Systematic review of international evidence on the effectiveness and costs of paediatric home care for children and young people who are ill.

Promoting 'care closer to home' for ill children is a policy and practice objective internationally. Progress towards this goal is hampered by a perceived lack of evidence on effectiveness and costs. The aim of the work reported here was to establish the strength of current international evidence on the effectiveness and costs of paediatric home care by updating and extending an earlier systematic review. A systematic review following Centre for Reviews and Dissemination guidelines involved updating electronic searches, and extending them to cover paediatric home care for short-term acute conditions. Twenty-one databases were searched from 1990 to April 2007. Hand searching was also carried out. Pairs of team members, guided by an algorithm, selected randomized controlled trials (RCTs), other comparative studies and studies including health economics data. A third reviewer resolved any disagreements. The quality of RCTs was assessed, but a 'best-evidence' approach was taken overall. Data were extracted into specifically designed spreadsheets and a second team member checked all data. Narrative synthesis was used throughout. This paper reports findings from RCTs and studies with health economics data. In total, 16 570 publications were identified after de-duplication. Eleven new RCTs (reported in 17 papers) and 20 papers with health economics data were included and reviewed. Evidence on costs and effectiveness of paediatric home care has not grown substantially since the previous review, but this updated review adds weight to the conclusion that it can deliver equivalent clinical outcomes for children and not impose a greater burden on families. Indeed, in some cases, there is evidence of reduced burden and costs for families compared with hospital care. There is also growing evidence, albeit based on weaker evidence, that paediatric home care may reduce costs for health services, particularly for children with complex and long-term needs.

The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1-24) ligand structure activity relationships at the melanocortin-2 receptor.

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors, and ancillary proteins that mediate the function of the endogenous antagonists. The melanocortin-4 receptor (MC4R) is involved in the regulation of obesity and the melanocortin-2 receptor (MC2R) is involved in the regulation of steroidogenesis. Herein, we present the effects of voluntary exercise on the MC4R knockout mice in terms of bypassing the morbid obesity and hyperphagia phenotypes associated with this genetic obesity model. Additionally, a systematic truncation study of the adrenocorticotropin hormone (ACTH 1-24) has been performed and characterized at the cloned MC2R.

A novel, synergistic interaction between 17 beta-estradiol and glutathione in the protection of neurons against beta-amyloid 25-35-induced toxicity in vitro.

The present studies were undertaken to investigate the possibility of an interaction between 17 beta-estradiol (E2) and glutathione in protecting cells against the presence of beta-amyloid 25-35 (betaAP 25-35). We demonstrate that when evaluated individually, supraphysiological concentrations of either E2 (200 nM) or of reduced glutathione (GSH; 325 microM) can protect SK-N-SH human neuroblastoma cells from betaAP 25-35 (20 microM) toxicity. This dose of betaAP 25-35 was chosen based on the LD50 (28.9 microM) obtained in our earlier work. However, in the presence of 3.25 microM GSH, the neuroprotective EC50 of E2 was shifted from 126 +/- 89 nM to 0.033 +/- 0.031 nM, approximately 4000-fold. Similarly, in primary rat cortical neurons, the addition of GSH (3.25 microM) increased the potency of E2 against betaAP 25-35 (10 microM) toxicity, as evidenced by a shift in the EC50 values of E2 from 68 +/- 79 nM in the absence of GSH to 4 +/- 6 nM in its presence. The synergy between E2 and GSH was not antagonized by the addition of the estrogen receptor antagonist, ICI 182,780. Other thiol-containing compounds did not interact synergistically with E2, nor were any synergistic interactions observed between E2 and ascorbic acid or alpha-tocopherol. Based on these data, we propose an estrogen-receptor independent synergistic interaction between glutathione and E2 that dramatically increases the neuroprotective potency of the steroid and may provide insight for the development of new treatment strategies for neurodegenerative diseases.

Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione.

Post-menopausal estrogen replacement therapy is associated with a reduction in the risk of Alzheimer's disease and has been reported to improve cognitive functioning in several small clinical trials. The present study evaluates the dependence of estrogenic neuroprotection on the presence of estrogen receptors using the murine neuronal cell line, HT-22, exposed to the neurotoxic beta-amyloid peptide. These cells lack functional estrogen receptors. The amyloid peptide killed 50-60% of these cells and concurrent treatment with either of three estratrienes, beta-estradiol, alpha-estradiol, or estratrien-3-ol, resulted in a dose-dependent protection. The potency of this estrogen neuroprotection was dependent on the presence of glutathione in the culture media. The presence of reduced glutathione in the media increases the neuroprotective potency of estrogens by an average of 400-fold. These results demonstrate that a nuclear estrogen receptor is not necessary for the neuroprotective actions of estrogens; however, the presence of an appropriate antioxidant in the extracellular milieu is needed for estratriene neuroprotection at physiologically and pharmacologically relevant doses. These data suggest the possibility of combined estrogen-antioxidant therapy for neurodegenerative diseases such as Alzheimer's disease.

Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease.

