Development of a 22q11DS psycho-educational programme: exploration of the views, concerns and educational needs of parents caring for children or adolescents with 22q11DS in relation to mental health issues.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a multisystem genetic condition with a broad phenotype. It is associated with a high prevalence of depression and anxiety during childhood and increased risk of schizophrenia in adulthood. Despite this, studies report that families may receive inadequate information of mental health (MH) risks at diagnosis. Therefore, this study investigated parents' experiences of caring for a child with 22q11DS, investigated their knowledge regarding the risk of MH problems and assessed the need for a psycho-educational programme. METHODS: A qualitative design and purposeful sampling was utilized. Parents registered with the '22q11 Ireland' support group, and parents listed on the cleft palate database in a children's hospital in Ireland were invited to participate. Focus groups were held with 22 parents. Data were thematically analysed using Burnard's method of analysis. RESULTS: Most parents had some knowledge of the relationship between 22q11DS and an increased risk of MH issues. Parents reported that MH information relating to 22q11DS was mainly obtained from 22q11DS conferences, the '22q11 Ireland' support group and the Internet. Parents expressed a need for information to prevent or cope with their child's MH issues. Parents suggested that the following topics would be quite useful in a psycho-educational programme. These included information on the early warning signs of MH issues and guidance on when and how to tell the child about the condition and how to manage the child or young person's anxiety, obsessive behaviour or hearing voices. CONCLUSIONS: The findings indicated parental support for a psycho-educational programme that would provide relevant, accurate and timely information on how to effectively care for a child with 22q11DS MH needs.

A Multiparametric Model for Mapping Cellularity in Glioblastoma Using Radiographically Localized Biopsies.

BACKGROUND AND PURPOSE: The complex MR imaging appearance of glioblastoma is a function of underlying histopathologic heterogeneity. A better understanding of these correlations, particularly the influence of infiltrating glioma cells and vasogenic edema on T2 and diffusivity signal in nonenhancing areas, has important implications in the management of these patients. With localized biopsies, the objective of this study was to generate a model capable of predicting cellularity at each voxel within an entire tumor volume as a function of signal intensity, thus providing a means of quantifying tumor infiltration into surrounding brain tissue. MATERIALS AND METHODS: Ninety-one localized biopsies were obtained from 36 patients with glioblastoma. Signal intensities corresponding to these samples were derived from T1-postcontrast subtraction, T2-FLAIR, and ADC sequences by using an automated coregistration algorithm. Cell density was calculated for each specimen by using an automated cell-counting algorithm. Signal intensity was plotted against cell density for each MR image. RESULTS: T2-FLAIR (r = -0.61) and ADC (r = -0.63) sequences were inversely correlated with cell density. T1-postcontrast (r = 0.69) subtraction was directly correlated with cell density. Combining these relationships yielded a multiparametric model with improved correlation (r = 0.74), suggesting that each sequence offers different and complementary information. CONCLUSIONS: Using localized biopsies, we have generated a model that illustrates a quantitative and significant relationship between MR signal and cell density. Projecting this relationship over the entire tumor volume allows mapping of the intratumoral heterogeneity in both the contrast-enhancing tumor core and nonenhancing margins of glioblastoma and may be used to guide extended surgical resection, localized biopsies, and radiation field mapping.

An e-health intervention to support the transition of young people with long-term illnesses to adult healthcare services: Design and early use.

OBJECTIVE: Co-design information and website to support adolescents and young adults with long-term illnesses in their transition to adult healthcare. METHODS: A participatory iterative process involving a survey (n=207), twenty-one interviews, six participatory workshops, six video recordings, two advisory groups, and a co-design group to identify needs and preferences for e-health and information provision, was used to develop an appropriate intervention. RESULTS: Adolescents and young people expressed preferences for information that was trustworthy, empowering, colorful, easily downloaded online and written using non-patronizing language. They desired video testimonials of experiences from young adults who had transitioned to adult healthcare and wanted advice about becoming more independent, managing their condition, preparing for the transition, and information about medications and the differences between child and adult healthcare. They also wanted information about the location and configuration of adult healthcare, key hospital personnel, and frequently asked questions. CONCLUSION: The participatory iterative process led to the development of an online resource specifically tailored to the adolescents and young people's transition needs and information preferences. Preliminary feedback indicates that it is a valued resource. PRACTICE IMPLICATIONS: The www.SteppingUP.ie website has the potential to help prepare its target population group for the transition to adult healthcare.

Hormone replacement therapy in a postmenopausal woman with epilepsy.

