Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase.

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 µM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.

Porphyrin derivatives as potent and selective blockers of neuronal Kv1 channels.

Selective inhibitors of voltage-activated K(+) channels are needed for the treatment of multiple sclerosis. In this work it was discovered that porphyrins bearing 2-4 carbon alkyl ammonium side chains predominantly blocked the Kv1.1 current whilst Kv1.2 was susceptible to a porphyrin bearing polyamine side chains.

Fragile X-associated tremor/ataxia phenotype in a male carrier of unmethylated full mutation in the FMR1 gene.

The Fragile X syndrome is caused by a CGG repeat expansion >200 in the promoter of the Fragile X mental retardation 1 (FMR1) gene termed full mutation (FM). These alleles are silenced through methylation of the FMR1 promoter, leading to deficit of the FMR1 protein (FMRP), and neurodevelopmental changes. However, occasional FM individuals have a complete lack of methylation, and those typically have only minor deficit of FMRP levels compared with normal controls and their intelligence may be in the normal range. FM alleles are generated through expansion of the CGG repeat from the premutation (PM) range of 55-200 repeats, linked to the late onset Fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder has been attributed to a 'toxicity' of the FMR1 mRNA, which is significantly elevated in male carriers of PM alleles and of unmethylated FM alleles. This is the first report of a 65-year-old male with an unmethylated FM allele and history of alcohol abuse, who developed symptoms of FXTAS. We postulate that, although the elevation of FMR1 transcripts associated with unmethylated FM alleles have a potential to cause FXTAS, in some cases this disorder may occur through an additional effect of exposure to neurotoxicants including alcohol.

White matter changes in basis pontis in small expansion FMR1 allele carriers with parkinsonism.

Examples of white matter hyperintensities (wmh) on magnetic resonance images in a basis pontis are presented in two male carriers, each of whom carry a small CGG expansion fragile X mental retardation (FMR1) allele. One carried a premutation (PM) allele of 85 CGG repeats and the other, a gray zone (GZ) allele of 47 repeats. Both were originally diagnosed with idiopathic Parkinson's disease (iPD). Similar changes are also shown in one PM carrier of 99 repeats affected with mild tremor and imbalance, who was ascertained through a fragile X syndrome family. These examples draw attention to the occurrence of wmh in a basis pontis in the carriers of small CGG expansions presenting with tremor and ataxia. Moreover, the presence of this change in GZ, as well as PM, allele carriers originally diagnosed with iPD supports our earlier suggestion that both these alleles may contribute to the neurodegenerative changes in this disorder which, in the examples presented, have been reflected by wmh, most prominent in the cerebellar peduncles and/or pontine area.

Early intervention for mild cognitive impairment: a randomised controlled trial.

BACKGROUND: Positive effects are reported for memory training for healthy older adults, and yet there is limited information about the benefit of cognitive intervention for older adults with increasing memory difficulties-mild cognitive impairment. OBJECTIVE: To investigate the usefulness of an early cognitive intervention for the memory difficulties experienced by people with amnestic mild cognitive impairment. METHODS: Using a randomised control design, 52 participants with amnestic mild cognitive impairment and their family partners were randomly assigned to a cognitive intervention (memory rehabilitation group) or waitlist (control group). Participants were assessed on primary measures of everyday memory (prospective memory) and memory strategies at 2 weeks' and 4 months' follow-up; secondary measures of contentment with memory and the family participants' knowledge of memory strategies were also assessed. RESULTS: Everyday memory, measured by performance on prospective memory tasks, significantly improved following intervention, although self-appraisal of everyday memory did not demonstrate a similar intervention effect. Knowledge and use of memory strategies also significantly increased following intervention. Furthermore, family knowledge of memory strategies increased following intervention. There was a strong trend towards improvement in contentment with memory immediately following intervention, but this effect was not significant. CONCLUSIONS: Early intervention for memory difficulties in amnestic mild cognitive impairment, using cognitive rehabilitation in compensatory strategies, can assist in minimising everyday memory failures as evaluated by performance on prospective memory tasks and knowledge of memory strategies.

