Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions.</p> <p>Results</p> <p>In apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts.</p> <p>Conclusion</p> <p>The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.</p

Is Seladin-1 really a selective Alzheimer\u27s disease indicator?

Selective Alzheimer\u27s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer\u27s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Small Drains, Big Problems: The Impact of Dry Weather Runoff on Shoreline Water Quality at Enclosed Beaches

Enclosed beaches along urban coastlines are frequent hot spots of fecal indicator bacteria (FIB) pollution. In this paper we present field measurements and modeling studies aimed at evaluating the impact of small storm drains on FIB pollution at enclosed beaches in Newport Bay, the second largest tidal embayment in Southern California. Our results suggest that small drains have a disproportionate impact on enclosed beach water quality for five reasons: (1) dry weather surface flows (primarily from overirrigation of lawns and ornamental plants) harbor FIB at concentrations exceeding recreational water quality criteria; (2) small drains can trap dry weather runoff during high tide, and then release it in a bolus during the falling tide when drainpipe outlets are exposed; (3) nearshore turbulence is low (turbulent diffusivities approximately 10(-3) m(2) s(-1)), limiting dilution of FIB and other runoff-associated pollutants once they enter the bay; (4) once in the bay, runoff can form buoyant plumes that further limit vertical mixing and dilution; and (5) local winds can force buoyant runoff plumes back against the shoreline, where water depth is minimal and human contact likely. Outdoor water conservation and urban retrofits that minimize the volume of dry and wet weather runoff entering the local storm drain system may be the best option for improving beach water quality in Newport Bay and other urban-impacted enclosed beaches

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

The effect of cement gun and cement syringe use on the tibial cement mantle in total knee arthroplasty

Evidence suggests that a thicker cement mantle improves fixation strength and resistance to tensile and shear forces in the tibial component of total knee arthroplasty. A low proportion of orthopaedic surgeons currently employ techniques to improve cement penetration in the tibial plateau. We demonstrate that the use of a pressurised cement gun or cement syringe provides a highly statistically significant difference (p<0.001) to the depth of the tibial cement mantle and reduction in radiolucent lines when compared to cement applied by hand. This ensures a thicker cement mantle and may reduce the possibility of early failure by improving the strength of fixation and the resistance to tensile and shear forces. There is no statistical difference in the cement mantle produced by the cement syringe and the cement gun