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Lead (Pb) is a well-known neurotoxicant and environmental hazard. Recent experimental evidence has linked Pb exposure with neurological deterioration leading to neurodegenerative diseases, such as Alzheimer’s disease. To understand brain regional distribution of Pb and its interaction with other metal ions, we used synchrotron micro-x-ray fluorescence technique (μ-XRF) to map the metal distribution pattern and to quantify metal concentrations in mouse brains. Lead-exposed mice received oral gavage of Pb acetate once daily for 4 weeks; the control mice received sodium acetate. Brain tissues were cut into slices and subjected for analysis. Synchrotron μ-XRF scans were run on the PETRA III P06 beamline (DESY). Coarse scans of the entire brain were performed to locate the cortex and hippocampus, after which scans with higher resolution were run in these areas. The results showed that: a) the total Pb intensity in Pb-exposed brain slices was significantly higher than in control brain; b) Pb typically deposited in localized particles of

The concrete-filled steel tube (CFST) columns using high-strength materials have the advantages of small sections and high capacity. However, the high-strength steel tube is susceptible to local buckling which will affect the seismic performance of CFST columns. The experimental study on seismic performance of CFRP confined rectangular CFST columns using high-strength materials indicated that the reinforcement of CFRP improves the bearing capacity and energy dissipation capacity efficiently. Based on the experimental investigation, the refined finite element model (FE model) of the CFRP confined high-strength rectangular CFST column was established in ABAQUS and verified in this paper. Parametric analysis was carried out to learn the influence of important factors such as material strength, width-to-thickness ratio, number of wrapped CFRP layers, and axial compression ratio. By combining the experimental research and parametric analysis, the restoring force model of FRP confined high-strength rectangular CFST column was proposed. The restoring force model could accurately predict the load–displacement curve and provided theoretical support for the design and application of CFRP confined high-strength rectangular CFST column.

Introduction: Aldosterone synthase inhibitors are emerging as important future treatment options for diseases associated with aldosterone signaling, such as resistant hypertension and chronic renal disease. PB6440 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The goal of the current study was to determine whether PB6440 was capable of reducing aldosterone production and blood pressure in an established human aldosterone synthase-transgenic mouse strain (hAS +/- ) that is associated with aldosterone excess and the development of hypertension under a 4% salt diet. Methods: hAS +/- mice were administered PB6440, positive controls and vehicle by oral gavage. In a single-dose study, plasma aldosterone levels were assessed 8 hours after the administration of PB6440 at 2, 10 and 30 mg/kg as well as the positive control fadrozole at 5 mg/kg. In a pilot study, blood pressure was assessed following 10 days of PB6440 once daily at 10 mg/kg as well as the positive control spironolactone at 50 mg/kg. In a definitive study, blood pressure was assessed following 8 weeks of PB6440 once daily at 30 mg/kg as well as spironolactone at 50 mg/kg. Blood pressure was assessed 4-6 hours after drug dosing using a tail-cuff system. Results: In the single-dose study, PB6440 markedly reduced plasma aldosterone with a similar potency to fadrozole (e.g., PB6440 10 mg/kg -96% compared to vehicle; fadrozole 5 mg/kg -96%). In the pilot study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice, with a somewhat greater effect on both parameters than spironolactone at day 10. In the definitive study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice through 8 weeks with an efficacy similar to spironolactone. The decreases in SBP were approximately 30 mm Hg and DBP approximately 20 mm Hg in both drug groups compared to vehicle-treated hAS +/- mice. Conclusions: PB6440 was shown to lower aldosterone levels and normalize blood pressure through 8 weeks in an established mouse model of aldosterone excess and hypertension. PB6440 is a promising potential therapy for the treatment of conditions associated with aldosterone signaling in humans.

