Integrating children's services in England: national evaluation of children's trusts

Background Poor co‐ordination of services can have severe consequences for disadvantaged children with complex needs. Since 2003 national and local governments in England embarked on sweeping reforms aimed at improving and integrating local health, education and social services for children. These were to be organized locally by children's trusts and piloted by 35 children's trust pathfinders. Methods This study described and compared the experience of integrating children's services in all 35 children's trust pathfinders, covering 20% of children in England. It had a prospective mixed‐methods design. Over 3 years we interviewed 147 managers and professionals working in the children's trusts, including 172 semi‐structured interviews, carried out two questionnaire surveys of the 35 children's trusts and analysed official documents. Results In most areas different agencies jointly commissioned children's services, especially for mental health, disabilities and multi‐purpose children's centres, and increasingly pooled finances. Provision of multi‐agency and multi‐professional services was increasing. Professionals generally supported these changes but found them stressful. All children's trusts appointed directors of children's services and established boards representing multiple agencies. Systems for sharing information about individual children were mostly in place but were still underused. Health services were generally less involved in joint work than were local authorities' education and social care services, with notable exceptions. Areas where local authorities and health authorities shared geographical boundaries made most progress. Some children's trusts made few changes beyond their statutory obligations. Conclusion Children's trusts enabled major changes to services in areas where local actors and organizations were motivated and empowered. In other areas the remit of children's trusts was often too broad and vague to overcome entrenched organizational and professional divisions and interests. Policymakers need to balance facilitation of change in areas with dynamic change agents with methods for ensuring that dormant areas and agencies are not left behind.     

Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative

The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase. Unlike the tricyclic antidepressants, it was not antimuscarinic in the guinea pig ileum, nor did it have any appreciable affinity for brain alpha-1 adrenergic or histamine-1 binding sites. Wy-45,030 was also without affinity for alpha-2 or beta adrenergic, benzodiazepine, serotonin-1, serotonin-2, dopamine-2, and opiate receptors. Such a profile is predictive of antidepressant activity devoid of the side-effects common to tricyclic therapy.     

The effect of 1-(4,5-dihydro-1H-imidazol-2-yl) isoquinoline on monoamine release and turnover in the rat frontal cortex

Imidazoline-(2) binding sites (I(2)-BS) are widely distributed in rat brain and our studies have shown that drugs selective for these sites regulate central extrasynaptic monoamine concentrations. Radioligand binding studies have recently shown that BU98008 (1-[4,5-dihydro-1H-imidazol-2-yl] isoquinoline) displays high affinity at I(2)-binding sites. The aim of this study was set to assess the pharmacological actions of BU98008 in a functional in vivo model using the technique of in vivo brain microdialysis. Systemic injection of 20 mg/kg BU98008 produced an 85% rise in extracellular noradrenaline levels compared with basal values in the rat frontal cortex. Further experiments demonstrated that peripheral administration of 10 and 20 mg/kg BU98008 elicited a transient 25% elevation in dopamine overflow compared with basal values and simultaneously produced an 18% decrease in extracellular DOPAC (3-4-dihydroxyphenylacetic acid) levels compared to basal values. In addition, BU98008 did not appear to affect serotonergic neurotransmission in the frontal cortex. In conclusion, the present study demonstrates that BU98008 shares some functional similarities with known selective I(2)-BS ligands.     

Loop diuretics are open-channel blockers of the cystic fibrosis transmembrane conductance regulator with distinct kinetics

BACKGROUND AND PURPOSE

Loop diuretics are widely used to inhibit the Na⁺, K⁺, 2Cl⁻ co-transporter, but they also inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel. Here, we investigated the mechanism of CFTR inhibition by loop diuretics and explored the effects of chemical structure on channel blockade.

EXPERIMENTAL APPROACH

Using the patch-clamp technique, we tested the effects of bumetanide, furosemide, piretanide and xipamide on recombinant wild-type human CFTR.

