Effectiveness and cost-effectiveness of a brief school-based group programme for parents of children at risk of ADHD: a cluster randomised controlled trial.

BACKGROUND: National Institute for Health and Care Excellence guidelines recommend a stepped care approach for the identification and management of children with, or at risk of, attention-deficit/hyperactivity disorder (ADHD). We investigated the effectiveness, cost-effectiveness and acceptability of a group parenting intervention programme (+/- a teacher session) for children at risk of ADHD. METHODS: In a three-arm cluster randomised controlled trial, 12 primary schools were randomly assigned to control, parent-only and combined (parent + teacher) intervention arms. Eligible children had high levels of parent-rated hyperactivity/inattention (n = 199). At 6 month follow-up, the primary outcome measure was the parent-completed Conners' Rating Scale - Revised (ADHD index). Secondary outcomes included the Conners' sub-scales (hyperactivity, cognitive problems/inattention and oppositional behaviour), the teacher-completed Conners' Rating Scale - Revised, child health-related quality of life, parental burden and parental mental health. The cost-effectiveness analyses reflected a health and personal social services perspective. TRIAL REGISTRATION: ISRCTN87634685. RESULTS: Follow-up data were obtained from 76 parents and 169 teachers. There was no effect of the parent-only (mean difference = -1.1, 95% CI -5.1,2.9; p = 0.57) or combined interventions (mean difference = -2.1, 95% CI -6.4,2.1; p = 0.31) on the ADHD index. The combined intervention was associated with reduced parent-reported hyperactivity symptoms (mean difference = -5.3; 95% CI -10.5,-0.01; p = 0.05) and the parent-only intervention with improved parental mental health (mean difference = -1.9; 95% CI -3.2,-0.5; p = 0.009). The incremental costs of the parent-only and the combined interventions were £73 and £123, respectively. Above a willingness-to-pay of £31 per one-point improvement in the ADHD index, the parent-only programme had the highest probability of cost-effectiveness. Participants found the interventions acceptable. CONCLUSIONS: For children at risk of ADHD, this school-based parenting programme was not associated with improvement in core ADHD symptoms. Secondary analyses suggested a possible reduction in parent-reported hyperactivity and parental mental health problems. Future research should compare targeted interventions against watchful waiting and specialist referral.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Occupational therapy predischarge home visits for patients with a stroke (HOVIS): results of a feasibility randomized controlled trial.

OBJECTIVE: To assess the feasibility of conducting a randomized controlled trial of occupational therapy predischarge home visits for people after stroke. DESIGN: Randomized controlled trial and cohort study. We randomized eligible patients for whom there was clinical uncertainty about the need to conduct a home visit to a randomized controlled trial; patients for whom a visit was judged 'essential' were enrolled into a cohort study. SETTING: Stroke rehabilitation unit of teaching hospital. PARTICIPANTS: One hundred and twenty-six participants hospitalized following recent stroke. INTERVENTIONS: Predischarge home visit or structured, hospital-based interview. MAIN OUTCOME MEASURES: The primary objective was to collect information on the feasibility of a randomized controlled trial, including eligibility, control intervention and outcome assessments. The primary outcome measure was the Nottingham Extended Activities of Daily Living Scale at one month after discharge from hospital. Secondary outcomes included mood, quality of life and costs at one week and one month following discharge. RESULTS: Ninety-three people were allocated to the randomized controlled trial; 47 were randomized to intervention and 46 to control. Thirty-three were enrolled into the cohort study. More people were allocated to the randomized controlled trial as the study progressed. One hundred and thirteen people (90%) received the proposed intervention, although there was a need for stricter protocol adherence. Follow-up was good: at one month 114 (90%) were assessed. There were no significant differences between the groups in the randomized controlled trial for the primary outcome measure at one month. The average cost of a home visit was £208. CONCLUSION: A trial is feasible and warranted given the resource implications of predischarge occupational therapy home visits.

Roles of dopamine D1 and D2 receptors in the acquisition and expression of fat-conditioned flavor preferences in rats.