Elaborated spaced-retrieval and prospective memory in mild Alzheimer's disease.

Prospective memory, or the timely remembering of a planned action, is conceptualised as a cognitive process demanding episodic memory and executive attention. Impairments in these skills are characteristic of the cognitive decline in early Alzheimer's disease, providing an expectation of prominent prospective memory difficulties in this population, and yet surprisingly, memory performance in early Alzheimer's disease has rarely been evaluated within a prospective memory framework. In a preliminary study we demonstrated that older adults with early Alzheimer's disease (n=14), as compared to healthy older adults (n=14), were significantly impaired in a simple experimental paradigm of prospective remembering (a text-reading task). In a subsequent intervention study, we investigated the efficacy of spaced-retrieval for improving the prospective remembering performance of older adults with early Alzheimer's disease (n=16) compared to healthy older adults (n=16) under two learning conditions: a spaced-retrieval technique alone or spaced-retrieval combined with elaborated encoding of task. The majority of the Alzheimer's disease group (63%) demonstrated benefit in prospective remembering in the combined condition as compared to spaced-retrieval alone. Participants with Alzheimer's disease who demonstrated better executive attention (Trail Making- set-shifting) and/or better retrospective memory (Hopkins Verbal Learning Test-Revised- recognition) were more successful in the combined learning condition.

Electronic surveillance of wall-mounted soap and alcohol gel dispensers in an intensive care unit.

We describe a battery-powered recording device incorporating a force-sensitive resistor and a microcontroller that records depressions of wall-mounted soap and alcohol gel dispensers. The device has a two-second (2 s) lockout built into it, so that a single record is associated with a single hand-hygiene episode. Recorders were implanted within the wall-mounted dispensers found in two bed areas and the entrance of a 16-bedded intensive care unit. The use of the bed area dispensers was correlated (r) with the dependency of the patient in the open bed area (r=0.5, P<0.01), as assessed using the UK Department of Health critical care minimum data set. Both bed areas and the entrance dispensers showed wide but different fluctuations in use throughout the 24h day. The recording device may help in feedback about soap and gel use for hand-hygiene quality improvement and educational initiatives.

Do executive function deficits differentiate between adolescents with ADHD and oppositional defiant/conduct disorder? A neuropsychological study using the Six Elements Test and Hayling Sentence Completion Test.

Two neuropsychological measures of executive functions--Six Elements Tests (SET) and Hayling Sentence Completion Test (HSCT)--were administered to 110 adolescents, aged 12-15 years. Participants comprised four groups: Attention Deficit Hyperactivity Disorder (ADHD) only (n = 35). ADHD and Oppositional Defiant Disorder/Conduct Disorder (ODD/CD) (n = 38), ODD/CD only (n = 11), and a normal community control group (n = 26). Results indicated that adolescents with ADHD performed significantly worse on both the SET and HSCT than those without ADHD, whether or not they also had ODD/CD. The adolescents with ADHD and with comorbid ADHD and ODD/CD were significantly more impaired in their ability to generate strategies and to monitor their ongoing behavior compared with age-matched controls and adolescents with ODD/CD only. It is argued that among adolescents with clinically significant levels of externalizing behavior problems, executive function deficits are specific to those with ADHD. The findings support the sensitivity of these two relatively new tests of executive functions and their ecological validity in tapping into everyday situations, which are potentially problematic for individuals with ADHD.

A neuropsychological investigation of dementia in motor neurone disease (MND).