KEY RESULTS

When added to the intracellular solution, loop diuretics inhibited CFTR Cl⁻ currents with potency approaching that of glibenclamide, a widely used CFTR blocker with some structural similarity to loop diuretics. To begin to study the kinetics of channel blockade, we examined the time dependence of macroscopic current inhibition following a hyperpolarizing voltage step. Like glibenclamide, piretanide blockade of CFTR was time and voltage dependent. By contrast, furosemide blockade was voltage dependent, but time independent. Consistent with these data, furosemide blocked individual CFTR Cl⁻ channels with ‘very fast’ speed and drug-induced blocking events overlapped brief channel closures, whereas piretanide inhibited individual channels with ‘intermediate’ speed and drug-induced blocking events were distinct from channel closures.

CONCLUSIONS AND IMPLICATIONS

Structure–activity analysis of the loop diuretics suggests that the phenoxy group present in bumetanide and piretanide, but absent in furosemide and xipamide, might account for the different kinetics of channel block by locking loop diuretics within the intracellular vestibule of the CFTR pore. We conclude that loop diuretics are open-channel blockers of CFTR with distinct kinetics, affected by molecular dimensions and lipophilicity.     

Failure of tubal sterilization accompanying cesarean section

Pomeroy tubal resection during cesarean section has had a reputation of a high failure rate, since a report of 7 failures in 400 (Prystowsky et al. Journal of the American Medical Association 158: 463. 1955). In this survey, 400 women sterilized by the Pomeroy technique after cesarean section were followed an average of 6 years. One failure occurred 2.5 years after the operation where there had been histologic evidence of complete section of the tube.     

Effects of substitution on the pyrrole N atom in derivatives of tetrahydronaltrindole, tetrahydrooxymorphindole, and a related 4,5-epoxyphenylpyrrolomorphinan

The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI), tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4'-phenyl-6,7:2',3'-pyrrolomorphinan (4) is reported. In opioid functional assays 4 were potent deltaopioid receptor (DOR) antagonists while the TNTI derivatives (7) were potent DOR antagonists or low-efficacy DOR partial agonists without substantial selectivity. The TOMI derivatives (8) were DOR agonists with significant selectivity. In vivo the DOR antagonist activity of 7d was confirmed, but the predominant agonist effect of 8d was shown to be mu opioid receptor mediated.     

Pharmacological characterisation of novel alpha 2-adrenoceptor antagonists as potential brain imaging agents

Development of suitable imaging ligands to facilitate in vivo characterisation of alpha(2)-adrenoceptors has been limited in its success. In the present study, a series of iodinated derivatives and a fluorinated derivative of the classical alpha(2)-adrenoceptor antagonist, idazoxan, have been evaluated as potential imaging ligands. These compounds are based on the structure of idazoxan but more closely resemble the selective alpha(2)-adrenoceptor antagonists 2-methoxy-idazoxan (RX821002) and 2-ethoxy-idazoxan (RX811059). Preliminary studies, investigating their affinities at alpha(2)-adrenoceptors, using brain membranes prepared from a variety of species, and their ability to antagonise UK14, 304-induced inhibition of twitch in mouse vas deferens highlighted 2-iodopropoxy-idazoxan and 2-fluoroethoxy-idazoxan as the most promising candidates. Further characterisation of these two compounds showed they had a good selectivity for alpha(2)-adrenoceptors compared with imidazoline(2)-binding sites and beta-adrenoceptors. Additional functional studies also showed a lack of intrinsic activity at alpha(2)-adrenoceptors. Following intravenous injection, both compounds were able to cross the blood brain barrier when tested using an ex vivo binding assay. These data show that both 2-iodopropoxy-idazoxan and 2-fluoroethoxy-idazoxan have binding and functional properties suitable for imaging ligands. Further studies using radiolabelled forms of these ligands and a more extensive characterisation of their binding profiles are necessary but these initial evaluations demonstrate their potential.