Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and ...tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.
We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis.
The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.
Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.
In this study the fluoride removal potential of nanoscale aluminium oxide hydroxide (nano-AlOOH) has been investigated. The material was produced using aluminium nitrate (Al(NO.sub.3).sub.3 x ...9H.sub.2O, 95%), and ammonium bicarbonate (NH.sub.4HCO.sub.3, 98%) and its density and mineralogy were investigated. A series of batch adsorption experiments were carried out to assess parameters that influence the adsorption process. The parameters considered were contact time and adsorbent dose, initial fluoride concentration, and pH. Results showed that most of the adsorption took place during the first 30 min; and equilibrium was reached at one hour contact time with an optimum adsorbent dose of 1.6 g L.sup.-1 for initial fluoride concentration of 20 mg L.sup.-1. The removal efficiency of fluoride increased with increase in adsorbent dosage. The fluoride removal efficiency was increased as the pH of the solution increases from pH 3 to 8, but any further increase in pH led to a decrease in fluoride removal efficiency. Maximum adsorption occurred at around pH 7 with initial fluoride concentration of 20 mg L.sup.-1. The adsorption data were well fitted to the Langmuir isotherm model with a maximum adsorption capacity of 62.5 mg F.sup.- g.sup.-1. The kinetic studies showed that the adsorption of fluoride by nano-AlOOH obeys a pseudo-second order rate equation. The intraparticle diffusion was not a rate-controlling step for the adsorption process. Thus, the overall study indicates that nano-AlOOH is an efficient defluoridating material. KEY WORDS: Nanoscale AlOOH, Defluoridation, Fluoride removal efficiency, Adsorption capacity, Adsorption kinetics, Adsorption mechanism
Due to industrial automation of liquid composite molding processes and increasing geometrical complexity of composite components, dry-spots from flow front junctions have become increasingly ...difficult to avoid. The impact and behavior of voids (microscopic or small macroscopic gas entrapments) during preform impregnation is well known, but no attention is given to dry-spots (large macroscopic gas entrapments). Experiments show that formation of a dry-spot in an early stage of an injection process does not necessarily lead to scrap parts. Therefore, simulation-based predictions of dry-spots are no sufficient condition for identification of unsuitable injection strategies. In this paper, the resolution mechanisms of dry-spots under controlled process conditions are investigated and the resulting findings of fundamental formation- and dispersion-mechanisms are presented.
There are five subtypes of muscarinic acetylcholine receptors (M(1) to M(5)) which control a large number of physiological processes, such as the function of heart and smooth muscles, glandular ...secretion, release of neurotransmitters, gene expression and cognitive functions as learning and memory. A selective ligand is very useful for studying the function of a subtype in presence of other subtypes, which is the most common situation, since a cell or an organ usually has several subtypes. There are many non-selective muscarinic ligands, but only few selective ones. Mambas, African snakes of genus Dendroaspis have toxins, muscarinic toxins, that are selective for M(1), M(2) and M(4) receptors. They consist of 63-66 amino acids and four disulfides which form four loops. They are members of a large group of snake toxins, three-finger toxins; three loops are extended like the middle fingers of a hand and the disulfides and the shortest loop are in the palm of the hand. Some of the toxins target the allosteric site which is located in a cleft of the receptor molecule close to its extracellular part. A possible explanation to the good selectivity is that the toxins bind to the allosteric site, but because of their size they probably also bind to extracellular parts of the receptors which are rather different in the various subtypes. Some other allosteric ligands also have good selectivity, the alkaloid brucine and derivatives are selective for M(1), M(3) and M(4) receptors. Muscarinic toxins have been used in several types of experiments. For instance radioactively labeled M(1) and M(4) selective toxins were used in autoradiography of hippocampus from Alzheimer patients. One significant change in the receptor content was detected in one region of the hippocampus, dentate gyrus, where M(4) receptors were reduced by 50% in patients as compared to age-matched controls. Hippocampus is essential for memory consolidation. M(4) receptors in dentate gyrus may play a role, since they decreased in Alzheimers disease which destroys the memory. Another indication of the role of M(4) receptors for memory is that injection of the M(4) selective antagonist muscarinic toxin 3 (M(4)-toxin 1) into rat hippocampus produced amnesia.