Recent evidence supports a role for estrogens in both normal neural development and neuronal maintenance throughout life. Women spend 25-33% of their life in an estrogen-deprived state and retrospective studies have shown an inverse correlation between dose and duration of estrogen replacement therapy (ERT) and incidence of Alzheimer's disease (AD), suggesting a role for estrogen in the prevention and/or treatment of neurodegenerative diseases. To explore these observations further, an animal model was developed using ovariectomy (OVX) and ovariectomy with estradiol replacement (E2) in female Sprague-Dawley rats to mimic postmenopausal changes. Using an active-avoidance paradigm and a spatial memory task, the effects of estrogen deprivation were tested on memory-related behaviors. OVX caused a decline in avoidance behavior, and estrogen replacement normalized the response. In the Morris water task of spatial memory, OVX animals showed normal spatial learning but were deficient in spatial memory, an effect that was prevented by estrogen treatment. Together these data indicate that OVX in rats results in an estrogen-reversible impairment of learning/memory behavior. Because a plethora of information has been generated that links decline in memory-related behavior to dysfunction of cholinergic neurons, the effects of estrogens on cholinergic neurons were tested. We demonstrated that OVX causes a decrease in high affinity choline uptake and choline acetyltransferase activity in the hippocampus and frontal cortex; ERT reverses this effect. Further, we showed that estrogens promote the expression of mRNA for brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), 2 neurotrophic substances that have been shown to ameliorate the effects of age and injury on cholinergic neurons. Tissue culture models were used to evaluate whether estrogen treatment increases the survival of neurons when exposed to a variety of insults. 17-beta-Estradiol (beta-E2) protects cells from the neurotoxic effects of serum deprivation and hypoglycemia in human neuroblastoma cell lines. We have also observed that 17-alpha-estradiol (alpha-E2), a weak estrogen, shows neuroprotective efficacy in the SK-N-SH cell line at concentrations equivalent to beta-E2. Finally, we have observed that tamoxifen, a classic estrogen antagonist, blocks only one-third of the neuroprotective effects of either alpha-E2 or beta-E2. Collectively, these results indicate that estrogen is behaviorally active in tests of learning/ memory; activates basal forebrain cholinergic neurons and neurotrophin expression; and is neuroprotective for human neuronal cultures. We conclude that estrogen may be a useful therapy for AD and other neurodegenerative diseases.

Simultaneous cocaine exposure abolishes ethanol tolerance.

We measured changes in locomotor impairment in rats caused by ethanol exposure either given alone or simultaneously with cocaine. An initial ethanol injection (2.1 g/kg, intraperitoneally (i.p.) disrupted rotorod performance and this disruption was not significantly affected by the cocaine injection (15 mg/kg, i.p.). After 13 daily drug treatments, performance in the ethanol group was significantly improved whereas in the cocaine+ethanol group, performance remained disrupted to the same extent throughout testing (49 +/- 14 min). Cocaine sensitization developed after repeated exposure and this sensitization was greater in the cocaine+ethanol group. Next, all groups were tested with simultaneous ethanol and cocaine. Tolerance was not diminished in the ethanol group, whereas groups receiving saline, cocaine, or cocaine+ethanol exhibited equally disrupted behavior. During an ethanol-only test, the cocaine+ethanol group also did not respond differently from groups receiving saline or cocaine alone. There was no difference in tolerance of the GABAA receptor to ethanol enhancement in cortical microsacs from the ethanol and cocaine+ethanol groups, nor did cocaine affect blood ethanol levels after initial or repeated exposure. A non-sensitizing dose of cocaine (7.5 mg/kg, i.p.) had no effect on the development or expression of ethanol tolerance. Cocaine disruption of ethanol tolerance thus appears to be partly due to interference of expression of ethanol tolerance by cocaine sensitization and partly due to inhibition of the development of ethanol tolerance by non-GABAergic mechanisms.

Low concentrations of estradiol reduce beta-amyloid (25-35)-induced toxicity, lipid peroxidation and glucose utilization in human SK-N-SH neuroblastoma cells.

The present studies were undertaken to determine the role of physiologically relevant concentrations of estrogens on amyloid-induced changes in cell viability, metabolic demands, and lipid peroxidation in response to the toxic fragment of beta-amyloid (betaAP 25-35). To this end, SK-N-SH human neuroblastoma cells were exposed to betaAP 25-35 or betaAP 25-35 plus 17beta-estradiol, and cell viability, media glucose use and lactate production were measured at time points ranging from 3 to 15 h for examination of acute effects, or at 48 and 72 h time points for chronic effects. Addition of betaAP 25-35 to SK-N-SH cells decreased the number of viable cells from 5% at 3 h to 35% at 15 h when compared to vehicle controls. Chronic treatment for 48 and 72 h caused decreases in viable cell number of 70% and 65%, respectively. Paradoxically, both glucose utilization and lactate production were found to be increased for the betaAP-treated cells. Concomitant estrogen treatment was found to be neuroprotective, as the severity of the insult on cell viability was decreased by 40% at 15 h and up to 71% at 72 h. Likewise, the addition of 17beta-estradiol decreased both the glucose use and lactate production of the cells. Chronic treatment with betaAP caused increases in lipid peroxidation over vehicle treated controls of 82% and 78% at 48 and 72 h, respectively, while decreases in peroxidation of 48% were seen with simultaneous estrogen treatment. These results indicate that the neuroprotective effects of estrogens against betaAP-induced toxicity are due in part to their capability to decrease lipid peroxidation and may additionally be attributable to decreasing the metabolic load of the cell.

Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells.

Estrogen-replacement therapy has been associated with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clinical trials. We assessed the possibility that estrogens may reduce toxicity of beta-amyloid (A beta) by testing the effects of beta-estradiol on the toxicity of the neurotoxic fragment of beta-amyloid (A beta 25-35) in SK-N-SH neuroblastoma cells. A beta 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.9 muM. In cultures simultaneously exposed to 20 muM A beta and 17 beta-estradiol (2 nM). A beta-induced toxicity was reduced by 83 and 51% in two separate studies. Further studies show that 0.2 nM 17 beta-estradiol was as effective as the 2 nM concentration. 17 alpha-Estradiol (2 nM) conferred neuroprotection equivalent to that of 17 beta-estradiol. These data support the hypothesis that estrogens reduce beta-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.