BackgroundThe iron concentration increases during normal brain development and is identified as a risk factor for many neurodegenerative diseases, it is vital to monitor iron content in the brain non-invasively.PurposeThis study aimed to quantify in vivo brain iron concentration with a 3D rosette-based ultra-short echo time (UTE) magnetic resonance imaging (MRI) sequence.MethodsA cylindrical phantom containing nine vials of different iron concentrations (iron (II) chloride) from 0.5 millimoles to 50 millimoles and six healthy subjects were scanned using 3D high-resolution (0.94×0.94×0.94 mm3) rosette UTE sequence at an echo time (TE) of 20 μs.ResultsIron-related hyperintense signals (i.e., positive contrast) were detected based on the phantom scan, and were used to establish an association between iron concentration and signal intensity. The signal intensities from in vivo scans were then converted to iron concentrations based on the association. The deep brain structures, such as the substantia nigra, putamen, and globus pallidus, were highlighted after the conversion, which indicated potential iron accumulations.ConclusionThis study suggested that T1-weighted signal intensity could be used for brain iron mapping.

Welded hollow spherical joints are comprehensively used in spatial steel structures. However, the original joints cannot meet the strength requirements in some conditions, such as the corrosion, the fire and the change of structural load. Therefore, it is necessary to explore effective methods of strengthening the joints to maintain the durability and safety of the structures. This paper proposes and investigates the method of strengthening welded hollow spherical joints using unidirectional annular ribs. Experiments were conducted to study the failure modes, axial load–displacement curves and ultimate bearing capacity under axial compressive and tensile load. Nonlinear finite element (FE) model was established and verified to study the failure mechanism and bearing capacity of the test joints using ABAQUS. Based on the accurate FE model, parametric studies were performed to study the influence of the thickness and height of unidirectional annular rib, the dimensions of the steel tubes and the welded hollow spheres on the capacity of the joints. Practical design formulas were proposed based on the test and the FE analysis. The conclusions presented in this study can provide theoretical and numerical basis for the design of welded hollow spheres strengthened with unidirectional annular ribs in spatial steel structures.

Beam-to-column connection configurations, such as welded, bolted, and mixed welded-bolted connections, play an important role in structural resistance and ductility under middle column-removal scenarios. This paper illustrates full-scale laboratory tests of two steel frame assemblies with different connection details under the progressive collapse scenario. One specimen adopts the modified conventional technique which has reinforced welded flange-bolted web connection (SC-WR), and the other specimen uses a slotted-hole connection based on the former (SC-WB). The failure modes, load transfer mechanism, and vertical resistance are analyzed in the test. Both connection configurations exhibit satisfactory load resistance and ductility supply. Specimen SC-WB shows the higher ultimate vertical capacity and greater chord rotation at later catenary stage due to a sufficient redistribution of the stress with the modified bolted shear tab. Moreover, finite element models (FEM) are developed and validated against the test data. FEM can accurately simulate the mechanical behaviors and the failure of specimens, which can provide an effective reference for the beam-to-column connection configurations in similar working conditions. Finally, a simplified mechanical model is exhibited in accordance with the experimental and numerical results to reveal the effect of the catenary mechanism. This result suggests that the duration of the catenary mechanism, rather than the magnitude of the axial force, plays an essential role in the resistance of vertical load.

A synergistic system of water falling film dielectric barrier discharge (DBD) plasma and persulfate (PS) was set up and used for oxidizing ciprofloxacin (CIP) in water. Results of reactive species formation in the DBD-only system as well as the DBD–PS system verified the PS activation in the DBD system. Influencing factors on CIP degradation and the degradation process were also been studied. The obtained results showed that the presence of PS could greatly improve the degradation and mineralization of CIP and that the degradation efficiency could reach 97.73% after only 40 min treatment with 4 mM PS addition. The increase of PS concentration, the lower CIP concentration, the acidic solution pH and the addition of metal ions (Fe2+ and Cu2+) enhanced the CIP degradation, while the existence of Cl− and HC O 3 − had a negative effect. The experiments related to scavenger addition confirmed the contribution of the main reactive species to the CIP oxidation. Three probable degradation pathways were proposed by analyzing the inorganic ions and organic byproducts formed during the CIP degradation. The toxicity evaluation results of the CIP and its intermediates confirmed the effectiveness of the DBD–PS synergistic system.

A synergetic system of water falling film dielectric barrier discharge (DBD) plasma and persulfate (PS) was established and applied to enhance the enrofloxacin (EFA) degradation in this study. The simultaneous existence of electrons, reactive species, heat and UV-visible light in the DBD plasma system were utilized together to activate the PS to form SO

Minocycline and doxycycline, two semisynthetic second-generation tetracyclines, are reported to provide neuroprotection against brain injury and glutamate-induced neurotoxicity in neuronal cultures. Doxycycline has been postulated as the potential ideal candidate for further therapeutic development as it has fewer adverse effects than minocycline. In this study, we determined whether minocycline and doxycycline could similarly protect neurons against excitotoxic insults. We treated cultured rat cortical neurons and cerebellar granule neurons (CGN) with excitotoxic concentrations of NMDA or glutamate in the presence or absence of minocycline or doxycycline. Intracellular Ca concentration ([Ca]i) was also measured using a Fluorescent Light Imaging Plate Reader (FLIPR; Molecular Devices) with the calcium sensitive dye Fluo-3 AM. We found that minocycline and tetracycline markedly protected neurons against NMDA- and glutamate-induced neuronal death. In contrast, the structurally related tetracycline, doxycycline, was ineffective at concentrations up to 100 μM. Furthermore, minocycline, but not doxycycline, also significantly attenuated NMDA- or glutamate-induced [Ca]i in both cortical neurons and CGN. Our results suggest that minocycline but not doxycycline is able to directly block NMDA- or glutamate-induced excitotoxicity in neurons most likely by inhibiting NMDA- and glutamate-induced [Ca]i. This finding may contribute to our understanding of the molecular mechanisms underlying doxycycline- and minocycline-induced neuroprotection.

Background Lead (Pb) is an environmental factor has been suspected of contributing to the dementia including Alzheimer’s disease (AD). Our previous studies have shown that Pb exposure at the subtoxic dose increased brain levels of beta-amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in amyloid precursor protein (APP) transgenic mice, and is hypothesized to inhibit Aβ clearance in the blood- cerebrospinal fluid (CSF) barrier. However, it remains unclear how different levels of Pb affect Aβ clearance in the whole blood-brain barrier system. This study was designed to investigate whether chronic exposure of Pb affected the permeability of the blood-brain barrier system by using the Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) method. Methods DEC-CT was used to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system. Results Data showed that Pb exposure increased permeability surface area product, and also significantly induced brain perfusion. However, Pb exposure did not alter extracellular volumes or fractional blood volumes of mouse brain. Conclusion Our data suggest that Pb exposure at subtoxic and toxic levels directly targets the brain vasculature and damages the blood brain barrier system.

Rectangular concrete-filled thin-walled steel tube (CFT) columns using high-strength steel and concrete are susceptible to local buckling, which will weaken the constraint effect and reduce the advantages of high-strength materials. Fiber reinforced polymer (FRP) has favorable mechanical properties, which can be used to delay or even prevent the outward buckling of steel tube. This paper presents the experimental and theoretical study on axial compressive behavior of FRP confined concrete-filled thin-walled steel tube (FRP-CFT) stub columns with high-strength materials. The test variables included the aspect ratio of section, concrete strength and the layers of FRP, etc. Results show that the confinement of FRP delays the local buckling of steel tubes and increases the restraint strength of core concrete. The ductility of high-strength concrete is also improved. Based on the superposition theory and the effective width theory, this paper proposed the design approach to calculate the ultimate compressive resistance, considering the effect of local buckling of thin-walled steel tube and the confinement of the FRP. The design approach was verified with experimental results and can be used in practice.

This paper aims to investigate the shear performance of a new and innovative type of vertical stiffener connection between steel beams and L-shaped columns composed of concrete-filled steel tubes connected by transverse and vertical steel plates (L-CFST columns) in high-rise residential buildings. Quasi-static cyclic loading tests were performed on five full-scale specimens to investigate the panel zone behaviours. Based on the experimental results, the hysteretic responses, skeleton curves of the shear force–deformation, ductility, stiffness degradation, energy dissipation and strain are discussed. The variables studied in these experiments include the joint type, axial compression ratio, cross-sectional area and width-to-thickness ratio of the vertical stiffener, and presence of concrete. The results indicate that the cross-sectional area of the vertical stiffeners plays a critical role in the performance of the panel zone. Two types of failure modes were observed outside the panel zone: fracturing of the vertical stiffeners and fracturing of the beam flange connecting plate. Shear deformation of the panel zone was obvious in the exterior joint specimens, and the corresponding maximum shear deformation reached 0.05 rad. Furthermore, the scopes of the panel zone in the corner and exterior joint specimens were determined by the strain distribution.

