Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer

Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. In this study, hyaluronic acid derived nanoparticles with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG was not cytotoxic to healthy pancreatic epithelial cells and did not induce chemotaxis or phagocytosis, it accumulated significantly within the pancreas in an orthotopic pancreatic ductal adenocarcinoma model, and demonstrated contrast-enhancement for pancreatic lesions relative to non-diseased portions of the pancreas. Fluorescence microscopy showed higher fluorescence intensity in pancreatic lesions and splenic metastases due to NanoICG compared to ICG alone. The in vivo safety profile of NanoICG, including, biochemical, hematological, and pathological analysis of NanoICG-treated healthy mice, indicates negligible toxicity. These results suggest that NanoICG is a promising contrast agent for intraoperative detection of pancreatic tumors.     

Influence of amphiphilic block copolymer induced changes in membrane ion conductance on the reversal of multidrug resistance

Block copolymers are able to reverse multidrug resistance (MDR) of tumor cells by a yet unknown mechanism. The drug efflux system's direct and indirect inhibition mediated by polymer P-glycoprotein (Pgp) interactions or adenosine triphosphate (ATP) depletion, respectively, may be involved in MDR reversal as well as damage to the membrane barrier caused by polymer insertion into the membrane. To test the latter hypothesis, cellular drug accumulation was monitored in the presence of both overexpressed fluorescently labeled Pgp and different block copolymers. Therefore, a new triblock copolymer (poly(ethylene oxide)- block-poly(hexafluoropropylene oxide)- block-poly(ethylene oxide)) was designed and synthesized by combined polymerization and polymer analogous reaction. Its administration induced drug uptake, whereas control cells with high Pgp expression levels showed no drug accumulation. Drug uptake was even more pronounced in the presence of another triblock copolymer: (poly(perfluorohexylethyl methacrylate)- block-poly(ethylene oxide)- block-poly(perfluorohexylethyl methacrylate). The latter polymer's lack of ionophoric activity suggests that ion transport facilitation by polymers is not a determinative factor for MDR reversal.     

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

Proton magnetic resonance spectroscopy was performed at 4 T to determine effects of age, region and gender on glutamate and glutamine in the normal human brain. Furthermore, glutamate and glutamine alterations with age were tested for correlations with other cerebral metabolites. Two 8 cm3 volumes were selected in corona radiata and mesial motor cortex in normal subjects (N = 24) between 24 and 68 years old. Older subjects had lower glutamate concentration in the motor cortex compared to younger subjects (p < 0.001). In corona radiata, older subjects demonstrated a trend in higher glutamine compared to younger subjects (p = 0.05). Glutamate in the motor cortex was positively correlated with glutamine, N-acetyl aspartate and creatine. Reduced glutamate and N-acetyl aspartate in the motor cortex is consistent with neuronal loss/shrinkage with age. In conclusion, different patterns in association with normal aging in these brain regions were detected in this study.     

Association of total tau and phosphorylated tau 181 protein levels in cerebrospinal fluid with cerebral atrophy in mild cognitive impairment and Alzheimer disease

Background

We sought to examine the association of levels of total tau (t-tau) and phosphorylated tau 181 (p-tau181) protein with brain morphology in mild cognitive impairment, as defined by the concept of aging-associated cognitive decline (AACD) and Alzheimer disease.

Methods

Twenty-three participants with AACD, 16 with Alzheimer disease and 15 healthy controls underwent magnetic resonance imaging and lumbar puncture. We performed voxel-based morphometry to investigate the association between tau levels in cerebrospinal fluid (CSF) and cerebral grey matter density throughout the entire brain.

Results

Voxel-based morphometry revealed that both elevated t-tau and p-tau181 concentrations were associated with reduced grey matter density in temporal, parietal and frontal regions. Among participants with AACD, elevated levels of p-tau181 (but not t-tau) in CSF were correlated with a pronounced atrophy in the right hippocampus.

Limitations

Our study was limited by the small sample, especially with respect to the analysis comprising the AACD subgroups. Moreover, we did not correct our voxel-based morphometry analyses for multiple dependent comparisons, therefore they harbour a risk of false-positive results.

Conclusion

Elevated levels of t-tau and p-tau181 in CSF reflect degenerative processes in the cortical regions typically affected in Alzheimer disease. Our findings in participants with AACD support the hypothesis that p-tau181 might be more specifically related to neurodegenerative changes in early Alzheimer disease.     

Teaching children with autism to attend to socially relevant stimuli

Research has shown that children with autism often fail to attend to relevant stimuli in social situations, likely resulting in unsuccessful or absent social interactions. The purpose of this study was to teach children with autism to attend to stimuli with socially relevant features. Specifically, this study evaluated a teaching package including rules, modeling, role play, and specific feedback across multiple exemplars to teach children with autism to attend and respond to others’ bids for social attention (e.g., “Whoa!” or “Ouch!”). Three participants successfully learned to shift attention toward others and emit a response to gain more information in response to a socially relevant stimulus. Furthermore, generalization was observed across novel exemplars and people.     

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

The cytotoxicity and genotoxicity of pesticide mixtures viz. endosulfan?+?chlorpyrifos, chlorpyrifos?+?profenofos, and endosulfan?+?profenofos were evaluated on cultured human peripheral blood lymphocytes using assays for cell viability, and genotoxicity using chromosomal aberrations test and comet assay. The LC₅₀ values for cytotoxicity were 3.50?μM, 4.18?μM, and 10.5?μM for profenofos, endosulfan, and chlorpyrifos respectively. When combined in equimolar concentrations, the LC₅₀ values for cytotoxicity were 1.4?μM, 1.8?μM, and 2.0?μM for endosulfan?+?chlorpyrifos, chlorpyrifos?+?profenofos, and endosulfan?+?profenofos, respectively. Higher concentrations of individual pesticides (0.5–4.0?μM) but very low concentrations of pesticide mixtures caused significant DNA damage. Additive index values indicated a synergistic effect of toxicity for endosulfan?+?chlorpyrifos combination (1.12 TTU). The binary mixture of chlorpyrifos?+?profenofos showed an additive toxicity (0.46 TTU) while an antagonistic effect was observed for endosulfan?+?profenofos combination. Synergism could be due to these complementary pesticides simultaneously acting in different ways, magnifying their efficacy, whereas an additive interaction would imply that the chemicals are acting by the same mechanism and at the same target. Analysis of toxicity of pesticide mixtures may serve as important biomarker for occupational and household exposure to pesticides, with different modes of action.