [4].While various methods have been developed for accurate and objective characterization of physical activity [5], at the present time, there is no accurate, inexpensive, non-intrusive way for objective Monitoring of Ingestive Behavior (MIB) in free living conditions. The most precise method of measuring energy intake is the Doubly-Labeled Water (DLW) technique which provides accurate estimates of caloric energy intake over long periods of time (10-14 days), if subjects remain weight stable. However, the DLW technique cannot identify daily intake patterns. Dietary self-report methods like food frequency questionnaires [6], selfreported diet diaries [7], and multimedia diaries [8] have been shown to be ...

We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1β monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1β protein. This antibody also neutralizes the effects of interleukin-1β protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1β monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 minutes of carotid occlusion and 24 hours of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1β antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154 M NaCl) or anti-interleukin-1β monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 minutes and 4 hours after ischemia. Concentrations of interleukin-1β protein and anti-interleukin-1β monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1β protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1β protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1β monoclonal antibody infusions, plasma anti-interleukin-1β monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1β monoclonal antibody levels were higher (P<0.03), and interleukin-1β protein concentrations (P<0.03) and protein expressions (P<0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion-related increases in Ki across the brain regions (P<0.04), and Ki showed an inverse linear correlation (r = −0.65, P<0.02) with anti-interleukin-1β monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1β monoclonal antibody infusions after ischemia result in brain anti-interleukin-1β antibody uptake, and attenuate ischemia-reperfusion-related interleukin-1β protein up-regulation and increases in blood-brain barrier permeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1β, contributes to impaired blood-brain barrier function after ischemia in the fetus.

Noninvasive concentric ring electrodes are a promising alternative to conventional disc electrodes. Currently, the superiority of tripolar concentric ring electrodes over disc electrodes, in particular, in accuracy of Laplacian estimation, has been demonstrated in a range of applications. In our recent work, we have shown that accuracy of Laplacian estimation can be improved with multipolar concentric ring electrodes using a general approach to estimation of the Laplacian for an (n + 1)-polar electrode with n rings using the (4n + 1)-point method for n ≥ 2. This paper takes the next step toward further improving the Laplacian estimate by proposing novel variable inter-ring distances concentric ring electrodes. Derived using a modified (4n + 1)-point method, linearly increasing and decreasing inter-ring distances tripolar (n = 2) and quadripolar (n = 3) electrode configurations are compared to their constant inter-ring distances counterparts. Finite element method modeling and analytic results are consistent and suggest that increasing inter-ring distances electrode configurations may decrease the truncation error resulting in more accurate Laplacian estimates compared to respective constant inter-ring distances configurations. For currently used tripolar electrode configuration, the truncation error may be decreased more than two-fold, while for the quadripolar configuration more than a six-fold decrease is expected.

IntroductIonRates of overweight and obesity are increasing globally. The World Health Organization estimated that there were ~1.6 billion overweight and at least 400 million obese adults worldwide in 2005 and that there will be 2.3 billion overweight and 700 million obese adults worldwide by 2015 (ref. 1). Overweight and obese individuals have an increased risk of developing chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer (2-5).Overweight and obesity result from an imbalance between energy intake and energy expenditure, but the etiology of that imbalance and the underlying mechanisms are still incompletely understood. Our physiology, our behavior, and our environment must all be considered in understanding the etiology of obesity. There is a debate about the relative importance of genetic/physiological factors and environmental factors in the etiology of obesity. Clearly there are genetic/physiological contributions to obesity (6-9) but some weight gain can be attributed to an environment that provides an abundance of inexpensive, highly palatable, and energy dense foods, while requiring only minimal levels of physical activity (10-13). Part of our lack of understanding of the etiology of obesity is the fact that most weight gain likely occurs due to very small differences between energy intake and energy expenditure, necessitating very accurate measurements of energy intake and energy expenditure.A variety of methods are available for accurate and objective measurement of energy expenditure and its components, including doubly labeled water, indirect calorimetry, and accelerometry (14-16). These techniques can be used in the laboratory and in free-living populations. Energy and food intake can be accurately monitored in the laboratory by directly measuring consumed food. It is currently not possible to accurately monitor food intake in free-living populations. Several methods have been proposed to measure free-living food intake including observation, weighed food records, estimated records, diet history, food-frequency questionnaires, food recall methods, etc. (17). In a review of 43 studies comparing these methods to indirect measurement using doubly labeled water, the majority suffered from underestimation of energy intake on the order of 0.83 (ratio of intake estimate to energy expenditure) (18).There is an urgent need for innovative strategies for the accurate assessment of free-living energy intake and monitoring of

Conventional electroencephalography with disc electrodes has major drawbacks including poor spatial resolution, selectivity and low signal-to-noise ratio that are critically limiting its use. Concentric ring electrodes, consisting of several elements including the central disc and a number of concentric rings, are a promising alternative with potential to improve all of the aforementioned aspects significantly. In our previous work, the tripolar concentric ring electrode was successfully used in a wide range of applications demonstrating its superiority to conventional disc electrode, in particular, in accuracy of Laplacian estimation. This paper takes the next step toward further improving the Laplacian estimation with novel multipolar concentric ring electrodes by completing and validating a general approach to estimation of the Laplacian for an (n + 1)-polar electrode with n rings using the (4n + 1)-point method for n ≥ 2 that allows cancellation of all the truncation terms up to the order of 2n. An explicit formula based on inversion of a square Vandermonde matrix is derived to make computation of multipolar Laplacian more efficient. To confirm the analytic result of the accuracy of Laplacian estimate increasing with the increase of n and to assess the significance of this gain in accuracy for practical applications finite element method model analysis has been performed. Multipolar concentric ring electrode configurations with n ranging from 1 ring (bipolar electrode configuration) to 6 rings (septapolar electrode configuration) were directly compared and obtained results suggest the significance of the increase in Laplacian accuracy caused by increase of n.

Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, bloodbrain barrier permeability was quantified using the bloodto-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemiarelated increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after