Sugars and fats elicit innate and learned flavor preferences with the latter mediated by flavor-flavor (orosensory) and flavor-nutrient (post-ingestive) processes. Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC), but not opioid antagonists blocked the acquisition and expression of flavor-flavor preferences conditioned by sugars. In addition, systemic D1, but not D2 or opioid antagonists blocked the acquisition of flavor-nutrient preferences conditioned by intragastric (IG) sugar infusions. Given that DA antagonists reduce fat intake, the present study examined whether systemic D1 or D2 antagonists altered the acquisition and/or expression of conditioned flavor preferences (CFP) produced by pairing one novel flavor (CS+, e.g., cherry) with a 3.5% corn oil (CO: fat) solution relative to another flavor (CS-, e.g., grape) paired with a 0.9% CO solution. In an expression study, food-restricted rats were trained to drink either flavored 3.5% or 0.9% CO solutions on alternate days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), SCH (50-800 nmol/kg) or RAC (50-800 nmol/kg). The rats displayed a robust CS+ preference following VEH treatment (87-88%) the expression of which was attenuated by treatment with moderate doses of RAC, and to a lesser degree, SCH. In an acquisition study, six groups of rats received VEH, SCH (25, 50, 200 nmol/kg) or RAC (50, 200 nmol/kg) 0.5 h prior to 1-bottle training trials with CS+ flavored 3.5% and CS- flavored 0.9% (CS-) CO solutions. A seventh Limited VEH group was trained with its training intakes limited to that of the SCH and RAC groups. Subsequent two-bottle tests were conducted with the CS+ and CS- flavors presented in 0.9% CO without injections. Significant and persistent CS+ preferences were observed in VEH (75-82%), Limited VEH (70-88%), SCH25 (75-84%), SCH50 (64-87%), SCH200 (78-91%) and RAC200 (74-91%) groups. In contrast, the group trained with RAC50 displayed a significant initial CS+ preference (76%) which declined over testing to 61%. These data indicate limited DA D1 and D2 receptor signaling involvement in the expression and acquisition of a fat-CFP relative to previous robust effects for sugar-CFP.

Critical role of NMDA but not opioid receptors in the acquisition of fat-conditioned flavor preferences in rats.

Animals learn to prefer flavors associated with the intake of dietary fats such as corn oil (CO) solutions. We previously reported that fat-conditioned flavor preferences in rats were relatively unaffected by systemic treatment with dopamine D1 and D2 antagonsits. The present study examined whether systemic opioid (naltrexone, NTX) or NMDA (MK-801) receptor antagonists altered the acquisition and/or expression of CO-CFP. The CFP was produced by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in a 3.5% CO solution and another flavor (CS-, e.g., grape) in a 0.9% CO solution. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 d. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), NTX (0.1-5 mg/kg) or MK-801 (50-200 µg/kg). Rats displayed a robust CS+ preference following VEH treatment (85-88%) which was significantly though moderately attenuated by NTX (69-70%). The lower doses of MK-801 slightly reduced the CS+ preference; the high dose blocked the CS+ preference (49%) but also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH or NTX (0.1, 0.5, 1mg/kg) or MK-801 (100 µg/kg) 0.5h prior to 1-bottle training trials with CS+/3.5% CO and CS-/0.9% CO training solutions. Additional Limited VEH groups were trained with intakes limited to that of the NTX and MK-801 groups. Subsequent two-bottle CS+ vs. CS- tests were conducted without injections. Significant and persistent CS+ preferences were observed in VEH (77-84%) and Limited VEH (88%) groups. NTX treatment during training failed to block the acquisition of CO-CFP although the magnitude of the CS+ preference was reduced by 0.5 (70%) and 1.0 (72%) mg/kg doses relative to the Limited VEH treatment (88%). In contrast, MK-801 (100 µg/kg) treatment during training blocked the acquisition of the CO-CFP. These data suggest a critical role for NMDA, but not opioid receptor signaling in the acquisition of a fat conditioned flavor preferences, and at best limited involvement of NMDA and opioid receptors in the expression of a previously learned preference.

Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft.

Composite facial allotransplantation is emerging as a treatment option for severe facial disfigurements. The technical feasibility of facial transplantation has been demonstrated, and the initial clinical outcomes have been encouraging. We report an excellent functional and anatomical restoration 1 year after face transplantation. A 59-year-old male with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore midfacial form and function. An initial potent antirejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient demonstrated facial redness during the initial postoperative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life. Composite facial allotransplantation, along with minimal and well-tolerated immunosuppression, was successfully utilized to restore facial form and function in a patient with severe disfigurement of the midface.

c-Fos induction in mesotelencephalic dopamine pathway projection targets and dorsal striatum following oral intake of sugars and fats in rats.

Overconsumption of nutrients high in fats and sugars can lead to obesity. Previous studies indicate that sugar or fat consumption activate individual brain sites using Fos-like immunoreactivity (FLI). Sugars and fats also elicit conditioned flavor preferences (CFP) that are differentially mediated by flavor-flavor (orosensory: f/f) and flavor-nutrient (post-ingestive: f/n) processes. Dopamine (DA) signaling in the medial prefrontal cortex (mPFC), the amygdala (AMY) and the nucleus accumbens (NAc), has been implicated in acquisition and expression of fat- and sugar-CFP. The present study examined the effects of acute consumption of fat (corn oil: f/f and f/n), glucose (f/f and f/n), fructose, (f/f only), saccharin, xanthan gum or water upon simultaneous FLI activation of DA mesotelencephalic nuclei (ventral tegmental area (VTA)) and projections (infralimbic and prelimbic mPFC, basolateral and central-cortico-medial AMY, core and shell of NAc as well as the dorsal striatum). Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell. Glucose intake significantly increased FLI in both AMY areas, dorsal striatum and NAc core, but not in either mPFC area, VTA or Nac shell. Correspondingly, fructose intake significantly increased FLI in the both AMY areas, the infralimbic mPFC and dorsal striatum, but not the prelimbic mPFC, VTA or either NAc area. Saccharin and xanthan gum intake failed to activate FLI relative to water. When significant FLI activation occurred, highly positive relationships were observed among sites, supporting the idea of activation of a distributed brain network mediating sugar and fat intake.

Platelet-free calcium and vascular calcium uptake in ethanol-induced hypertensive rats.

This study examined the effect of moderate ethanol intake on systolic blood pressure, platelet cytosolic free calcium, aortic calcium, and rubidium-86 uptake in Wistar-Kyoto rats. Twelve Wistar-Kyoto rats, aged 6 weeks, were given 5% ethanol in drinking water the first week followed by 10% ethanol in drinking water for the next 6 weeks. Twelve control animals were given regular tap water. Systolic blood pressure in the ethanol-treated rats was significantly higher (p less than 0.05) than that in controls after 1 week and remained higher throughout the study. At 13 weeks of age, platelet cytosolic free calcium and calcium uptake by aortas were significantly higher (p less than 0.001) in ethanol-treated animals as compared with those in controls. Ethanol intake did not affect aortic ouabain-sensitive 86Rb uptake. The in vitro effect of ethanol on calcium-45 and 86Rb uptake was also investigated in aortas of untreated Wistar-Kyoto rats at 13 weeks of age. In vitro ethanol (2.5-20 mmols/l) did not significantly affect 45Ca and 86Rb uptake in rat aortas. The increases in systolic blood pressure, platelet cytosolic free calcium, and vascular calcium uptake suggest that increases in cytosolic free calcium and calcium uptake mechanisms are associated with ethanol-induced hypertension.

Deuterium oxide normalizes blood pressure and vascular calcium uptake in Dahl salt-sensitive hypertensive rats.

