BackgroundImaging agents capable of quantifying the brain’s tau aggregates will allow a more precise staging of Alzheimer’s disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [18F]MK-6240.MethodsIn vitro properties of [18F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging.ResultsIn vitro [18F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates.ConclusionsThis evaluation shows an [18F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.
The synthesis, structural, and photophysical properties of a novel family of neutral fac-[Re(N(∧)N)(CO)(3)(L)] complexes, where N(∧)N is either 2,2'-bipyridine or 1,10-phenanthroline and L is a para functionalized 5-aryltetrazolate [namely, 5-phenyltetrazolate (Tph(-)), 4-(tetrazolate-5-yl)benzaldehyde (Tbdz(-)), 5-(4-acetylphenyl)tetrazolate (Tacy(-)), and methyl 4-(tetrazolate-5-yl)benzoate (Tmeb(-))] are reported. The complexes were prepared by direct addition of the corresponding tetrazolate anion to the acetonitrile solvated fac-[Re(N(∧)N)(CO)(3)](+) precursor. NMR data demonstrate that the coordination of the metal fragment is regiospecific at the N2 atom of the tetrazolate ring. These conclusions are also supported by X-ray structural determinations. Photophysical data were obtained in diluted and deaerated dichloromethane solutions displaying broad and structureless profiles with emission maxima ranging from 566 to 578 nm. The absorption profiles indicate the presence of higher energy intraligand (IL) π-π* transitions and lower energies ligand-to-ligand charge transfer (LLCT) and metal-to-ligand charge transfer (MLCT). As the last two transitions are mixed, they are better described as a metal-ligand-to-ligand charge transfer (MLLCT), a result that is also supported by density functional theory (DFT) calculations. The complexes show excited state lifetime values ranging from 102 to 955 ns, with associated quantum yield between 0.012 and 0.099. Compared to the parent neutral chloro or bromo [Re(N(∧)N)(CO)(3)X], the complexes show a slightly improved performance because of the π accepting nature of the tetrazolato ligand. The metal-to-ligand backbonding is in fact depleting the Re center of electron density, thus widening the HOMO-LUMO gap and reducing the non-radiative decay mechanism in accordance with the energy gap law. Finally, the electron-withdrawing or donating nature of the substituent on the phenyltetrazolato ligand allows the fine-tuning of the photophysical properties.
Dynamic pulmonary hyperinflation and intrinsic PEEP (PEEPi) are known to play an important role in causing acute respiratory failure in COPD patients. In the present study, we have explored (1) the prevalence and magnitude of PEEPi in stable COPD patients, and (2) the correlation of PEEPi with respiratory mechanics and PaCO2. In 96 stable COPD patients with varying degrees of airway obstruction, we measured pulmonary flow resistance (RL), dynamic lung compliance (CLdyn), breathing pattern, arterial blood gases, and dynamic PEEPi. Dynamic PEEPi was determined as a negative deflection in esophageal pressure from the start of inspiratory effort to the onset of inspiratory flow. A significant correlation was found between dynamic PEEPi and FEVi (% predicted; r = -0.56, p less than 0.001), between PEEPi and RL (r = 0.69, p less than 0.001), and between PaCO2 and PEEPi (r = 0.6, p less than 0.001). These results indicate that increased severity of airway obstruction promotes PEEPi and concomitant dynamic hyperinflation. This implies increased inspiratory work in the face of decreased effectiveness of the inspiratory muscles as pressure generators. The present results suggest that dynamic hyperinflation may play a role in causing chronic hypoventilation in COPD patients.
The authors conclude that during anesthesia, the primary and association auditory cortices remain responsive to complex auditory stimuli, but in a nonspecific way such that the ability for higher-level analysis is lost.
The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.
A high-temperature, microwave synthesis of [Ru(qpy)3](2+) (qpy = 4,4':2',2'':4'',4'''-quaterpyridine) affords the photosensitiser in quantitative yield. The complex produces H2 photocatalytically in a range extending from the UV region of the spectrum to the red with greater efficiency when compared to [Ru(bpy)3](2+).
In the Intraoperative Hypothermia for Aneurysm Surgery Trial, neither systemic hypothermia nor supplemental protective drug affected short- or long-term neurologic outcomes of patients undergoing temporary clipping.
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