OBJECTIVE: To prospectively evaluate the effects of hormone replacement therapy (HRT) on seizure activity in a postmenopausal woman with epilepsy. BACKGROUND: Postmenopausal women are at an increased risk for cardiovascular disease and osteoporosis secondary to a lack of estrogen's protective effects. As a result, women without known contraindications often take HRT to counteract this risk. Postmenopausal women with epilepsy are at a greater risk for osteoporosis because of the negative effects that certain antiepileptic drugs have on bone density. Clinical studies and experience have shown that hormonal variances across a woman's lifetime play a significant role in seizure activity, but the effects of HRT in postmenopausal women with epilepsy are unknown. CASE SUMMARY: We report the case of a 51-year-old postmenopausal white woman with epilepsy who presented with frequent vasomotor flushing. To determine individual effects of HRT on seizure activity, therapy was initiated in two three-month phases, with monthly evaluation. A weekly transdermal patch of estradiol 0.1 mg/d was initiated for the first three months. During the second three months, the regimen was expanded to include oral medroxyprogesterone acetate 2.5 mg once daily. Antiepileptic medications and their dosages remained constant. HRT was associated with a decreased incidence of seizures, cessation of vasomotor flushing, improved sleep, and a positive impact on the lipid profile. CONCLUSIONS: This case report describing the prospective addition of HRT in a postmenopausal woman with epilepsy suggests that HRT can be initiated in certain women to achieve therapeutic benefits without adversely affecting seizure activity.

Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448.

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.

Glyburide-reversible cardioprotective effects of BMS-180448: functional and energetic considerations.

Adenosine triphosphate (ATP)-sensitive potassium channel openers as a class exert cardioprotective effects, and we can separate vasodilator from glyburide-reversible cardioprotective activity in cromakalim analogs (e.g., BMS-180448). The purpose of this study was to determine the relation between cardiac function, energy status, and cardioprotective effects for BMS-180448 in isolated rat hearts compared with diltiazem. BMS-180448 (1-30 microM) or 0.1-1 microM diltiazem were given 10 min before 25-min global ischemia in rat hearts followed by 30 min of reperfusion. Both compounds significantly increased time to the onset of contracture during ischemia and improved postischemic recovery of contractile function in a concentration-dependent manner. At equivalent cardioprotective concentrations, BMS-180448 depressed preischemic cardiac function significantly less than did diltiazem. During ischemia, diltiazem significantly accelerated the functional decline observed in vehicle-treated hearts, whereas BMS-180448 attenuated the net rate of decline of function. Despite these different effects on preischemic and ischemic cardiac function, diltiazem and BMS-180448 conserved cardiac ATP during ischemia to a similar degree. BMS-180448 enhanced the recovery of ATP (also seen for diltiazem, but not to the same magnitude) and creatine phosphate during reperfusion compared with vehicle-treated hearts. For BMS-180448, this enhanced ATP recovery was accompanied by a significant improvement in the efficiency of oxygen use, which was profoundly reduced in reperfused vehicle-treated hearts. BMS-180448 also significantly enhanced the functional reserve after the 25-min period of global ischemia. Thus BMS-180448 protects ischemic myocardium and conserves ATP with less reduction in cardiac function compared with diltiazem.

KATP-channel openers protect against increased cytosolic calcium during ischaemia and reperfusion.

There is ample evidence that potassium channel openers protect the ischaemic myocardium. Although the protective mechanism is unknown, indirect evidence suggests that potassium channel openers reduce calcium influx during ischaemia which may explain their protective effects. However, recently discovered potassium channel openers such as BMS-180448 are cardioprotective without displaying classical indications of calcium lowering. The current study was designed to provide direct evidence that potassium channel openers delay or prevent increased intracellular free calcium in the myocardium during ischaemia and reperfusion. Cytosolic calcium concentrations were directly measured in perfused rat hearts during global ischaemia by 19F-NMR of the calcium chelator 5F-BAPTA. The cytosolic Ca2+ concentration in vehicle-treated hearts increased from a pre-ischaemia average of 310 +/- 40 nM to 1000 +/- 130 nM during 25 min of ischaemia, followed by partial recovery to 530 +/- 100 nM during 19 min of reperfusion. In contrast, the cytosolic Ca2+ concentration in hearts treated with potassium channel openers BMS-180448 and cromakalim remained low throughout ischaemia, changing from pre-ischaemia averages of 270 +/- 30 nM to 230 +/- 60 nM and from 240 +/- 20 nM to 170 +/- 30 nM during 25 min of ischaemia, respectively. The cytosolic Ca2+ concentrations in these hearts increased to 440 +/- 110 nM in BMS-180448 treated hearts and 290 +/- 60 nM in cromakalim treated hearts during the first 6 min of reperfusion, and were 460 +/- 60 nM for BMS-180448 and 600 +/- 70 nM for after cromakalim 19 min of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

An electrophysiological investigation of the properties of 5-HT3 receptors of rabbit nodose ganglion neurones in culture.