This study examined the effect of 25% deuterium oxide in drinking water on systolic blood pressure, uptakes of calcium, and rubidium 86 by aortas of Dahl salt-sensitive rats on 0.4% (low) and 8% (high) sodium chloride (salt) diet. Twenty-four rats were divided into four groups. Groups I and II were on the low salt diet and groups III and IV on the high salt diet from 6 weeks of age. Additionally, at 10 weeks of age groups I and III were placed on 100% water and groups II and IV on 25% deuterium oxide. At 14 weeks, systolic blood pressure, uptakes of calcium, and rubidium 86 by aortas were significantly higher (p less than 0.01) in rats on the high salt diet as compared with those on the low salt diet. Deuterium oxide intake normalized systolic blood pressure and aortic calcium uptake but not aortic rubidium 86 uptake in hypertensive rats on the high salt diet. Deuterium oxide had no effect on blood pressure or aortic calcium uptake in rats on the low salt diet. The parallel increase in systolic blood pressure and vascular calcium uptake suggests that increased calcium uptake mechanisms are associated with hypertension in salt-sensitive Dahl rats. Furthermore, deuterium oxide appears to normalize elevated blood pressure in salt-sensitive hypertensive rats by normalizing elevated vascular (aortic) calcium uptake.

Deuterium oxide prevents hypertension and elevated cytosolic calcium in hypertensive rats.

Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium, has been implicated in the pathophysiology of hypertension. This study examined the dose-dependent effect of deuterium oxide (5%, 10%, or 20% in drinking water) on systolic blood pressure, aortic calcium uptake, and platelet cytosolic free calcium in spontaneously hypertensive rats. Starting at age 8 weeks, spontaneously hypertensive rats were divided into four groups of six animals each. The drinking water of groups 1, 2, 3, and 4 was replaced by 100% water and 5%, 10%, and 20% deuterium oxide in water, respectively, for another 7 weeks. Ten Wistar-Kyoto rats, age 8 weeks, were given 100% water for the next 7 weeks. The usual increase in systolic blood pressure and the associated increase in aortic calcium uptake and platelet cytosolic free calcium in spontaneously hypertensive rats at age 15 weeks was lowered in a dose-dependent manner by deuterium oxide. Deuterium oxide also prevented renal vascular changes in spontaneously hypertensive rats. A minimum dose of 10% deuterium oxide was needed to completely prevent the development of hypertension, elevated aortic calcium uptake, platelet cytosolic free calcium, and renal vascular changes in spontaneously hypertensive rats.

Transforming growth factor-beta has contrasting effects in the presence or absence of exogenous interleukin-12 on the in vitro activation of cells that transfer experimental autoimmune thyroiditis.

Mouse thyroglobulin (MuTg)-sensitized spleen cells activated in vitro with MuTg induce experimental autoimmune thyroiditis (EAT) in recipient mice with a thyroid infiltrate consisting primarily of lymphocytes. A more severe and histologically distinct granulomatous form of EAT (G-EAT) is induced when donor cells are activated with MuTg together with anti-interferon-gamma (IFN-gamma), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and often has inhibitory effects on lymphocytes. To determine if TGF-beta could modulate the in vitro activation of effector cells for G-EAT, TGF-beta was added to cultures of MuTg-sensitized donor spleen cells together with MuTg. Cells activated in the presence of 2 ng/ml TGF-beta induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-beta was histologically similar but less severe than the G-EAT induced by cells activated in the presence of IL-12. IL-12 and TGF-beta modulate the activation of G-EAT effector cells by distinct mechanisms, as cells activated by TGF-beta could induce G-EAT in the presence of anti-IL-12, and TGF-beta inhibited the effects of IL-12 on EAT effector cells. TGF-beta exerted its activity during the first 24 h of the 72-h culture, whereas IL-12 functioned primarily during the final 24 h of culture. These results indicate that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-beta can exert both positive and negative effects on the effector cells for G-EAT.

Radiation fractionation sensitivity of epiphyseal cartilage in a weanling rat model.