This paper studied the axial compression behaviour of stainless-steel stub square tubular columns (SSSSTCs) at low temperatures (T). Firstly, mechanical properties of stainless steel (SS) S30408 at −80–20 °C were experimentally studied. Test results revealed that decreasing low temperature significantly improved the strength of SS especially the ultimate strength, but reduced its ductility. Twenty SSSSTCs with varying wall thickness were tested at different T of −80–20 °C. Test results showed that inward and outward local buckling took place for SSSSTCs under low temperature-compression. The decreasing T value had significantly positive influence on strength and stiffness of SSSSTCs, but reduced the nonlinear branch of P-Δ curves and ductility of SSSSTCs. The increasing wall thickness significantly improves both strength and ductility of SSSSTCs at different low temperatures due to the reduced width-to-thickness ratio. This paper also developed finite element model (FEM) on simulating compression behaviour of SSSSTCs at different low temperatures that considered geometric imperfections and material nonlinearities. Different code prediction equations were also adopted for predictions of the ultimate low-temperature compression resistances of SSSSTCs. Their accuracies were checked by reported test results.

The behaviour of unusual composite column sections is difficult to examine owing to their asymmetric geometry. In this study, seven L-shaped columns fabricated using concrete-filled steel tubes connected via double-vertical steel plates (LCFST-D columns) were tested under axial compression. The failure modes, load–deformation relationship, strain distribution, ductility, and strength index of the columns were studied. Test results demonstrated that the local buckling of the vertical steel plates was delayed by filling with concrete. The bearing capacity and ductility ratio increased by 21.1% and 8.1%, respectively, compared with the specimen without concrete in the vertical steel plates. Transverse stiffeners were used to increase the axial stiffness by restraining the deformation of the vertical steel plates. However, the effect of the transverse stiffeners on the bearing capacity was negligible. The behaviour of the LCFST-D columns with concrete filled in between the two vertical steel plates, without the transverse stiffeners, was more favorable than the LCFST-D columns with the transverse stiffeners, and thus recommended for practical engineering application. The mono-columns worked more cooperatively in this connecting pattern. 3D nonlinear finite element models were developed and verified to analyze the mechanical properties and bearing capacity of the LCFST-D columns. The approach is verified by the experimental results and the available current design codes to be reasonably conservative. EC4 showed the best agreement with the experimental values. The results of this study provide a basis for the application of LCFST-D columns in high-rise composite structures.

The bearing capacity of concrete-filled steel tube (CFST) columns can be significantly increased by using high-strength materials. However, the ductility of high-strength CFST columns is reduced due to the brittleness of high-strength concrete and the buckling of thin-walled high-strength steel tubes, especially for slender columns. By wrapping the carbon fiber reinforced polymer (CFRP) to increase the confinement on the steel tube, the ductility can be improved. This paper presents experimental and theoretical studies on the axial compressive performance of CFRP confined rectangular CFST columns using high-strength steel and concrete with moderate slenderness. The influence of the section aspect ratio, concrete strength, and CFRP confinement on the axial behavior was analyzed. The experimental results indicate that the local buckling of CFRP-confined specimens is delayed compared with the unconfined specimens. The horizontal CFRP confinement increases the yield load by 1.5–25.6%, and the peak load by 2.5–11.2%. The bearing capacity and ductility of specimens are improved under the confinement of CFRP. The calculation method for axial compression bearing capacity considering the stability of moderate slender specimens was proposed. The ratio of the experimental results to the calculated value is between 0.86 and 1.09, which verified the accuracy of the calculation method.

To promote the application of special-shaped concrete-filled rectangular steel tubular (SCFRT) columns in high-rise residential buildings, this paper proposed innovative SCFRT column frame-buckling restrained steel plate shear wall structure. Three sets of 1:2 scale structural model specimens with a single span and two stories were designed and tested under the quasi-static load. The connection form between the frame and the shear wall includes four-side connection, four-corner connection, and groove connection. The hysteretic performance of the specimens was evaluated, and the mechanical properties were analyzed. The parametric analysis was carried out by the verified finite element model. The results revealed that the SCFRT columns frame-buckling restrained steel plate shear wall structure has favorable seismic performance, and the connection form significantly affects the mechanical properties of the structure. The bearing capacity and stiffness of the four-side connection form are relatively prominent, while the groove connection and four-corner connection have better ductility. The results can guide the engineering application to choose the proper connection form between the frame and the shear wall.

Acute traumatic spinal cord injury (tSCI) results in a lifetime of paralysis associated with a host of medical complications. The developing secondary complications of tSCI may result in further chronic neurodegenerative diseases. Sevoflurane preconditioning (SF-PreCon) has shown guaranteed protective effects in myocardial or cerebral ischemic/reperfusion injury. However, the role of SF-PreCon in tSCI still remains to be elucidated. Here, we found that SF-PreCon ameliorated the developing secondary complications through reducing the apoptosis rate and the secretion of inflammatory cytokines in injured spinal cord tissues, and therefore enhancing the recovery after tSCI. Notably, we demonstrated that SF-PreCon ameliorates tSCI through inhibiting Cycloxygenase-2 (COX-2). Importantly, we verified that SF-PreCon inhibits the expression of COX-2 and reduces the apoptosis rate after tSCI via the induction of Caveolin-3 (Cav-3). Taken together, our results suggest that SF-PreCon ameliorates tSCI via Cav-3-dependent COX-2 inhibition and provide an economical and practical method against the secondary injury after tSCI.

High-strength steel is permitted in steel structures, whereas, further studies are needed to allow the use of high-strength steel in concrete-filled tubular (CFT) structures. In this study, twelve rectangular CFT columns using Q460-grade steel were tested under eccentric load and the test results were discussed. A nonlinear finite element model (FEM) was developed to predict the load-displacement and ultimate resistance behaviors of the test columns. Parametric studies were conducted using the verified FEM to investigate the influence of aspect ratios, steel strength, and width-to-thickness (h/t) ratio of steel plate. The ultimate resistance calculated by European Code (EC4), American Code (AISC 360) and Chinese Code (CECS 159) is compared with the FEM predictions to evaluate their feasibility in the use of higher aspect ratios, high-strength steel, and various h/t ratios. The results indicate that the three design codes are safe in the design of columns with higher aspect ratios. EC4 is conservative in the design of rectangular CFT columns with high-strength steel up to 690 MPa under its h/t ratio limitation. AISC 360 method can accurately predict the maximum resistance of rectangular CFT columns with steel strength 550 MPa. CECS 159 method is highly conservative and can be safely extended to the use of steel strength up to 690 MPa and plate slenderness ratio 85 235 / f y .

Concrete-filled steel tubular (CFT) columns and high-strength steel have been increasingly used in construction. However, the application of high-strength steel in CFT columns has not been permitted in many design codes. This paper reports an experimental investigation on the behavior of rectangular CFT beam-columns using high-strength steel. The influences of the in-fill concrete, eccentricity ratio and the width-to-thickness ratio on the resistance of the test columns are discussed. The contact behavior is studied using the finite element analysis. Chinese code DB 29-57 adopts the assumption that the concrete bears the axial load only, and the steel tube withstands the bending moment and part of the axial load. A new N-M interaction approach is developed based on the foresaid assumption to account for the plastic behavior of high-strength steel. The approach is verified by the experimental results and the available current design codes to be reasonably conservative, and it can be employed to design rectangular CFT beam-columns using high-strength steel.

