Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease

Loss of Locus coeruleus (LC) noradrenergic (NA) neurons occurs in several neurodegenerative conditions including Alzheimer's disease (AD). In vitro and in vivo studies have shown that NA influences several features of AD disease including inflammation, neurodegeneration, and cognitive function. In the current study we tested if LC loss influenced beta amyloid (Abeta) plaque deposition. LC neuronal degeneration was induced in transgenic mice expressing mutant V717F human amyloid precursor protein (APP) by treatment with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine DSP4 (5mg/kg every 2 weeks beginning at age 3 months). At 9 months of age, when control mice show low amyloid load, DSP4-treated mice showed an approximately 5-fold increase in the average number of Abeta plaques. This was accompanied by an increase in the levels of APP C-terminal cleavage fragments. DSP4-treatment increased both microglial and astroglial activation. In vivo, DSP4-treatment decreased expression and activity of the Abeta degrading enzyme neprilysin, while in vitro NA increased phagocytosis of Abeta1-42 by microglia. These findings suggest that noradrenergic innervation from LC are needed to maintain adequate Abeta clearance, and therefore that LC degeneration could contribute to AD pathogenesis.     

Emergency Hybrid Correction in a Newborn with Critical Aortic Valve Stenosis with Acute Pulmonary Edema in the First Hour after Birth

Critical aortic valve stenosis in newborns is the cause of a severe clinical condition with the onset of symptoms during first hours after birth. We present a clinical case of a successful surgical correction of a critical aortic stenosis using a hybrid method applied in a newborn during the first day of life. The infant was diagnosed with a hypoplastic left heart complex with an intact atrial septum (aortic and mitral valves stenosis variant), that led to the cardiogenic shock and acute pulmonary edema. The procedure included bilateral banding of the pulmonary artery branches and atrioseptostomy with stenting of the interatrial septum. The surgery was performed through a median sternotomy.     

Aerobic respiratory chain of Escherichia coli is not allowed to work in fully uncoupled mode

Escherichia coli is known to couple aerobic respiratory catabolism to ATP synthesis by virtue of the primary generators of the proton motive force-NADH dehydrogenase I, cytochrome bo(3), and cytochrome bd-I. An E. coli mutant deficient in NADH dehydrogenase I, bo(3) and bd-I can, nevertheless, grow aerobically on nonfermentable substrates, although its sole terminal oxidase cytochrome bd-II has been reported to be nonelectrogenic. In the current work, the ability of cytochrome bd-II to generate a proton motive force is reexamined. Absorption and fluorescence spectroscopy and oxygen pulse methods show that in the steady-state, cytochrome bd-II does generate a proton motive force with a H(+)/e(-) ratio of 0.94 ± 0.18. This proton motive force is sufficient to drive ATP synthesis and transport of nutrients. Microsecond time-resolved, single-turnover electrometry shows that the molecular mechanism of generating the proton motive force is identical to that in cytochrome bd-I. The ability to induce cytochrome bd-II biosynthesis allows E. coli to remain energetically competent under a variety of environmental conditions.     

High-frequency oscillatory response to illusory contour in typically developing boys and boys with autism spectrum disorders

Illusory contour (IC) perception, a fruitful model for studying the automatic contextual integration of local image features, can be used to investigate the putative impairment of such integration in children with autism spectrum disorders (ASD). We used the illusory Kanizsa square to test how the phase-locked (PL) gamma and beta electroencephalogram (EEG) responses of typically developing (TD) children aged 3-7 years and those with ASD were modulated by the presence of IC in the image. The PL beta and gamma activity strongly differentiated between IC and control figures in both groups of children (IC effect). However, the timing, topography, and direction of the IC effect differed in TD and ASD children. Between 40 msec and 120 msec after stimulus onset, both groups demonstrated lower power of gamma oscillations at occipital areas in response to IC than in response to the control figure. In TD children, this relative gamma suppression was followed by relatively higher parieto-occipital gamma and beta responses to IC within 120-270 msec after stimulus onset. This second stage of IC processing was absent in children with ASD. Instead, their response to IC was characterized by protracted (40-270 msec) relative reduction of gamma and beta oscillations at occipital areas. We hypothesize that children with ASD rely more heavily on lower-order processing in the primary visual areas and have atypical later stage related to higher-order processes of contour integration.     

Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine

The generation of phospholipid oxidation products in atherosclerosis, sepsis, and lung pathologies affects endothelial barrier function, which exerts significant consequences on disease outcomes in general. Our group previously showed that oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (OxPAPC) at low concentrations increases endothelial cell (EC) barrier function, but decreases it at higher concentrations. In this study, we determined the mechanisms responsible for the pulmonary endothelial cell barrier dysfunction induced by high OxPAPC concentrations. OxPAPC at a range of 5-20 μg/ml enhanced EC barriers, as indicated by increased transendothelial electrical resistance. In contrast, higher OxPAPC concentrations (50-100 μg/ml) rapidly increased EC permeability, which was accompanied by increased total cell protein tyrosine (Tyr) phosphorylation, phosphorylation at Tyr-418, the activation of Src kinase, and the phosphorylation of adherens junction (AJ) protein vascular endothelial cadherin (VE-cadherin) at Tyr-731 and Tyr-658, which was not observed in ECs stimulated with low OxPAPC doses. The early tyrosine phosphorylation of VE-cadherin was linked to the dissociation of VE-cadherin-p120-catenin/β-catenin complexes and VE-cadherin internalization, whereas low OxPAPC doses promoted the formation of VE-cadherin-p120-catenin/β-catenin complexes. High but not low doses of OxPAPC increased the production of reactive oxygen species (ROS) and protein oxidation. The inhibition of Src by PP2 and ROS production by N-acetyl cysteine inhibited the disassembly of VE-cadherin-p120-catenin complexes, and attenuated high OxPAPC-induced EC barrier disruption. These results show the differential effects of OxPAPC doses on VE-cadherin-p120-catenin complex assembly and EC barrier function. These data suggest that the rapid tyrosine phosphorylation of VE-cadherin and other potential targets mediated by Src and ROS-dependent mechanisms plays a key role in the dissociation of AJ complexes and EC barrier dysfunction induced by high OxPAPC doses.     

β1-Adrenoceptor distribution in the rat brain: An immunohistochemical study

Current knowledge of the central nervous system distribution of the β₁-adrenergic receptors (β₁-AR) is incomplete. Here we present a general map of the β₁-AR distribution in the rat brain. β₁-AR-immunoreactivity was detected throughout the entire rat brain, but particularly dense staining was observed in the cerebellar cortex and basal ganglia. Brainstem areas displaying significant β₁-AR-immunoreactivity include the ventrolateral medulla, nucleus ambiguus and the nucleus of the solitary tract. Within the hypothalamus, only the paraventricular nucleus and the median eminence (ME) showed β₁-AR immunostaining. Numerous β₁-AR-immunoreactive cells were also found in the hippocampus, basal ganglia and cerebral cortex. These results extend our knowledge of the expression profile of β₁-AR in the central nervous system. The identification of several distinct β₁-AR immunoreactive substrates linked with neuropathophysiological roles in cardiovascular disease supports the hypothesis that the therapeutic benefit of β₁-AR blockade may be conferred at least in part through central nervous system mechanisms.