Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an ...early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.
Aims
To determine inactivation of Cryptosporidium parvum oocysts and reduction of Escherichia coli and enterococci in cattle slurry added aqueous ammonia.
Methods and Results
Escherichia coli, ...enterococci and nonviable C. parvum oocysts (DAPI+PI+) were enumerated every second day for 2 weeks in cattle slurry amended with 60 mmol l−1 aq. ammonia and compared with untreated slurry at three temperatures. Regardless of temperature, the proportion of nonviable C. parvum oocysts increased significantly faster over time in slurry with added ammonia than raw slurry (P = 0·021) corresponding to 62·0% higher inactivation (P = 0·001) at day 14. Additionally, 91·8% fewer E. coli and 27·3% fewer enterococci were observed in slurry added ammonia at day 14 compared to raw slurry.
Conclusion
The addition of aqueous ammonia to raw slurry significantly reduced the viability of C. parvum oocysts and numbers of bacterial indicators. Hence, ammonia is usable at lower pathogen concentrations in slurry before application to agricultural land.
Significance and Impact of the Study
Livestock waste is a valuable source of plant nutrients and organic matter, but may contain high concentrations of pathogens like E. coli and Cryptosporidium sp. that can be spread in the environment, and cause disease outbreaks. However, die‐off rates of pathogens in organic waste can increase following increasing ammonia concentrations.
To determine whether IL-6 increases lipolysis and fat oxidation in patients with type 2 diabetes and/or whether it exerts this effect independently of changes to the hormonal milieu, patients with ...type 2 diabetes (D) and healthy control subjects (CON) underwent recombinant human (rh)IL-6 infusion for 3 h. Rates of appearance (Ra) and disappearance (Rd) of U-(13C)palmitate and 6,6-(2H2)glucose were determined. rhIL-6 infusion increased (P < 0.05) palmitate Ra and Rd in a similar fashion in both groups. Neither plasma glucose concentration nor glucose Ra/Rd was affected by rhIL-6 infusion in either group, whereas rhIL-6 infusion resulted in a reduction (P < 0.05) in circulating insulin in D. Plasma growth hormone (GH) was increased (P < 0.05) by IL-6 in CON, and cortisol increased (P < 0.05) in response to IL-6 in both groups. To determine whether IL-6 was exerting its effect directly or through activation of these hormones, we performed cell culture experiments. Fully differentiated 3T3-L1 adipocytes were treated with PBS (control) IL-6, or IL-6 plus dexamethasone and GH. IL-6 treatment alone increased (P < 0.05) lipolysis, but this effect was reduced by the addition of dexamethasone and GH such that IL-6 plus dexamethasone and GH had blunted (P < 0.05) lipolysis compared with IL-6 alone. To assess whether IL-6 increases fat oxidation, L6 myotubes were treated with PBS (Control), IL-6, or AICAR, a compound known to increase lipid oxidation. Both IL-6 and AICAR markedly increased (P < 0.05) oxidation of (14)Cpalmitate compared with Control. Acute IL-6 treatment increased fatty acid turnover in D patients as well as healthy CON subjects. Moreover, IL-6 appears to be activating lipolysis independently of elevations in GH and/or cortisol and appears to be a potent catalyst for fat oxidation in muscle cells.
Recombinant adeno-associated viruses are important vectors for retinal gene delivery. Currently utilized vectors have relatively slow onset, and for efficient transduction it is necessary to deliver ...treatment subretinally, with the potential for damage to the retina. Amino-acid substitutions in the viral capsid improve efficiency in rodent eyes by evading host responses. As dogs are important large animal models for human retinitis pigmentosa, we evaluated the speed and efficiency of retinal transduction using capsid-mutant vectors injected both subretinally and intravitreally. We evaluated AAV serotypes 2 and 8 with amino-acid substitutions of surface-exposed capsid tyrosine residues. The chicken beta-actin promoter was used to drive green fluorescent protein expression. Twelve normal adult beagles were injected; four dogs received intravitreal injections and eight dogs received subretinal injections. Capsid-mutant viruses tested included AAV2(quad Y-F) (intravitreal and subretinal) and self-complementary scAAV8(Y733F) (subretinal only). Contralateral control eyes received injections of scAAV5 (subretinal) or scAAV2 (intravitreal). Subretinally delivered vectors had a faster expression onset than intravitreally delivered vectors. Subretinally delivered scAAV8(Y733F) had a faster onset of expression than scAAV5. All subretinally injected vector types transduced the outer retina with high efficiency and the inner retina with moderate efficiency. Intravitreally delivered AAV2(quad Y-F) had a marginally higher efficiency of transduction of both outer retinal and inner retinal cells than scAAV2. Because of their rapid expression onset and efficient transduction, subretinally delivered capsid-mutant AAV8 vectors may increase the efficacy of gene therapy treatment for rapid photoreceptor degenerative diseases. With further refinement, capsid-mutant AAV2 vectors show promise for retinal gene delivery from an intravitreal approach.
