Bernard V. North

Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial

BACKGROUNDnAggressive challenging behaviour is frequently reported in adults with intellectual disability and it is often treated with antipsychotic drugs. However, no adequate evidence base for this practice exists. We compared flexible doses of haloperidol (a typical, first-generation antipsychotic drug), risperidone (an atypical, second-generation antipsychotic), and placebo, in the treatment of this behaviour.nnnMETHODSn86 non-psychotic patients presenting with aggressive challenging behaviour from ten centres in England and Wales, and one in Queensland, Australia, were randomly assigned to haloperidol (n=28), risperidone (n=29), or placebo (n=29). Clinical assessments of aggression, aberrant behaviour, quality of life, adverse drug effects, and carer uplift (positive feelings about the care of the disabled person) and burden, together with total costs, were recorded at 4, 12, and 26 weeks. The primary outcome was change in aggression after 4 weeks treatment, which was recorded with the modified overt aggression scale (MOAS). Analysis was by intention to treat. This study is registered as ISRCTN 11736448.nnnFINDINGSn80 patients had adherence of 80% or more to prescribed drug. Aggression decreased substantially with all three treatments by 4 weeks, with the placebo group showing the greatest change (median decrease in MOAS score after 4 weeks=9 [95% CI 5-14] for placebo, 79% from baseline; 7 [4-14] for risperidone, 58% from baseline; 6.5 [5-14] for haloperidol, 65% from baseline; p=0.06). Furthermore, although no important differences between the treatments were recorded, including adverse effects, patients given placebo showed no evidence at any time points of worse response than did patients assigned to either of the antipsychotic drugs.nnnINTERPRETATIONnAntipsychotic drugs should no longer be regarded as an acceptable routine treatment for aggressive challenging behaviour in people with intellectual disability.

Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling

OBJECTIVES:Distinguishing between the inflammatory bowel disease (IBD), Crohns disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy.METHODS:NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA).RESULTS:Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort.CONCLUSIONS:Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.

A novel and validated prognostic index in hepatocellular carcinoma: The inflammation based index (IBI)

BACKGROUND & AIMSnOutcome prediction is uniquely different in hepatocellular carcinoma (HCC) as the progressive functional impairment of the liver impacts patient survival independently of tumour stage. As chronic inflammation is associated with the pathogenesis of HCC, we explored the prognostic impact of a panel of inflammatory based scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in independent cohorts.nnnMETHODSnInflammatory markers, Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) scores were studied in a training set of 112 patients with predominantly unresectable HCC (75%). Independent predictors of survival identified in multivariate analysis were validated in an independent cohort of 466 patients with an overall lower tumour burden (BCLC-A, 56%).nnnRESULTSnIn both training and validation sets, mGPS and CLIP scores emerged as independent predictors of overall survival. The predictive accuracy of the combined mGPS and CLIP score (c score 0.7, 95% CI 0.6-0.8) appeared superior to that of the CLIP score alone (c score 0.6, 95% CI 0.5-0.7).nnnCONCLUSIONSnSystemic inflammation as measured by the mGPS, independently predicts overall survival in HCC. We have validated a novel, easy to use inflammatory score that can be used to stratify individuals. These data enable formulation of a new prognostic system, the inflammation based index in HCC (IBI). Further validation of the IBI considering treatment allocation and survival is warranted in an independent patient cohort.

Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID)

OBJECTIVE(S)nTo assess the effects and cost-effectiveness of haloperidol, risperidone and placebo on aggressive challenging behaviour in adults with intellectual disability.nnnDESIGNnA double-blind randomised controlled trial of two drugs and placebo administered in flexible dosage, with full, independent assessments of aggressive and aberrant behaviour, global improvement, carer burden, quality of life and adverse drug effects at baseline, 4, 12 and 26 weeks, and comparison of total care costs in the 6 months before and after randomisation. At 12 weeks, patients were given the option of leaving the trial or continuing until 26 weeks. Assessments of observed aggression were also carried out with key workers at weekly intervals throughout the trial.nnnSETTINGnPatients were recruited from all those being treated by intellectual disability services in eight sites in England, one in Wales and one in Queensland, Australia.nnnPARTICIPANTSnPatients from all severity levels of intellectual disability; recruitment was extended to include those who may have been treated with neuroleptic drugs in the past.nnnEXCLUSION CRITERIAntreatment with depot neuroleptics/another form of injected neuroleptic medication within the last 3 months; continuous oral neuroleptic medication within the last week; those under a section of the Mental Health Act 1983 or Queensland Mental Health Act 2000.nnnINTERVENTIONSnRandomisation to treatment with haloperidol (a typical neuroleptic drug), risperidone (an atypical neuroleptic drug) or placebo using a permuted blocks procedure. Dosages were: haloperidol 1.25-5.0 mg daily; risperidone 0.5-2.0 mg daily.nnnMAIN OUTCOME MEASURESnPrimary: reduction in aggressive episodes between baseline and 4 weeks using Modified Overt Aggression Scale. Secondary: Aberrant Behaviour Checklist; Uplift/Burden Scale; 40-item Quality of Life Questionnaire; Udvalg for Kliniske Undersøgelser scale; Clinical Global Impressions scale. Economic costs recorded using a modified version of Client Service Receipt Inventory for 6 months before and after randomisation.nnnRESULTSnThere were considerable difficulties in recruitment because of ethical and consent doubts. Twenty-two clinicians recruited a total of 86 patients. Mean daily dosages were 1.07 mg rising to 1.78 mg for risperidone and 2.54 mg rising to 2.94 mg for haloperidol. Aggression declined dramatically with all three treatments by 4 weeks, with placebo showing the greatest reduction (79%, versus 57% for combined drugs) (p = 0.06). Placebo-treated patients showed no evidence of inferior response in comparison to patients receiving neuroleptic drugs. An additional study found that clinicians who had not participated in clinical trials before were less likely to recruit. Mean total cost of accommodation, services, informal care and treatment over the 6 months of the trial was 16,336 pounds for placebo, 17,626 pounds for haloperidol and 18,954 pounds for risperidone.nnnCONCLUSIONSnThere were no significant important benefits conferred by treatment with risperidone or haloperidol, and treatment with these drugs was not cost-effective. While neuroleptic drugs may be of value in the treatment of aggressive behaviour in some patients with intellectual disability, the underlying pathology needs to be evaluated before these are given. The specific diagnostic indications for such treatment require further investigation. Prescription of low doses of neuroleptic drugs in intellectual disability on the grounds of greater responsiveness and greater liability to adverse effects also needs to be re-examined.

Overexpression of the mammalian target of rapamycin: a novel biomarker for poor survival in resected early stage non-small cell lung cancer.

Introduction: The best hope of cure for patients with non-small cell lung cancer (NSCLC) is surgical resection. However, even in stage IA patients, 30% die within 5 years. Further improvements in survival require a biomarker(s), which defines the subset of these patients destined to do badly so that they could be targeted for additional therapies. Here, we investigate whether the immunohistochemical expression of a key kinase implicated in lung cancer biology, the mammalian target of rapamycin (mTOR) can predict survival outcome in patients with early stage resected NSCLC. Materials and Methods: One hundred thirty-four patients with resected early stage (IA–IIB) NSCLC were pathologically reviewed centrally before staining for mTOR. Multiple variables including age, sex, stage, angioinvasion, lymph node status, and mTOR staining were assessed by univariate and multivariate analyses. Results: Stage (p = 0.044), lymph node status (p = 0.049), angioinvasion (p = 0.017), and mTOR staining (p = 0.007) were significant univariate predictors of poor survival. However, only angioinvasion (p = 0.016) and mTOR staining (p = 0.046) remained significant after multivariate analysis. Moreover, mTOR staining was the only variable to predict poor outcome in patients who either had negative lymph nodes (p = 0.016) or were stage IA (p = 0.0016). Conclusions: The mTOR staining provides a new biomarker for poor outcome in early stage NSCLC and could enable resected stage IA patients to be selected for novel therapies possibly with an mTOR inhibitor.

Hepatic lipid profiling in chronic hepatitis C: An in vitro and in vivo proton magnetic resonance spectroscopy study

