Cognitive impairment and Alzheimer’s Disease are linked with intake of a Western Diet, characterized by high levels of saturated fats and simple carbohydrates. In rats, these dietary components have been shown to disrupt hippocampal-dependent learning and memory processes, particularly those involving spatial memory. Using a rat model, the present research assessed the degree to which consumption of a high-energy (HE) diet, similar to those found in modern Western cultures, produces a selective impairment in hippocampal function as opposed to a more global cognitive disruption. Learning and memory performance was examined following 90-days consumption of an HE-diet in three nonspatial discrimination learning problems that differed with respect to their dependence on the integrity of the hippocampus. The results showed that consumption of the HE-diet impaired performance in a hippocampal-dependent feature negative discrimination problem relative to chow-fed controls, whereas performance was spared on two discrimination problems that do not rely on the hippocampus. To explore the mechanism whereby consuming HE-diets impairs cognitive function, we investigated the effect of HE-diets on the integrity of the blood-brain barrier (BBB). We found that HE-diet consumption produced a decrease in mRNA expression of tight junction proteins, particularly Claudin-5 and -12, in the choroid plexus and the BBB. Consequently, an increased blood-to-brain permeability of sodium fluorescein was observed in the hippocampus, but not in the striatum and prefrontal cortex following HE-diet access. There results indicate that hippocampal function may be particularly vulnerable to disruption by HE-diets, and this disruption may be related to impaired BBB integrity.

Para-aminosalicylic acid (PAS), an FDA-approved anti-tuberculosis drug, has been used successfully in the treatment of severe manganese (Mn)-induced Parkinsonism in humans (Jiang et al., JOEM 48:644, 2006). This study was conducted to explore the capability of PAS in reducing Mn concentrations in body fluids and tissues of Mn-exposed animals. Sprague-Dawley rats received daily intraperitoneally (i.p.) injections of 6 mg Mn/kg, 5 d/wk for 4 wks, followed by a daily subcutaneously (sc.) dose of PAS (100 and 200 mg/kg as the PAS-L and PAS-H group, respectively) for another 2, 3 or 6 wks. Mn exposure significantly increased the concentrations of Mn in plasma, red blood cells (RBC), cerebrospinal fluid (CSF), brain and soft tissues. Following PAS-H treatment for 3 wks, Mn levels in liver, heart, spleen and pancreas were significantly reduced by 25 to 33%, while 3 wks of PAS-L treatment did not show any effect. Further therapy with PAS-H for 6 wk reduced Mn levels in striatum, thalamus, choroid plexus, hippocampus and frontal cortex by 16 to 29% (p<0.05). Mn exposure greatly increased iron (Fe) and copper (Cu) concentrations in CSF, brain and liver. Treatment with PAS-H restored Fe and Cu levels comparable with control. These data suggest that PAS likely acts as a chelating agent to mobilize and remove tissue Mn. A high-dose and prolonged PAS treatment appears necessary for its therapeutic effectiveness.

This phase II/III, double-blind, randomized trial assessed the efficacy, immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women (ClinicalTrials.gov registration NCT00779766). Women aged 18–25 years from Jiangsu province were randomized (1:1) to receive HPV vaccine (n = 3,026) or Al(OH)3 control (n = 3,025) at months 0, 1 and 6. The primary objective was vaccine efficacy (VE) against HPV-16/18 associated 6-month persistent infection (PI) and/or cervical intraepithelial neoplasia (CIN) 1+. Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types, immunogenicity and safety. Mean follow-up for the according-to-protocol cohort for efficacy (ATP-E) was ∼15 months after the third dose. In the ATP-E (vaccine = 2,889; control = 2,894), for initially HPV DNA negative and seronegative subjects, HPV-16/18 related VE (95% CI) was 94.2% (62.7, 99.9) against 6-month PI and/or CIN1+ and 93.8% (60.2, 99.9) against cytological abnormalities. VE against HPV-16/18 associated CIN1+ and CIN2+ was 100% (−50.4, 100) and 100% (−140.2, 100), respectively (no cases in the vaccine group and 4 CIN1+ and 3 CIN2+ cases in the control group). At Month 7, at least 99.7% of initially seronegative vaccine recipients had seroconverted for HPV-16/18; geometric mean antibody titres (95% CI) were 6,996 (6,212 to 7,880) EU/mL for anti-HPV-16 and 3,309 (2,942 to 3,723) EU/mL for anti-HPV-18. Safety outcomes between groups were generally similar. The HPV-16/18 AS04-adjuvanted vaccine is effective, immunogenic and has a clinically acceptable safety profile in young Chinese women. Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China.What's New?With an estimated 75,000 new cases and 34,000 women dying from the disease annually, cervical cancer is a major public-health concern in China. This is the first large scale randomised clinical trial of a human papillomavirus (HPV) vaccine in China. The vaccine was found to be effective, immunogenic, and to have a clinically acceptable safety profile in young Chinese women. Prophylactic HPV vaccination thus has the potential to substantially reduce the burden of cervical cancers and precancers in China.

Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.

The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain's homeostasis of Aβ, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered Aβ levels in the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hr later, an FAM-labeled Aβ (200 pmol) was infused into the lateral ventricle and the plexus tissues removed to quantify Aβ accumulation. Results revealed a significant increase in intracellular Aβ accumulation in the Pb-exposed animals compared to controls (p<0.001). When choroidal epithelial Z310 cells were treated with 10 μM Pb for 24h and 48h, Aβ (2 μM in culture medium) accumulation was significantly increased by 1.5 fold (p<0.05) and 1.8 fold (p<0.05), respectively. To explore the mechanism, the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular Aβ transport protein, was examined. Following acute Pb exposure with the aforementioned dose regimen, levels of LRP1 mRNA and proteins in the choroid plexus were decreased by 35 % (p<0.05) and 31.8% (p<0.05), respectively, in comparison to those of controls. In Z310 cells exposed to 10 μM Pb for 24 h and 48 h, a 33.1% and 33.4% decrease in the protein expression of LRP1 was observed (p<0.05), respectively. Knocking down LRP1 resulted in even more substantial increases of cellular accumulation of Aβ, from 31% in cells without knockdown to 72% in cells with LRP1 knockdown (p<0.05). Taken together, these results suggest that the acute exposure to Pb results in an increased accumulation of intracellular Aβ in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure.

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Characterization of systemic performance of gold nanostructures is critical to the advancement of biomedical applications of these nanomaterials as imaging or therapeutic agents. The accuracy of current in vitro methods, however, is limited by interanimal variability. We present a novel method capable of monitoring the pharmacokinetics of PEGylated gold nanorods (GNRs) in the same animal by using intravital two-photon luminescence (TPL) imaging of GNRs flowing through a surface blood vessel. The TPL imaging with high speed and submicrometer resolution allowed for studying the clearance of GNRs as a function of surface coating. PEGylated-GNRs (PEG-NRs) were found to exhibit a biphasic clearance mode, with a significantly prolonged blood residence time for branched poly(ethylene glycol) (PEG) as compared to the linear PEG. With spectral detection to distinguish GNR TPL from tissue autofluorescence, we also mapped the cellular distribution of GNRs in the explanted organs, and found most GNRs resided in the macrophages in liver and spleen.

Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury.