Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.Shohreh Majd, John H. Power and Hugh J.M. Grantha

The impact of tau hyperphosphorylation at Ser(262) on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest

An increase in phosphorylated tau (p-tau) is associated with Alzheimer's disease (AD), and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1) and Adenosine Monophosphate Kinase Protein Kinase (AMPK), in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3β), Protein kinase A (PKA) and Protein Phosphatase 2A (PP2A). Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA). The phosphorylation levels of LKB1, AMPK, GSK-3β, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser262). The animals showed unchanged levels of GSK-3β specific p-tau (Ser202/Thr205), phospho-PP2A (Tyr307), total GSK-3β, PP2A, phospho-cAMP response element-binding protein (CREB) which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser262, Ser202 and Thr205, with increased phosphorylation of both AMPK (Thr172) and GSK-3β (Ser9), and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits.Shohreh Majd, John H.T.Power, Simon A.Koblar, Hugh J.M.Grantha

Early glycogen synthase kinase-3beta and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway

Abnormal tau phosphorylation (p-tau) has been shown after hypoxic damage to the brain associated with traumatic brain injury and stroke. As the level of p-tau is controlled by Glycogen Synthase Kinase (GSK)-3β, Protein Phosphatase 2A (PP2A) and Adenosine Monophosphate Kinase (AMPK), different activity levels of these enzymes could be involved in tau phosphorylation following ischaemia. This study assessed the effects of global brain ischaemia/reperfusion on the immediate status of p-tau in a rat model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We reported an early dephosphorylation of tau at its AMPK sensitive residues, Ser(396) and Ser(262) after 2 min of ischaemia, which did not recover during the first two hours of reperfusion, while the tau phosphorylation at GSK-3β sensitive but AMPK insensitive residues, Ser(202) /Thr(205) (AT8), as well as the total amount of tau remained unchanged. Our data showed no alteration in the activities of GSK-3β and PP2A during similar episodes of ischaemia of up to 8 min and reperfusion of up to 2 h, and 4 weeks recovery. Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischaemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p-AMPK, in ischaemic/reperfusion groups. This suggests the involvement of AMPK in changing the p-tau levels, indicating that tau dephosphorylation following ischaemia is not dependent on GSK-3β or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction in AMPK activity is a possible early mechanism responsible for tau dephosphorylation.Shohreh Majd, John H. T. Power, Simon A. Koblar and Hugh J. M. Grantha

Beaufort/Bering 1979 microwave remote sensing data catalog report, 14-24 March 1979

The airborne microwave remote sending measurements obtained by the Langley Research Center in support of the 1979 Sea-Ice Radar Experiment (SIRE) in the Beaufort and Bering Seas are discussed. The remote sensing objective of SIRE was to define correlations between both active and passive microwave signatures and ice phenomena assocated with practical applications in the Arctic. The instruments used by Langley during SIRE include the stepped frequency microwave radiometer (SFMR), the airborne microwave scatterometer (AMSCAT), the precision radiation thermometer (PRT-5), and metric aerial photography. Remote sensing data are inventoried and cataloged in a user-friendly format. The data catalog is presented as time-history plots when and where data were obtained as well as the sensor configuration

ANALYTICAL INVESTIGATION AND PREDICTION OF SPIN AND RECOVERY CHARACTERISTICS OF THE NORTH AMERICAN X-15 AIRPLANE

Spin and recovery characteristics of north american x-15 aircraf

Greenland 1979 microwave remote sensing data catalog report, 14-15 October 1979

Microwave remote sensing measurements were cataloged for active and passive instruments in support of the 1979 Greenland Remote Sensing Experiment. Instruments used in this field experiment include the stepped frequency microwave radiometer (4 to 8 GHz) and the airborne microwave scatterometer (14.6 GHz). The microwave signature data are inventoried and cataloged in a user friendly format and are available on 9 track computer compatible tapes upon request

Handling qualities of a wide-body transport airplane utilizing Pitch Active Control Systems (PACS) for relaxed static stability application

Piloted simulation studies have been conducted to evaluate the effectiveness of two pitch active control systems (PACS) on the flying qualities of a wide-body transport airplane when operating at negative static margins. These two pitch active control systems consisted of a simple 'near-term' PACS and a more complex 'advanced' PACS. Eight different flight conditions, representing the entire flight envelope, were evaluated with emphasis on the cruise flight conditions. These studies were made utilizing the Langley Visual/Motion Simulator (VMS) which has six degrees of freedom. The simulation tests indicated that (1) the flying qualities of the baseline aircraft (PACS off) for the cruise and other high-speed flight conditions were unacceptable at center-of-gravity positions aft of the neutral static stability point; (2) within the linear static stability flight envelope, the near-term PACS provided acceptable flying qualities for static stabilty margins to -3 percent; and (3) with the advanced PACS operative, the flying qualities were demonstrated to be good (satisfactory to very acceptable) for static stabilty margins to -20 percent

Delivering Parenting Interventions through Health Services in the Caribbean

Integrating early childhood interventions with health and nutrition services has been recommended, however there is limited information on interventions that are effective and feasible for delivery through health services. In this trial we developed and evaluated a parenting program that could be integrated into primary health center visits

Care during the third stage of labour: obstetricians views and practice in an Albanian maternity hospital

<p>Abstract</p> <p>Background</p> <p>Relatively little is known about current practice during the third stage of labour in low and middle income countries. We conducted a survey of attitudes and an audit of practice in a large maternity hospital in Albania.</p> <p>Methods</p> <p>Survey of 35 obstetricians and audit of practice during the third stage was conducted in July 2008 at a tertiary referral hospital in Tirana. The survey questionnaire was self completed. Responses were anonymous. For the audit, information collected included time of administration of the uterotonic drug, gestation at birth, position of the baby before cord clamping, cord traction, and need for resuscitation.</p> <p>Results</p> <p>77% (27/35) of obstetricians completed the questionnaire, of whom 78% (21/27) reported always or usually using active management, and 22% (6/27) always or usually using physiological care. When using active management: 56% (15/27) gave the uterotonic after cord clamping; intravenous oxytocin was almost always the drug used; and 71% (19/27) clamped the cord within one minute. For physiological care: 42% (8/19) clamped the cord within 20 seconds, and 96% (18/19) within one minute. 93% would randomise women to a trial of early versus late cord clamping.</p> <p>Practice was observed for 156 consecutive births, of which 26% (42/156) were by caesarean section. A prophylactic uterotonic was used for 87% (137/156): this was given after cord clamping for 55% (75/137), although timing of administration was not recorded for 21% (29/137). For 85% of births (132/156) cord clamping was within 20 seconds, and for all babies it was within 50 seconds. Controlled cord traction was used for 49% (76/156) of births.</p> <p>Conclusions</p> <p>Most obstetricians reported always or usually using active management for the third stage of labour. For timing and choice of the uterotonic drug, reported practice was similar to actual practice. Although some obstetricians reported they waited longer than one minute before clamping the cord, this was not observed in practice. Controlled cord traction was used for half the births.</p