Abstract Several lines of evidence suggest the existence of multiple progestin receptors that may account for rapid and delayed effects of progesterone in the CNS. The delayed effects have been long ...attributed to activation of the classical progestin receptor (Pgr). Recent studies have discovered novel progestin signaling molecules that may be responsible for rapid effects. These include progesterone receptor membrane component 1 (Pgrmc1), Pgrmc2, progestin and adipoQ receptor 7 (Paqr7) and Paqr8. The functions of these molecules have been investigated extensively in non-neural, but not in neural tissues, partly because it is unclear which are expressed in the brain and where they are expressed. To address these issues, we compared the distributions of mRNAs encoding Pgr, Pgrmc1, Pgrmc2, Paqr7 and Paqr8 using in situ hybridization with radiolabeled oligodeoxynucleotidyl probes in forebrain tissues of estradiol-treated female rats. We also examined the distribution of serpine mRNA binding protein 1 (Serbp1), a putative binding partner of Pgrmc1. Analyses of adjacent brain sections showed that the highest expression of mRNAs encoding Pgr, Pgrmc1, Pgrmc2 and Serbp1 was detected in several hypothalamic nuclei important for female reproduction. In contrast, expression patterns of Paqr7 and Paqr8 were low and homogeneous in the hypothalamus, and more abundant in thalamic nuclei. The neuroanatomical distributions of these putative progestin signaling molecules suggest that Pgrmc1 and Pgrmc2 may play roles in neuroendocrine functions while Paqr7 and Paqr8 are more likely to regulate sensory and cognitive functions.
Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptor-interacting protein kinase (RIPK) 1 and RIPK3, called the necrosome. ...RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.
Accelerometers can obtain precise measurements of movements during the day. However, the individual activity pattern varies from day-to-day and there is limited evidence on measurement days needed to ...obtain sufficient reliability. The aim of this study was to examine variability in accelerometer derived data on sedentary behaviour and physical activity at work and in leisure-time during week days among Danish office employees.
We included control participants (n = 135) from the Take a Stand! Intervention; a cluster randomized controlled trial conducted in 19 offices. Sitting time and physical activity were measured using an ActiGraph GT3X+ fixed on the thigh and data were processed using Acti4 software. Variability was examined for sitting time, standing time, steps and time spent in moderate-to-vigorous physical activity (MVPA) per day by multilevel mixed linear regression modelling.
Results of this study showed that the number of days needed to obtain a reliability of 80% when measuring sitting time was 4.7 days for work and 5.5 days for leisure time. For physical activity at work, 4.0 days and 4.2 days were required to measure steps and MVPA, respectively. During leisure time, more monitoring time was needed to reliably estimate physical activity (6.8 days for steps and 5.8 days for MVPA).
The number of measurement days needed to reliably estimate activity patterns was greater for leisure time than for work time. The domain specific variability is of great importance to researchers and health promotion workers planning to use objective measures of sedentary behaviour and physical activity.
Clinical trials NCT01996176 .
Livestock constitutes a potential reservoir of meticillin-resistant Staphylococcus aureus isolates belonging to a recently derived lineage within clonal complex 398 (MRSA CC398-IIa). Since its ...discovery in the early 2000s, this lineage has become a major cause of human disease in Europe, posing a serious public health challenge in countries with intensive livestock production. To retrace the history of human colonisation and infection with MRSA CC398-IIa in Denmark, we conducted a nationwide, retrospective study of MRSA isolates collected from 1999 to 2011. Among 7,429 MRSA isolates screened, we identified 416 MRSA CC398-IIa isolates. Of these, 148 were from people with infections, including 51 from patients reporting no livestock exposure. The first cases of MRSA CC398-IIa infection in Denmark occurred in 2004. Subsequently, the incidence of MRSA CC398-IIa infection showed a linear annual increase of 66% from 2004 to 2011 (from 0.09 to 1.1 per 100,000 person-years). There were clear temporal and spatial relationships between MRSA CC398-IIa-infected patients with and without livestock exposure. These findings suggest substantial dissemination of MRSA CC398-IIa from livestock or livestock workers into the Danish community and underscore the need for strategies to control its spread both on and off the farm.
Brain oxygen consumption reflects neuronal activity and can therefore be used to investigate brain development or neuronal injury in neonates. In this paper we present the first results of a ...non-invasive MRI method to evaluate whole brain oxygen consumption in neonates.
For this study 51 neonates were included. The T1 and T2 of blood in the sagittal sinus were fitted using the ‘T2 prepared tissue relaxation inversion recovery’ pulse sequence (T2-TRIR). From the T1 and the T2 of blood, the venous oxygenation and the oxygen extraction fraction (OEF) were calculated. The cerebral metabolic rate of oxygen (CMRO2) was the resultant of the venous oxygenation and arterial spin labeling whole brain cerebral blood flow (CBF) measurements.
Venous oxygenation was 59±14% (mean±sd), OEF was 40±14%, CBF was 14±5ml/100g/min and CMRO2 was 30±12μmol/100g/min. The OEF in preterms at term-equivalent age was higher than in the preterms and in the infants with hypoxic–ischemic encephalopathy (p<0.01). The OEF, CBF and CMRO2 increased (p<0.01, <0.05 and <0.01, respectively) with postnatal age.
We presented an MRI technique to evaluate whole-brain oxygen consumption in neonates non-invasively. The measured values are in line with reference values found by invasive measurement techniques. Preterms and infants with HIE demonstrated significant lower oxygen extraction fraction than the preterms at term-equivalent age. This could be due to decreased neuronal activity as a reflection of brain development or as a result of tissue damage, increased cerebral blood flow due to immature or impaired autoregulation, or could be caused by differences in postnatal age.
•We present a non-invasive method which evaluates the brain oxygen metabolism.•The results are in agreement with reference values found by invasive techniques.•We were able to detect differences related to postnatal age and disease state.
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