p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.

In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aß) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aß and mediates Aß-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aß. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aß deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aß deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing ß-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aß toxicity and would be a novel therapeutic target and biomarker for AD.

A study on the association between infectious burden and Alzheimer's disease.

BACKGROUND AND PURPOSE: Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimer's disease (AD) was examined. METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme-linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens. RESULTS: Seropositivities toward zero-two, three and four-five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini-Mental State Examination scores were negatively correlated with IB in all cases. Serum beta-amyloid protein (Aß) levels (i.e. Aß40, Aß42 and total Aß) and inflammatory cytokines (i.e. interferon-γ, tumor necrosis factor α, interleukin-1ß and interleukin-6) in individuals exposed to four-five infectious pathogens were significantly higher than those exposed to zero-two or three pathogens. CONCLUSIONS: IB consisting of CMV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.

Comparison of radiation dose, contrast enhancement and image quality of prospective ECG-Gated CT coronary angiography: Single versus dual source CT.

INTRODUCTION: The updated National Institute of Clinical Excellence (NICE) guidelines of 2017 state that new generation cardiac CT scanners (Aquilion ONE, Brilliance iCT, Discovery CT750 HD and Somatom Definition Flash) are recommended as an option for first-line imaging of the coronary arteries in people with suspected stable coronary artery disease (with an estimated likelihood of coronary artery disease of 10-29%) in whom imaging with earlier generation CT scanners is difficult. New generation cardiac CT scanners are also recommended as an option for first-line evaluation of disease progression, to establish need for revascularisation in people with known coronary artery disease in whom imaging with earlier generation CT scanners is difficult. CT scanning might not be necessary in situations in which immediate revascularisation is being considered. The European Society of Cardiology 2019 clinical practice guidelines recommend non-invasive functional imaging for myocardial ischaemia or coronary CT angiography (CTA) as the initial test to diagnose CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone. Given increased computed tomography coronary angiogram (CTCA) utilisation, radiation dose, contrast enhancement and image quality of prospective ECG-gated CTCA between 256-slice single-source and 192x2-slice dual-source CT scanners were retrospectively evaluated. METHODS: Prospectively gated CTCA data from 63 patients on a 256-slice CT (group A) and 71 patients on a 192x2-slice dual source CT (group B) from January to December 2016 were retrospectively evaluated respectively. Scanner-reported dose length product values were used with a conversion factor (k = 0.014 mSv/mGy x cm) to estimate effective dose. Contrast enhancement was assessed with mean CT attenuation at selected regions of interest on axial coronary images. Image quality of the coronary arteries was assessed by a 4-point grading score (1 = non-diagnostic, 4 = excellent image quality). RESULTS: The radiation doses in group B were significantly lower than group A (3.68 + 2.13 mSv versus 4.81 + 1.56 mSv, p < 0.001). There were no significant differences in contrast enhancement in the left coronary artery, proximal right coronary artery and left ventricular wall for both groups. Vessel image quality scores for group B were higher than group A (right coronary artery (RCA): 3.2 + 0.7 versus 2.4 + 0.7, p < 0.001; left anterior descending (LAD) artery: 3.0 + 0.8 vs 2.5 + 0.6, p < 0.001; left circumflex (LCx) artery: 3.3 + 0.7 vs 2.6 + 0.6, p < 0.001). Coronary artery contour scores for group B were significantly higher than group A (RCA: 3.2 + 0.8 versus 2.3 + 0.7, p < 0.001; LAD: 3.0 + 0.7 versus 2.4 + 0.6, p < 0.001; LCx: 3.3 + 0.6 versus 2.5 + 0.6, p < 0.001). CONCLUSION: Prospective ECG-gated CTCA performed on 192x2-slice CT results in better image quality and lower radiation dose than 256-slice CT. There were no significant differences in contrast enhancement in left main coronary artery (LMCA), proximal RCA and left ventricular wall in both groups. IMPLICATIONS FOR PRACTICE: In institutions with both 256-slice and 192x2-slice CT scanners, we recommend that CTCAs be preferentially performed using the 192x2-slice CT scanner.

Comparison of the intermediary metabolism of fatty acids in denervated and dystrophic murine skeletal muscle.

Certain aspects of lipid metabolism have been examined in denervated muscle from normal mice and in dystrophic muscle from mice of the Bar Harbor strain 129. A number of parameters show no change or similar changes. For example, the utilization of palmitate-[1-14C] and palmitylcarnitine by mitochondria from denervated and dystrophic hind leg skeletal muscle showed parallel decreased in the oxidation of palmitate (30-42%) and palmitylcarnite (37-66%). A comparable study with acetylcarnitine showed a striking difference with no change evident in mitochondria from denervated muscle and 80-85% decrease in dystrophic muscle. The study of succinate dehydrogenase and the enzymes of beta-oxidation in the above mitochondrial preparation showed similar findings except for acyl CoA dehydrogenase activity (an enzyme with a regulatory role in beta-oxidation) which was significantly diminished (29%) in denervated muscle, whereas no change was observed in dystrophic muscle. The findings show a close parallel in a number of parameters but distinct differences were observed in denervated as compared with dystrophic muscle. It is unlikely that the muscular disorder in murine muscular dystrophy can be explained solely on the basis of denervation or the loss of a neural trophic factor.

Osteoblastic phenotype of rat marrow stromal cells cultured in the presence of dexamethasone, beta-glycerolphosphate, and L-ascorbic acid.

We investigated the effects of the time course of addition of osteogenic supplements dexamethasone, beta-glycerolphosphate, and L-ascorbic acid to rat marrow stromal cells, and the exposure time on the proliferation and differentiation of the cells. It was the goal of these experiments to determine the time point for supplement addition to optimize marrow stromal cell proliferation and osteoblastic differentiation. To determine this, two studies were performed; one study was based on the age of the cells from harvest, and the other study was based on the duration of exposure to supplemented medium. Cells were seen to proliferate rapidly at early time points in the presence and absence of osteogenic supplements as determined by 3H-thymidine incorporation into the DNA of replicating cells. These results were supported by cell counts ascertained through total DNA analysis. Alkaline phosphatase (ALP) activity and osteocalcin production at 21 days were highest for both experimental designs when the cells were exposed to supplemented medium immediately upon harvest. The ALP levels at 21 days were six times greater for cells maintained in supplements throughout than for control cells cultured in the absence of supplements for both studies, reaching an absolute value of 75 x 10(-7) micromole/min/cell. Osteocalcin production reached 20 x 10(-6) ng/cell at 21 days in both studies for cells maintained in supplemented medium throughout the study, whereas the control cells produced an insignificant amount of osteocalcin. These results suggest that the addition of osteogenic supplements to marrow-derived cells early in the culture period did not inhibit proliferation and greatly enhanced the osteoblastic phenotype of cells in a rat model.