Adipose stromal cells conditioned media (ASC-CM) protect neurons in a variety of neuronal death models including potassium/serum deprivation-induced neuronal apoptosis. In this study, we found that ASC-CM contained glutamate oxaloacetate transaminase and its substrate, oxaloacetate (OAA) directly protected cerebellar granule neurons (CGN) from apoptosis induced by serum and potassium deprivation. Additionally, OAA inhibited serum and potassium deprivation-induced caspase 3 activation. ASC-CM and OAA in combination had a synergistic neuroprotective effect. Clearly, different from ASC-CM-induced neuroprotection, OAA-induced neuroprotection was Akt- independent but JNK-dependent. These data establish a mechanistic basis supporting that the application of ASC-CM for neuroprotective treatments could be significantly enhanced by addition of OAA.

High-strength steel members are susceptible to local buckling. Rectangular concrete-filled tubular (CFT) columns could make full use of high-strength steel by restraining its buckling inward. This paper reports an experimental investigation of rectangular CFT columns using high-strength steel. Three current design codes are evaluated with the experiments both from this study and the previous literature. It indicates that EC4, AISC 360 and GB50936 tend to be unsafe incorporating high-strength steel and high aspect ( h/b ) ratio. Design recommendations of the width-to-thickness ( h/t ) ratio are proposed to account for the different h/b ratio effects for rectangular CFT columns.

This paper investigates the behavior of fiber reinforced polymer (FRP)-steel composite plate and develops the fundamental theory for the analysis of FRP-steel structure. Uniaxial static tensile tests were conducted to investigate the mechanical properties of FRP-steel plate. Theoretical models to predict the stress–strain relationship of FRP-steel plate, derived from the rule of mixture of composite materials, were proposed and verified. The finite element model was established to study the detailed behaviors of the composite plate. Both theoretical model and the FE model showed good agreement with the test results, and could be applied to predict the mechanical properties of FRP-steel structures.

This paper experimentally and theoretically investigates the behavior of rectangular concrete-filled tubular (CFT) columns using Q460-grade steel. Analysis of concrete contribution ratio (CCR), ductility and strength index (SI) was performed based on the experimental results. Finite element analysis was conducted to predict the behaviors of the test columns and to choose the suitable steel material model for Q460-grade steel. A comprehensive database including this study was established to evaluate the current design approaches for rectangular CFT columns using high steel strength (HSS). Augmentation factor is proposed to evaluate the effect of both the width-to-thickness ratio and the HSS. A new design method was developed and verified to extend the steel strength limitation for designing rectangular CFT columns to 460 MPa in DB 29-57 based on this research.

Adipose tissue stroma contains a population of mesenchymal stem cells (MSC) promote new blood vessel formation and stabilization. These adipose-derived stem cells (ASC) promote de novo formation of vascular structures in vitro. We investigated the angiogenic factors secreted by ASC and discovered that glial-derived neurotrophic factor (GDNF) is a key mediator for endothelial cell network formation. It was found that both GDNF alone or present in ASC-conditioned medium (ASC-CM) stimulated capillary network formation by using human umbilical vein endothelial cells (HUVECs) and such an effect was totally independent of vascular endothelial growth factor (VEGF) activity. Additionally, we showed stimulation of capillary network formation by GDNF, but not VEGF, could be blocked by the Ret (rearranged during transfection) receptor antagonist RPI-1, a GDNF signaling inhibitor. Furthermore, GDNF were found to be overexpressed in cancer cells that were resistant to the anti-angiogenic treatment using the VEGF antibody. Cancer cells in the liver hepatocellular carcinoma (HCC), a non-nervous related cancer, highly overexpressed GDNF as compared to normal liver cells. Our data strongly suggest that, in addition to VEGF, GDNF secreted by ASC and HCC cells, may be another important factor promoting pathological neovascularization. Thus, GDNF may be a potential therapeutic target for HCC and obesity treatments.

Metformin, a wildly used drug for type 2 diabetes, has recently been proven to protect a variety of cells from stress including stroke. Glutamate is an excitatory neurotransmitter that contributes to excitatory neuronal damage involved in stroke and neurodegenerative disorders. In this study, we demonstrated that pretreatment of rat cerebellar granule neurons (CGN) with metformin greatly enhanced cell viability against glutamate-induced neurotoxicity. Metformin significantly attenuated neuronal apoptosis in glutamate-treated CGN by reducing cytochrome c releasing, caspase-3 activation and phosphorylation of MAP kinases. Our results suggested that metformin was able to directly inhibit glutamate induced excitotoxicity in neurons and might be beneficial to patients suffered from stroke and neurodegenerative disorders.

