Nanoparticle Accumulation in Angiogenic Tissues: Towards Predictable Pharmacokinetics

Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size.     

Carbon nanotubes in macrophages: imaging and chemical analysis by X-ray fluorescence microscopy

X-ray fluorescence microscopy (microXRF) is applied for the first time to study macrophages exposed to unpurified and purified single-walled (SW) and multiwalled (MW) carbon nanotubes (CNT). Investigating chemical elemental distributions allows one to (i) image nanotube localization within a cell and (ii) detect chemical modification of the cell after CNT internalization. An excess of calcium is detected for cells exposed to unpurified SWCNT and MWCNT and related toxicological assays are discussed.     

A restoration framework for ultrasonic tissue characterization

Ultrasonic tissue characterization has become an area of intensive research. This procedure generally relies on the analysis of the unprocessed echo signal. Because the ultrasound echo is degraded by the non-ideal system point spread function, a deconvolution step could be employed to provide an estimate of the tissue response that could then be exploited for a more accurate characterization. In medical ultrasound, deconvolution is commonly used to increase diagnostic reliability of ultrasound images by improving their contrast and resolution. Most successful algorithms address deconvolution in a maximum a posteriori estimation framework; this typically leads to the solution of l(2)-norm or (1)-norm constrained optimization problems, depending on the choice of the prior distribution. Although these techniques are sufficient to obtain relevant image visual quality improvements, the obtained reflectivity estimates are, however, not appropriate for classification purposes. In this context, we introduce in this paper a maximum a posteriori deconvolution framework expressly derived to improve tissue characterization. The algorithm overcomes limitations associated with standard techniques by using a nonstandard prior model for the tissue response. We present an evaluation of the algorithm performance using both computer simulations and tissue-mimicking phantoms. These studies reveal increased accuracy in the characterization of media with different properties. A comparison with state-of-the-art Wiener and l(1)-norm deconvolution techniques attests to the superiority of the proposed algorithm.     

RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist

The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.     

In situ interleukin 5 gene expression in pediatric Crohn's disease

BACKGROUND: Eosinophils contribute to the intestinal inflammatory infiltrate in Crohn's disease (CD). Eosinophilic infiltration occurs early in Crohn's recurrences, and a release of eosinophil cationic proteins has been observed in active CD. The proliferation, differentiation, and activation of eosinophils are highly dependent on the cytokine interleukin 5 (IL5). In the present study, we used in situ hybridization (ISH) to investigate the expression of the IL5 gene in intestinal specimens from patients with CD. METHODS: We studied 14 intestinal samples from eight children who had undergone ileocolectomy for advanced CD. The samples were examined for the intensity of the inflammatory infiltrate. Normal pediatric intestine specimens served as controls. In situ hybridization was performed on frozen tissue using radiolabeled IL5 mRNA probes. RESULTS: Positive signal with the IL5 antisense probe was observed within numerous cells infiltrating the specimens involved with CD. The number of IL5-expressing cells correlated with the histological grade of inflammation. Most of the labeled cells were eosinophils, characterized by their bilobed nuclei. Rare IL5-positive cells were detected in the control tissues. No positive signal was obtained with the IL5 sense probe. CONCLUSION: These results suggest that IL5 can be produced by eosinophils at the sites of inflammation in active CD and could be involved in the immune response by activating eosinophils, at least in part through an autocrine pathway, and perhaps by interacting with B and T cells.     

Metabolic impact of adenovirus-mediated overexpression of the glucose-6-phosphatase catalytic subunit in hepatocytes

Glucose-6-phosphatase (G6Pase) catalyzes the hydrolysis of glucose 6-phosphate (Glu-6-P) to free glucose and, as the last step in gluconeogenesis and glycogenolysis in liver, is thought to play an important role in glucose homeostasis. G6Pase activity appears to be conferred by a set of proteins localized to the endoplasmic reticulum, including a glucose-6-phosphate translocase, a G6Pase phosphohydrolase or catalytic subunit, and glucose and inorganic phosphate transporters in the endoplasmic reticulum membrane. In the current study, we used a recombinant adenovirus containing the cDNA encoding the G6Pase catalytic subunit (AdCMV-G6Pase) to evaluate the metabolic impact of overexpression of the enzyme in primary hepatocytes. We found that AdCMV-G6Pase-treated liver cells contain significantly less glycogen and Glu-6-P, but unchanged UDP-glucose levels, relative to control cells. Further, the glycogen synthase activity state was closely correlated with Glu-6-P levels over a wide range of glucose concentrations in both G6Pase-overexpressing and control cells. The reduction in glycogen synthesis in AdCMV-G6Pase-treated hepatocytes is therefore not a function of decreased substrate availability but rather occurs because of the regulatory effects of Glu-6-P on glycogen synthase activity. We also found that AdCMV-G6Pase-treated-cells had significantly lower rates of lactate production and [3-3H]glucose usage, coupled with enhanced rates of gluconeogenesis and Glu-6-P hydrolysis. We conclude that overexpression of the G6Pase catalytic subunit alone is sufficient to activate flux through the G6Pase system in liver cells. Further, hepatocytes treated with AdCMV-G6Pase exhibit a metabolic profile resembling that of liver cells from patients or animals with non-insulin-dependent diabetes mellitus, suggesting that dysregulation of the catalytic subunit of G6Pase could contribute to the etiology of the disease.     

Parents' ethnic-racial socialization practices: A review of research and directions for future study.

Recently, there has been an emergence of literature on the mechanisms through which parents transmit information, values, and perspectives about ethnicity and race to their children, commonly referred to as racial or ethnic socialization. This literature has sought to document the nature of such socialization, its antecedents in parents' and children's characteristics and experiences, and its consequences for children's well-being and development. In this article, the authors integrate and synthesize what is known about racial and ethnic socialization on the basis of current empirical research, examining studies concerning its nature and frequency; its child, parent, and ecological predictors; and its consequences for children's development, including ethnic identity, self-esteem, coping with discrimination, academic achievement, and psychosocial well-being. The authors also discuss conceptual and methodological limitations of the literature and suggest directions for future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Size and Slenderness on Ductility of Fracturing Structures

The ductility of an elastic structure with a growing crack may be defined as the ratio of the additional load-point displacement that is caused by the crack at the moment of loss of stability under displacement control to the elastic displacement at no crack at the moment of peak load. The stability loss at displacement control is known to occur when the load-deflection curve of the whole structural system with the loading device (characterized by a spring) reaches a snapback point. Based on the known stress intensity factor as a function of crack length, the well-known method of linear elastic fracture mechanics is used to calculate the load-deflection curve and determine the states of snapback and maximum loads. An example of a notched three-point bend beam with a growing crack is analyzed numerically. The ductility is determined and its dependence of the structure size, slenderness, and stiffness of the loading device is clarified. The family of the curves of ductility versus structure size at various loading device stiffnesses is found to exhibit at a certain critical stiffness a transition from bounded single-valued functions of D to unbounded two-valued functions of D. The method of solution is general and is applicable to cracked structures of any shape. The flexibility (force) method can be adapted to extend the ductility analysis to structural assemblages provided that the stress intensity factor of the cracked structural part considered alone is known. This study leads to an improved understanding of ductility, which should be useful mainly for design against dynamic loads.     

Examination of general health following Typhoon Xangsane: A pre–postanalysis.

An individual's health status immediately following a disaster may predict long-term morbidity and mortality. However, relative to the growing literature on postdisaster mental health, less is known about physical health outcomes, particularly in developing countries. Unlike most studies, the current investigation obtained physical health data both before and after Typhoon Xangsane, which struck the Da Nang province of Vietnam in 2006, and related these predisaster data to postdisaster health functioning, among other factors. Specifically, a sample of 795 randomly selected adults was interviewed both prior to, and after the typhoon. Results indicated that participants with symptoms of major depressive disorder and panic disorder, older participants, and participants who reported high distress during the actual typhoon were most at-risk for lower self-rated health postdisaster compared to those without these risk factors. Given that Vietnam is still designated a developing country, the present study enhances the literature on postdisaster physical health correlates in developing nations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)