Rapamycin Rescues Vascular, Metabolic and Learning Deficits in Apolipoprotein E4 Transgenic Mice with Pre-Symptomatic Alzheimer’s Disease

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer\u27s disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer\u27s disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer\u27s disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer\u27s disease intervention studies in human subjects

On the Amplitude of Convective Velocities in the Deep Solar Interior

We obtain lower limits on the amplitude of convective velocities in the deep solar convection zone based only on the observed properties of the differential rotation and meridional circulation together with simple and robust dynamical balances obtained from the fundamental MHD equations. The linchpin of the approach is the concept of gyroscopic pumping whereby the meridional circulation across isosurfaces of specific angular momentum is linked to the angular momentum transport by the convective Reynolds stress. We find that the amplitude of the convective velocity must be at least 30 m s$^{-1}$ in the upper CZ ($r \sim 0.95 R$) and at least 8 m s$^{-1}$ in the lower CZ ($r \sim 0.75 R$) in order to be consistent with the observed mean flows. Using the base of the near-surface shear layer as a probe of the rotational influence, we are further able to show that the characteristic length scale of deep convective motions must be no smaller than 5.5--30 Mm. These results are compatible with convection models but suggest that the efficiency of the turbulent transport assumed in advection-dominated flux-transport dynamo models is generally not consistent with the mean flows they employ.Comment: 16 pages, 4 figures, accepted to the Astrophysical Journa

Risk behaviors in a rural community with a known point-source exposure to chronic wasting disease

<p>Abstract</p> <p>Background</p> <p>The emergence and continuing spread of Chronic Wasting Disease (CWD) in cervids has now reached 14 U.S. states, two Canadian provinces, and South Korea, producing a potential for transmission of CWD prions to humans and other animals globally. In 2005, CWD spread for the first time from the Midwest to more densely populated regions of the East Coast. As a result, a large cohort of individuals attending a wild game feast in upstate New York were exposed to a deer that was subsequently confirmed positive for CWD.</p> <p>Methods</p> <p>Eighty-one participants who ingested or otherwise were exposed to a deer with chronic wasting disease at a local New York State sportsman's feast were recruited for this study. Participants were administered an exposure questionnaire and agreed to follow-up health evaluations longitudinally over the next six years.</p> <p>Results</p> <p>Our results indicate two types of risks for those who attended the feast, a <it>Feast Risk </it>and a G<it>eneral Risk</it>. The larger the number of risk factors, the greater the risk to human health if CWD is transmissible to humans. Long-term surveillance of feast participants exposed to CWD is ongoing.</p> <p>Conclusion</p> <p>The risk data from this study provide a relative scale for cumulative exposure to CWD-infected tissues and surfaces, and those in the upper tiers of cumulative risk may be most at risk if CWD is transmissible to humans.</p

Readmission for infection after blunt splenic injury: A national comparison of management techniques

As nonoperative management (NOM) of blunt splenic injury (BSI) increases, understanding risks, especially infectious complications, becomes more important. There are no national studies on BSI outcomes that track readmissions across hospitals. Prior studies demonstrate that infection is a major cause of readmission after trauma and that a significant proportion is readmitted to different hospitals. The purpose of this study was to compare nationwide outcomes of different treatment modalities for BSI including readmissions to different hospitals. The Nationwide Readmissions Database for 2010 to 2014 was queried for patients 18 years to 64 years old admitted nonelectively with a primary diagnosis of BSI. Organ space infection; a composite infectious incidence of surgical site infection (SSI), urinary tract infection, and pneumonia; and sepsis were identified in three groups: NOM, splenic artery embolization (SAE), and operative management (OM). Rates of infection were quantified during index admission and 30-day and 1-year readmission. Multivariable logistic regression was performed. Results were weighted for national estimates. Of the 37,986 patients admitted for BSI, 54.1% underwent NOM, 12.2% SAE, and 33.7% OM. Compared with OM and NOM, SAE had the highest rates of organ space SSI at 1 year (3.9% vs. 2.2% vs. 1.7%, p < 0.001). Compared with NOM, at 1 year, SAE had higher rates of infection (17.2% vs. 8.1%, p < 0.001) and sepsis (3.2% vs. 1.1%, p < 0.001). Compared with NOM, SAE had an increased risk of infection (odds ratio [OR], 1.24; 95 confidence interval [95% CI], 1.10-1.39; p < 0.001) and sepsis (OR, 1.37; 95% CI, 1.06-1.76; p < 0.001) at 1 year. At 1 year, SAE had increased risk of organ space SSI (OR, 1.99; 1.60-2.47; p < 0.001) but OM did not. Blunt splenic injury treated with SAE is at increased risk of both immediate and long-term infectious complications. Despite being considered splenic preservation, surgeons should be aware of these risks and incorporate such knowledge into their practice accordingly. Epidemiological study, level IV

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer\u27s disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer\u27s disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer\u27s disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer\u27s disease intervention studies in human subjects

Additional file 1 of Absolute quantitation of human wild-type DNAI1 protein in lung tissue using a nanoLC-PRM-MS-based targeted proteomics approach coupled with immunoprecipitation

Additional file 1: Fig. S1. Peptide mapping for recombinant human DNAI1 protein with trypsin/LysC digestion. Fig. S2. IP-MS analysis for human DNAI1 spiking in mouse lung matrix (A) and mouse lung matrix only (B). 1, hDNAI1 peptide AHIFDLAINK, 2, hDNAI1 peptide HSDPVWQVK. Fig. S3. Venn diagrams of protein ID numbers after IP-MS using Pierce IP, TER-1, Buffer A lysis buffer as IP loading buffer. Fig. S4. LOD (A) and LLOQ (B) of IP-MS assay for human DNAI1 in mouse lung matrix. 1, endogenous peptide AHIFDLAINK; 2, isotope labeled peptide AHIFDLAINK^