Formation of amyloid plaques is the hallmark of Alzheimer’s disease. Our early studies show that lead (Pb) exposure in PDAPP transgenic mice increases β-amyloid (Aβ) levels in the cerebrospinal fluid (CSF) and hippocampus, leading to the formation of amyloid plaques in mouse brain. Aβ in the CSF is regulated by the blood-CSF barrier (BCB) in the choroid plexus. However, the questions as to whether and how Pb exposure affected the influx and efflux of Aβ in BCB remained unknown. This study was conducted to investigate whether Pb exposure altered the Aβ efflux in the choroid plexus from the CSF to blood, and how Pb may affect the expression and subcellular translocation of two major Aβ transporters, i.e., the receptor for advanced glycation end-products (RAGE) and the low density lipoprotein receptor protein-1 (LRP1) in the choroid plexus. Sprague-Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ(40) (2.5 μg/mL) was infused to rat brain via a cannulated internal carotid artery. Subchronic Pb exposure at both dose levels significantly increased Aβ levels in the CSF and choroid plexus (p

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is devastating, leading to paralysis and death. Disease onset begins pre-symptomatically through spinal motor neuron (MN) axon die-back from musculature at ~47 days of age in the mutant superoxide dismutase 1 (mSOD1(G93A)) transgenic ALS mouse model. This period may be optimal to assess potential therapies. We previously demonstrated that post-symptomatic adipose-derived stem cell conditioned medium (ASC-CM) treatment is neuroprotective in mSOD1(G93A) mice. We hypothesized that early disease onset treatment could ameliorate neuromuscular junction (NMJ) disruption. OBJECTIVE: To determine whether pre-symptom administration of ASC-CM prevents early NMJ disconnection. METHODS: We confirmed the NMJ denervation time course in mSOD1(G93A) mice using co-labeling of neurofilament and post-synaptic acetylcholine receptors (AchR) by α-bungarotoxin. We determined whether ASC-CM ameliorates early NMJ loss in mSOD1(G93A) mice by systemically administering 200μl ASC-CM or vehicle medium daily from post-natal days 35 to 47 and quantifying intact NMJs through co-labeling of neurofilament and synaptophysin with α-bungarotoxin in gastrocnemius muscle. RESULTS: Intact NMJs were significantly decreased in 47 day old mSOD1(G93A) mice (p < 0.05), and daily systemic ASC-CM prevented disease-induced NMJ denervation compared to vehicle treated mice (p < 0.05). CONCLUSIONS: Our results lay the foundation for testing the long-term neurological benefits of systemic ASC-CM therapy in the mSOD1(G93A) mouse model of ALS.

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer’s disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Straussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

Hypoxia-induced plasma levels of VEGF and sFlt-1 are responsible for increased vascular permeability occurred in both brain and pulmonary edema. Currently, it remains unclear the exact roles of VEGF and sFlt-1 in High Altitude Pulmonary Edema (HAPE) pathogenesis. In this study, plasma levels of VEGF and sFlt-1 from 10 HAPE and 10 non-HAPE subjects were measured and compared. The results showed that plasma levels of both VEGF and sFlt-1 in HAPE patients were significantly increased as compared to the non-HAPE group. Interestingly, increased plasma levels of these two protein factors were markedly reduced after treatments. As compared to VEGF, sFlt-1 was much more affected by hypoxia and treatments, suggesting this factor was a key factor contributed to HAPE pathogenesis. Importantly, the ratio of sFlt-1 and VEGF in group of either non-HAPE or HAPE after recovery was significantly lower than the ratio in HAPE patients prior to treatments. Our findings suggested that sFlt-1 was a key factor that involved in HAPE pathogenesis and the sFlt-1/VEGF ratio could be used as a sensitive diagnostic marker for HAPE. J. Med. Invest. 65:64-68, February, 2018.