Tibial growth at 100 days of age was measured in Sprague-Dawley rats treated at 21 days to the proximal tibia with various courses of fractionated radiation. In split-dose and multiple-fraction experiments, a minimum interval of 5-6 hr was required to achieve maximal sparing of growth arrest. Total doses required to reduce growth to 80% of untreated controls were computed from dose-response curves for fractionated radiation (dose/fraction 1.0-10 Gy). When fitted to a linear-quadratic model of radiation response the data described an estimated alpha/beta of 4.47 (95% C.I. (3.71, 5.23) Gy). This value suggests that the fractionation sensitivity of the epiphyseal plate is substantially greater than that of most neoplasms, predicting a favorable therapeutic gain with the use of hyperfractionated radiation therapy.

Effects of deuterium oxide (D2O) on the development of hypertension and Ca2+ homeostasis in spontaneously hypertensive rats.

Increased calcium uptake in vascular tissues, leading to elevated cytosolic free calcium, has been implicated in the pathophysiology of hypertension. In this study we investigated the in vitro effect of deuterium oxide (D2O) on calcium uptake in Sprague-Dawley (SD) rat aortae as well as the effects of 25% D2O, orally administered to spontaneously hypertensive and Wistar-Kyoto (WKY) rats, on systolic blood pressure and aortic calcium uptake. The high calcium uptake induced by phenylephrine (50 mumols/l) via receptor-operated channels and by KCl (80 mmol/l) via voltage-operated channels in SD rat aortae was effectively reduced by D2O in a concentration-dependent manner. These results suggest that D2O, acting like a calcium channel blocker, effectively normalized vascular calcium uptake mechanisms. When, at 7 weeks of age, spontaneously hypertensive rats were given 25% D2O in their drinking water for a period of 6 weeks, the development of high systolic blood pressures and the associated increases in aortic calcium uptake were effectively prevented. D2O treatment did not affect blood pressures in normotensive WKY rats. The parallel increases in systolic blood pressure and in vascular calcium uptake suggest that increased calcium uptake mechanisms are associated with hypertension. Furthermore, D2O appears to prevent hypertension by normalizing calcium uptake in vascular smooth muscle.

Pentavalent [99mTc]DMSA, [131I]MIBG, and [99mTc]MDP--an evaluation of three imaging techniques in patients with medullary carcinoma of the thyroid.

Nine patients with histologically proven medullary carcinoma of the thyroid (MCT) were imaged using pentavalent [99mTc]dimercaptosuccinic acid [(V)DMSA], [131I] metaiodobenzylguanidine (MIBG) and [99mTc]methylene diphosphonate (MDP). Technetium-99m (V)DMSA demonstrated most of the tumor sites in eight patients with proven metastases, with an overall sensitivity of 95% in lesion detection. Iodine-131 MIBG showed definite uptake in some of the tumor sites in three of the nine patients imaged, with equivocal uptake seen in a further one patient, with sensitivity of only 11% for lesion detection. Technetium-99m MDP demonstrated bony metastases only, in four of the patients imaged yielding a sensitivity of 61%. Technetium-99m (V)DMSA has been demonstrated in this study to be a useful imaging agent in patients with MCT, showing uptake in significantly more lesions and with better imaging qualities than [131I]MIBG, and with the ability to detect soft tissue as well as bony metastases.

Genetic analysis of the complete gag and env genes of HIV type 1 subtype C primary isolates from South Africa.

South Africa has one of the fastest growing HIV-1 epidemics, with an estimated 4.7 million people infected. To better understand the genetic diversity of this epidemic and its potential impact on vaccine development, we have cloned and sequenced the complete gag and env genes of 13 primary virus isolates. Phylogenetic analysis of our sequences and 69 complete env genes from the Los Alamos and GenBank databases revealed multiple subclusters within subtype C. The V3 loop region was relatively conserved in all our strains when compared with other subtypes, but the region immediately downstream was highly variable. No intersubtype recombinant forms were observed when comparing the gag and env sequences. Characterization of the complete gag and env genes enabled us to select specific strains for further vaccine development.