CONTEXT Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), ...but large-scale multicenter studies have not been conducted. OBJECTIVE To determine the diagnostic accuracy of CSF β-amyloid1-42 (Aβ42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Aβ42, T-tau, and P-tau for identifying incipient AD. RESULTS During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Aβ42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Aβ42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Aβ42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval CI, 0.75-0.82) for Aβ42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Aβ42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS This multicenter study found that CSF Aβ42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
Vascular dementia (VaD) accounts for about 20% of all dementias, and vascular risk is a key factor in more than 40% of people with Alzheimer’s disease (AD). Little is known about inflammatory ...processes in the brains of these individuals. We have examined inflammatory mediators (interleukin (IL)-1β, IL-1α, IL-6 and tumour necrosis factor α) and chemokines (macrophage inflammatory protein 1, monocyte chemo-attractant protein (MCP)-1 and granulocyte macrophage colony-stimulating factor) in brain homogenates from grey and white matter of the frontal cortex (Brodmann area 9) from patients with VaD (n = 11), those with concurrent VaD and AD (mixed dementia; n = 8) and from age-matched controls (n = 13) using ELISA assays. We found a dramatic reduction of MCP-1 levels in the grey matter in VaD and mixed dementia in comparison to controls (55 and 66%, respectively). IL-6 decreases were also observed in the grey matter of VaD and mixed dementia (72 and 71%, respectively), with a more modest decrease (30%) in the white matter of patients with VaD or mixed dementia. In the first study to examine the status of inflammatory mediators in a brain region severely affected by white-matter lesions, our findings highlight – in contrast to previous reports in AD – that patients at the later stage of VaD or mixed dementia have a significantly attenuated neuro-inflammatory response.
BackgroundAlzheimer's disease (AD) pathology is found in a considerable portion of patients with Parkinson's disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid ...(CSF) levels of amyloid-β (Aβ) and tau proteins have been found in PDD, with intermediate changes for Aβ42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD.MethodsCSF concentrations of Aβ42, Aβ40 and Aβ38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD.ResultsPD patients displayed significant reductions in Aβ42 (19%; p=0.009), Aβ40 (15.5%; p=0.008) and Aβ38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Aβ42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Aβ42 (β=0.205; p=0.019), Aβ40 (β=0.378; p<0.001) and Aβ38 (β=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures.ConclusionCSF Aβ levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Aβ protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Aβ peptides as prognostic biomarkers in PD.
The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant ...causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions.
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•The NIPBL-MAU2 interaction is required for the stability of both proteins•A pathogenic MAU2 deletion impairs dimerization and causes NIPBL haploinsufficiency•Early frameshift mutations in NIPBL induce alternative translation initiation•Translation re-initiation rescues NIPBL expression and renders MAU2 dispensable
Parenti et al. describe mutations causative for CdLS that affect the interaction between NIPBL and MAU2, the two subunits of the cohesin loader complex. This study further reveals a protective mechanism that rescues NIPBL expression in the presence of early truncating variants by using alternative translation initiation site.
Experiments were conducted to investigate the interdependence between the different influencing factors on the spray washing process under low-pressure conditions. The washing effect as a function of ...standoff distance, spray pressure, and nozzle diameter is derived by considering the spray structure and the spray washing mechanism. Four measuring systems were used to determine the relevant spray structure parameters of different nozzles and their washing effects. Single droplets formed in the spray were submitted to an energetic assessment. The nozzles were evaluated with regard to their area washing performance
η
as a ratio of the effective erosion area to spray area and effectiveness
E
s,Ve
.
The agricultural nozzle for plant protection with a flow rate
Q lower than 3
l
min
−1 at pressure
p of 3
bar and a spray angle
α
h
=
0
of 90° was found to be ineffective considering the determined area washing performance (area ratio
η
=
0
·
10
) as its spray parameters proved to be inappropriate concerning the droplet size spectrum, volume intensity per unit area, and mean impulse distribution. Conversely, the flat-fan nozzle with a flow rate
Q of 6·2
l
min
−1 at pressure
p of 3
bar and a spray angle
α
h
=
0
of 90° produces a spray with a satisfactory area washing performance (area ratio
η
=
0
·
91
), but a smaller area washing effectiveness
E
s,Ve
for the spray conditions used in this experiment.
In the present work, two novel compounds were synthesized using zinc oxide nanoparticles through green synthesis protocol. The zinc oxide nanoparticles catalyzed reactions were afforded good to ...excellent yields of the target compounds 76.3-98.6%.
The synthesized compounds were characterized by UV-Vis, IR and NMR. The antibacterial activity of the synthesized compounds was screened against two Gram-positive bacteria (
and
) and two Gram-negative bacteria (
and
).
The synthesized compounds displayed potent activity against the bacterial strains. Among them, compound
showed strong activity against
relative to the standard drug. On the other hand, compound
exhibited strong activity against
. The molecular docking study of the synthesized compounds was conducted to investigate their binding pattern with DNA gyrase and
dihydropteroate synthase and all of them were found to have minimum binding energy ranging from -6.0 to -7.3 kcal/mol, and the best result achieved with compound
and
.
The findings of the in vitro antibacterial and molecular docking analysis demonstrated that the synthesized compounds have potential of antibacterial activity and can be further optimized to serve as a lead compound.
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