BACKGROUND & AIMSnHepatic steatosis is an important factor in pathogenesis, progression and response to treatment in hepatitis C. We aimed to investigate differences in hepatic lipid composition in liver biopsies from patients with chronic hepatitis C using proton magnetic resonance spectroscopy ((1)H MRS) and to translate these findings to the in vivo clinical setting.nnnMETHODSnTwo cohorts of patients with histologically defined chronic hepatitis C were studied. High-resolution MR spectra were obtained from 47 liver biopsy samples. These data were used to derive biologically relevant prior knowledge for the assignment and interpretation of lower-resolution in vivo hepatic MRS data acquired at 1.5T from a second cohort of 59 patients. MRS data were obtained both in vitro and in vivo from a subset of 11 patients.nnnRESULTSnMultivariate factor analysis demonstrated characteristic MR spectral differences by fibrosis stage and genotype. Total lipid increased with fibrosis stage (r=0.43, p=0.003) and was higher in genotype 3 compared to genotype 1 (p=0.03), while lipid polyunsaturation decreased with increasing fibrosis stage (r=-0.55, p<0.0005) and, independently, with increasing steatosis. Non-invasive assessment using in vivo hepatic (1)H MRS corroborated in vitro findings, but the signal-to-noise ratio was insufficient for reliable assessment of lipid polyunsaturation in vivo.nnnCONCLUSIONSnHepatic lipid composition was analysed using MRS in patients with chronic hepatitis C in vitro and in vivo, demonstrating significant differences in indices by disease severity. High-resolution data informed the analysis and interpretation of in vivo spectra, but further improvements in spectral quality in vivo are required.

Phenotyping murine models of non-alcoholic fatty liver disease through metabolic profiling of intact liver tissue

NAFLD (non-alcoholic fatty liver disease) is a common cause of chronic liver disease associated with the metabolic syndrome. Effective techniques are needed to investigate the potential of animal models of NAFLD. The present study aimed to characterize murine models of NAFLD by metabolic profiling of intact liver tissue. Mice of three strains (BALB/c, C3H and the novel mutant, Gena/263) were fed a control or high-fat diet. Biometric, biochemical and histological analysis demonstrated a spectrum of NAFLD from normal liver to steatohepatitis. Metabolic profiling of intact liver tissue, using (1)H MAS (proton magic angle spinning) MRS (magnetic resonance spectroscopy), showed an increase in the total lipid-to-water ratio, a decrease in polyunsaturation indices and a decrease in total choline with increasing disease severity. Principal components analysis and partial least-squares discriminant analysis showed separation of each model from its control and of each model from the total dataset. Class membership from the whole dataset was predicted with 100% accuracy in six out of eight models. Those models with steatosis discriminated from those with steatohepatitis with 100% accuracy. The separation of histologically defined steatohepatitis from simple steatosis is clinically important. Indices derived from (1)H MAS MRS studies may inform subsequent in vivo MRS studies at lower field strengths.

Right ventricular function in patients with pulmonary hypertension; the value of myocardial performance index measured by tissue Doppler imaging

AIMSnMyocardial performance index (MPI) measured by conventional Doppler is routinely used to assess right ventricular (RV) systolic function in patients with pulmonary hypertension (PH). Our aim was to determine whether MPI measured by Doppler tissue imaging (tMPI) is effective in assessing RV function in these patients.nnnMETHODS AND RESULTSnRetrospectively, we have studied 196 patients with chronic PH [pulmonary arterial systolic pressure (PASP) 81 +/- 40 mmHg] and 37 healthy volunteers (PASP of 27 +/- 7 mmHg). According to the exclusion criteria, 172 patients were included in the final study cohort. All patients were evaluated for RV systolic function by different parameters. MPI was measured by both conventional and tissue Doppler imaging. Bland-Altman analysis showed moderate agreement between MPI and tMPI (the mean difference was -0.02, absolute difference = -0.32 to 0.29; 95% intervals of agreement, percentage of average = -46.6 to 40.8%). In 50 consecutive PH patients where additional parameters were calculated, we found a significant correlation between tMPI and RV ejection fraction (r = -0.73, P< 0.0001) and RV fractional area change (r = -0.58, P< 0.0001). No significant inter- and intra-observer variability was identified.nnnCONCLUSIONnThis study demonstrated a moderate agreement between two methods of measuring MPI. A good correlation of tMPI with RV ejection fraction and RV fractional area change was found indicating that tMPI might be superior to MPI Doppler. tMPI is a parameter unaffected by RV geometry and importantly has the advantage of simultaneously recording the time intervals from the same cardiac cycle.

CCL18 in peritoneal dialysis patients and encapsulating peritoneal sclerosis

Eur J Clin Invest 2010; 40 (12): 1067–1073

Relationship Between Price Paid for Off-Trade Alcohol, Alcohol Consumption and Income in England: A Cross-Sectional Survey

AIMSnIn order to examine the potential impact of an increase in the minimum price per unit of alcohol to 50 pence (