Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators.

Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.

Laboratory evaluation of methanolic extract of Atlantia monophylla (Family: Rutaceae) against immature stages of mosquitoes and non-target organisms

Methanolic extracts of the leaves of Atlantia monophylla (Rutaceae) were evaluated for mosquitocidal activity against immature stages of three mosquito species, Culex quinquefasciatus, Anopheles stephensi, and Aedes aegypti in the laboratory.Larvae of Cx. quinquefasciatus and pupae of An. stephensi were found more susceptible, with LC50 values of 0.14 mg/l and 0.05 mg/l, respectively. Insect growth regulating activity of this extract was more pronounced against Ae. aegypti, with EI50 value 0.002 mg/l. The extract was found safe to aquatic mosquito predators Gambusia affinis, Poecilia reticulata, and Diplonychus indicus, with the respective LC50 values of 23.4, 21.3, and 5.7 mg/l. The results indicate that the mosquitocidal effects of the extract of this plant were comparable to neem extract and certain synthetic chemical larvicides like fenthion, methoprene, etc.

Observing workplace incivility towards women: The roles of target reactions, actor motives, and actor-target relationships

The current study conceptualized observer reactions to uncivil behavior towards women as an ethical behavior and examined three factors (target reaction, actor motive, and actor-target relationship) that influence these reactions. Two vignette studies with women and men undergraduate and graduate students in western Switzerland were conducted. Study 1 (N=148) was a written vignette study that assessed how the reaction of female targets to incivility and the motives of actors influenced observer reactions. Results showed that a female target's reaction influenced observers' evaluations of the harm caused by an uncivil incident, and that an actor's motive affected observers' assessments of the necessity to intervene. Study 2 (N=81) was a video vignette study that assessed the effects of the reactions by female targets to incivility and the relationship between the target and the actor on observer reactions.We found that female targets' reactions influenced observers' evaluations of harm and the perceived necessity to intervene. Furthermore, the effect of a female target's reaction on observers' evaluations of harm was moderated by the relationship between the actor and the target: a female target who laughed at the uncivil behavior was perceived as less harmed, when she and the actor had a personal relationship than when they had a professional relationship. When the female target reacted hurt or neutrally, actor-target relationship did not affect observers' evaluations of harm. We conclude by discussing the implications of our findings for theory and practice.

Insulin Resistance as a Therapeutic Target for Chronic Kidney Disease.

Insulin resistance (IR) is a prevalent metabolic feature in chronic kidney disease (CKD). Postreceptor insulin-signaling defects have been observed in uremia. A decrease in the activity of phosphatidylinositol 3-kinase appears critical in the pathophysiology of CKD-associated IR. Lipotoxicity due to ectopic accumulation of lipid moieties has recently emerged as another mechanism by which CKD and/or associated metabolic disorders may lead to IR through impairment of various insulin-signaling molecules. Metabolic acidosis, anemia, excess of fat mass, inflammation, vitamin D deficiency, adipokine imbalance, physical inactivity, and the accumulation of nitrogenous compounds of uremia all contribute to CKD-associated IR. The clinical impacts of IR in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD. This is why IR may be a therapeutic target in the attempt to improve outcomes in CKD. General measures to improve IR are directed to counteract causal factors. The use of pharmaceutical agents such as inhibitors of the renin-angiotensin system may improve IR in hypertensive and CKD patients. Pioglitazone appears a safe and promising therapeutic agent to reduce IR and uremic-associated abnormalities. However, interventional studies are needed to test if the reduction and/or normalization of IR may actually improve outcomes in these patients.

Mortality target monitoring (life expectancy and all-age all-cause mortality, overall and inequalities)

The latest annual update on life expectancy data and all age all cause mortality rates, with data updated to 2006-08, which are used to monitor progress against Department of Health targets for overall life expectancy in England, and for the gap in life expectancy between the areas with the worst health and deprivation indicators (the Spearhead group) and the England average, was released on 5th November 2009 according to the arrangements approved by the UK Statistics Authority. �� The key points from the latest release are: �� - The overall life expectancy and all age all cause mortality (AAACM) trends for both males and females are broadly on course to deliver the target of 78.6 years for men and 82.5 years for women by 2010 (2009-11). �� - In 2006-08, life expectancy at birth in England continued to increase for both males and females, and reached its highest level on record at 77.7 years for males and 81.9 years for females. �� - Three-year average AAACM rates for England have fallen in each period since 1995-97. �� - In 2006-08, average life expectancy at birth in the Spearhead Group was 75.8 years for males and 80.4 years for females, having increased in each period since 1995-97. �� - However, England average life expectancy at birth has increased more quickly over this period, and, in 2006-08, the relative gap ��� i.e. percentage difference - in life expectancy at birth between England and the Spearhead Group was wider than at the baseline for the target (1995-97) for both males and females. �� - For males the relative gap was 7% wider than at the baseline (compared with 4% wider in 2005-07), for females 14% wider (compared with 11% wider in 2005-07).�� �� Therefore, the target to narrow the life expectancy gap between the Spearhead Group and the England average, by at least 10% by 2010, remains challenging.��Three-year average AAACM rates for the Spearhead Group have fallen in each period since 1995-97 for both males and females. Download Mortality target monitoring (life expectancy and all-age all-cause mortality, overall and inequalities): update to include data for 2008 (PDF, 683K)Download pre-release access list (PDF, 10k)��

Dementia Care Services UK Market Briefing 2009

This brand new market briefing adds to the growing national debate on the future of dementia care services, making use of a unique and extensive L&B survey (2008) of over 6,000 care homes in the UK which provide care for people with dementia. It builds on the findings of the Alzheimer’s Society’s Dementia UK report (2007) and the national strategy for dementia Living Well with Dementia (2009) to identify market opportunities and provide essential guidance and information with regard to planning and developing new and existing services.Key issues, facts and figures highlighted in the report include:Dementia care is a multi-billion pound market in the UK and this market is set to grow considerably.��Dementia care in care homes dominates the sector in terms of current market value.��The use of dementia home care – though significantly smaller than the equivalent market in care homes – is set to rise markedly in the future.A significant proportion of residents for whom dementia is a known cause of admission are receiving care in settings which are not dedicated to dementia care.The new national dementia strategy for England, Living Well with Dementia should provide the strongest impetus yet for growth in the market for specialist dementia care.Growing awareness surrounding inappropriate use of anti-psychotic drugs on people with dementia in care homes may have a major operational impact on some homes if controls are increased and could substantially increase costs.Despite evidence of increasing dementia specialisation, there are, as yet, no organisations to emerge with full service dementia expertise and integrated care pathways.The supply of dedicated dementia services varies dramatically by region and locality, reflecting local and regional priorities and commissioning strategies.The design and layout of care homes for people with dementia is key and there is an increasing consensus around what constitutes best practice and ‘dementia friendly design’ .Care home fees for dementia are generally higher than fees for frail elderly residents.The report is essential reading for senior executives and managers within any organisation committed to, or considering involvement in, the dementia care sector, including for-profit, 'third sector' and public sector agencies.For further information, please contact:��Market ReportsTel.��020 7833 9123 orEmail��info@laingbuisson.co.uk��Download Full Brochure including Order Form��Download Contents and Tables�� Featured item on home page:��no��

Health Inequalities Target Data Web Tool - Updated to 2003-05

This tool contains the data for the LHO briefing "The London Health Inequalities Forecast: A briefing on inequalities in life expectancy and deaths from cancers, heart disease and stroke in London". The tool enables local areas to monitor their progress towards the national health inequalities targets for life expectancy, mortality from heart disease and stroke, and mortality from cancers.

Review of the health inequalities infant mortality PSA target

This review was established to consider why, despite a general improvement in infant mortality rates, health inequalities in infant mortality between different social groups remain. It identifies a range of issues and makes recommendations relevant to the health inequalities 2010 PSA target. Its recommendations are being shared with the NHS and others before the department issues further guidance.

Tackling health inequalities: 2004-06 data and policy update for the 2010 national target

This document provides an update on progress to meet the health inequalities national target to reduce the gap as measured by infant mortality and life expectancy, by 10% by 2010. It includes an assessment of whether the 70 spearhead area local authorities, which map to 62 PCTs, are on track to meet the life expectancy target.

Health inequality target monitoring: update to include data for 2006

These reports summarise progress against Department of Health inequality targets for 2010 in the following areas: Infant mortality; life expectancy at birth for males and for females; cancer (premature mortality rate) and all circulatory diseases (premature mortality rate). Key facts Infant mortality The inequality gap in the infant mortality rate has reduced for the second consecutive period, though not yet by a sufficient amount to meet the target, based on the trend since the current socio economic classifications were introduced in 2001. Life expectancy at birth (males and females) The inequality gaps in male and female life expectancy at birth have both increased since the baseline. If current trends continue, the target would not be met. Cancer mortality The inequality gap in cancer mortality has declined since the baseline (despite a slight increase in the latest period), and the minimum requirement for the 2010 target has already been met. All circulatory diseases mortality The inequality gap in circulatory disease mortality has declined, and is on track to meet the target.

Tackling health inequalities: 2005-07 policy and data update for the 2010 national target

This document provides an update on progress to meet the health inequalities national target to reduce the gap as measured by infant mortality and life expectancy, by 10% by 2010. It includes an assessment of whether the 70 spearhead area local authorities, which map to 62 PCTs, are on track to meet the life expectancy target.

CC-chemokine receptors: a potential therapeutic target for Trypanosoma cruzi-elicited myocarditis

The comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate new therapeutic strategies aiming to ameliorate the inflammation that leads to heart dysfunction, without hampering parasite control. The augmented expression of CCL5/RANTES and CCL3/MIP-1alpha, and their receptor CCR5, in the heart of T. cruzi-infected mice suggests a role for CC-chemokines and their receptors in the pathogenesis of T. cruzi-elicited myocarditis. Herein, we discuss our recent results using a CC-chemokine receptor inhibitor (Met-RANTES), showing the participation of CC-chemokines in T. cruzi infection and unraveling CC-chemokine receptors as an attractive therapeutic target for further evaluation in Chagas disease.

Mortality target monitoring: infant mortality, inequalities. Update to include data for 2008

The 2008 annual update on infant mortality rates to monitor progress against the Department of Health infant mortality inequality PSA target.

N-cadherin as a therapeutic target in cancer.

During tumor progression, cancer cells undergo dramatic changes in the expression profile of adhesion molecules resulting in detachment from original tissue and acquisition of a highly motile and invasive phenotype. A hallmark of this change, also referred to as the epithelial-mesenchymal transition, is the loss of E- (epithelial) cadherin and the de novo expression of N- (neural) cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and a high level of its expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer. A peptidic N-cadherin antagonist (ADH-1) has been developed and has entered clinical testing. In this review, the authors discuss the biochemical and functional features of N-cadherin, its potential role in cancer and angiogenesis, and summarize the preclinical and clinical results achieved with ADH-1.