1. The biophysical and pharmacological properties of 5-hydroxytryptamine (5-HT)-evoked currents in rabbit nodose ganglion neurones in culture have been determined by use of the whole-cell and outside-out membrane patch recording modes of the patch-clamp technique. 2. In 49% of cells investigated the bath application of 10(-5) M 5-HT at negative holding potentials elicited an inward current. The whole-cell response to 5-HT reversed in sign (E5-HT) at approximately -2 mV and exhibited inward rectification. 3. The influence of various ion substitutions upon E5-HT established that the 5-HT-evoked current is mainly mediated by a mixed Na+, K+ cation conductance with little or no contribution from Cl- ions. The omission of Ca2+ and Mg2+ from the extracellular solution enhanced the amplitude of the 5-HT-induced current. 4. On isolated outside-out membrane patches, the bath application of 10(-6) M 5-HT induced single channel currents with a chord conductance of approximately 17 pS at -70 mV and an average slope conductance of 19 pS over the range -100 to -40 mV. The 5-HT-induced single channels exhibited modest inward rectification and were reduced in frequency, but not amplitude, by the 5-HT3 receptor antagonist metoclopramide (10(-6) M). 5. The bath application of 5-HT (3 x 10(-7)-3 x 10(-5) M) to whole cells voltage clamped at -60 mV produced dose-dependent inward currents which were mimicked by 2-methyl-5-HT and 1-phenylbiguanide with equipotent molar ratios, relative to 5-HT, of 2.5 and 32 respectively. 6. Whole-cell inward currents produced by the local pressure application of 5-HT (10(-5) M) were unaffected by 10(-6) M methysergide, 10(-6) M ketanserin or 10(-6) M citalopram, but were concentration-dependently antagonized by the selective 5-HT3 receptor antagonists tropisetron (IC50 = 4.6 x 10(-11) M) ondansetron (IC50 = 5.7 x 10(-11) M), and bemesetron (IC50 = 3.3 x 10(-10) M). The response to 5-HT was also blocked by the non-selective antagonists metoclopramide (IC50 = 1.2 x 10(-8) M), cocaine (IC50 = 8.3 x 10(-8) M) and (+)-tubocurarine (IC50 = 1.6 x 10(-7) M).

Recent advances in the electrophysiological characterization of 5-HT3 receptors.

5-HT3 receptors are ligand-gated, cation-selective ion channels, mediating membrane depolarization and neuronal excitation. Established and potential therapeutic applications of selective 5-HT3 receptor antagonists, coupled with the localization of this receptor subtype within discrete areas of the CNS, have resulted in an intensification of research in this area. In this review, Jeremy Lambert and colleagues summarize recent developments in the electrophysiological characterization of 5-HT3 receptors, and comment upon the unresolved issue of 5-HT3 receptor heterogeneity.

Ketamine potentiates 5-HT3 receptor-mediated currents in rabbit nodose ganglion neurones.

The interaction of ketamine with the 5-HT3 receptor of rabbit nodose ganglion neurones is described. Ketamine (3-30 microM) enhanced 5-HT3 receptor-mediated currents recorded under voltage-clamp conditions. This action did not appear to be related to the known effect of ketamine of inhibiting 5-HT uptake.

Physiological and pharmacological properties of 5-HT3 receptors--a patch clamp-study.

Whole cell and patch clamp techniques were used to investigate the properties of 5-HT3 receptors of a murine neuroblastoma cell line (N1E-115) and adult rabbit nodose ganglion neurones. In addition, some preliminary results from guinea-pig nodose ganglion neurones are presented. In such cells, voltage-clamped at -60 mV, 5-HT (10 microM) induced an inward current associated with a conductance increase. The results of ion substitution experiments suggest that the 5-HT activated ion channel is permeable to both Na+ and K+ ions with a permeability ratio (PNa/PK) of 0.94 and 0.92 for rabbit nodose ganglion cells and N1E-115 cells respectively. On outside out membrane patches excised from rabbit nodose ganglion neurones, 5-HT (1 microM) activated clearly discernible single channel currents with a conductance of 16.6 +/- 0.7 pS (n = 4). In contrast, fluctuation analysis of 5-HT induced whole cell currents suggests that the single channel conductance of N1E-115 cells is only 0.3 pS, a value some 50 fold lower. The 5-HT-induced whole cell currents recorded from all three preparations were antagonised by the selective 5-HT3 receptor antagonist ondansetron (GR38032F) and by the less selective agents metoclopramide, cocaine and (+)-tubocurarine. However, these preparations demonstrate a differential sensitivity to some antagonists. In particular, (+)-tubocurarine was a potent antagonist in N1E-115 cells (IC50 = 0.85 nM) but was approximately 200 fold (IC50 = 156 nM) and 1200 fold (IC50 = 10 microM) less potent in rabbit and guinea-pig nodose ganglion neurones respectively. Additionally, a novel effect of ketamine (10 microM) to potentiate the 5-HT-induced current of rabbit nodose ganglion neurones is described.

Antagonism of 5-HT3 receptor mediated currents in murine N1E-115 neuroblastoma cells by (+)-tubocurarine.

5-HT3 receptor-mediated membrane currents were recorded from voltage-clamped clonal N1E-115 neuroblastoma cells. The inward current response to ionophoretically applied serotonin (5-HT) was reversibly antagonised by the 5-HT3 receptor antagonists GR 38032F and metoclopramide with IC50 values of 0.2 nM and 14 nM, respectively. Low concentrations of (+)-tubocurarine [+)-Tc) also blocked the response to 5-HT (IC50 = 0.8 nM), but other nicotinic cholinoceptor antagonists (gallamine, vecuronium and trimetaphan) were ineffective when applied at a relatively high concentration (1 microM). Blockade by (+)-Tc was neither voltage- nor use-dependent, suggesting that (+)-Tc does not block 5-HT-activated ion channels in N1E-115 cells.