Different clinical criteria for diagnosing dementia were compared in a sample of 69 patients with motor neurone disease (MND). Participants' performances on a computerised battery of neuropsychological tests were evaluated to assess the usefulness of these tests in predicting dementia in MND. The results indicated that when diagnostic criteria for frontotemporal (FTD) were used as part of a questionnaire method of diagnosing dementia the incidence of dementia in MND was considerably greater than traditional estimates suggest. Through a series of logistic and multiple regressions the results demonstrated that neuropsychological test performance related well to diagnostic classifications of dementia. MND patients with a clinical diagnosis of dementia were likely to demonstrate impaired new learning; poor working memory and planning; slowness in information processing and rigidity in thinking. These features, which are typical of cases of FTD, suggest that the dementia of MND is usefully characterised as a form of FTD. The finding that neuropsychological impairment correlated with behavioural features of dysexecutive impairment in daily living, indicates that the management focus in MND must be broadened to include cognitive/behavioural issues.

A study of performance of delayed intentions in multiple sclerosis.

The ability to remember and perform delayed intentions was investigated in a sample of 40 participants with Multiple Sclerosis (MS) and compared to a group of 36 healthy, neurologically intact, control participants. Using a model of task division, performance on both the prospective memory (PM) component (a failure to remember to do something at a specific time) and the retrospective memory (RM) component (a failure to remember the content of the intention) of two "naturalistic" delayed intention experimental tasks were examined. Significantly poorer performance of the MS group in completing one of the delayed intention tasks successfully appeared to be primarily attributable to retrospective memory deficits rather than prospective memory deficits. This proposition was further supported by group differences on RAVLT measures of retrospective memory. By utilising a paradigm that enables the nature of failure in performing delayed intention tasks to be identified, specific strategies for the clinical management of MS cognitive deficits can be developed.

Psychological distress and family satisfaction following traumatic brain injury: injured individuals and their primary, secondary, and tertiary carers.

OBJECTIVE: To assess family psychosocial outcome following traumatic brain injury (TBI) in all family members, including relatives more peripheral to the person with the injury. DESIGN: A cross-sectional design was used to gather outcome data from individuals with TBI and primary, secondary, and tertiary carers, 19.3 months posttrauma. Multivariate analyses of variance (ANOVAs) ascertained differences in levels of psychological distress and family satisfaction within families. SETTING AND PARTICIPANTS: Seventy-nine families (65 individuals with TBI, 72 primary carers, 43 secondary carers, and 22 tertiary carers) were drawn from a sample of outpatients of three metropolitan, acute rehabilitation hospitals over a 12-month period. OUTCOME MEASURES: In addition to using the Family Satisfaction Scale (FSS), measures of psychological distress included the Beck Depression Inventory (BDI), State Anxiety Inventory (SAI), and Profile of Mood States (POMS). RESULTS: Although it was noted that a significant proportion of family members were not psychologically distressed and reported good family satisfaction, people with TBI remain at greater risk of poor psychosocial outcome than do their relatives. Of other family members, primary carers-particularly wives-are at greatest risk of poor psychosocial outcome, and a number of secondary and tertiary carers also displayed high levels of psychological distress. CONCLUSIONS: Male relatives (the majority of whom were secondary or tertiary carers) may report their distress in terms of anger and fatigue, rather than as depression and anxiety. Future research could develop TBI-specific measures of anger and fatigue as screening instruments to identify peripheral family members requiring assistance in adapting to TBI. Many families-despite their initial traumatic experience-eventually cope well, encouraging researchers and clinicians to focus future research efforts on those families who have made good adjustments to TBI.

Goal-directed selective attention and response competition monitoring: evidence from unilateral parietal and anterior cingulate lesions.

Competing visual stimuli lead to slower responses to targets. This response competition must be resolved before correct responses are executed. Neuroimaging suggests that response competition monitoring may be subserved by an integrated neural network including the anterior cingulate cortex (ACC). In this study, 1 patient with a parietal lesion (Patient J.S.) and 1 with an ACC lesion (Patient G.M.) were presented with 2 flanker tasks; 1 required verbal identification of color targets, and the other required an opposite response to targets (e.g., see red and say "green"); a control group was also tested. For controls, perceptually incongruent flankers interfered with the ability to inhibit prepotent responses to targets. Patient J.S. performed in a similar manner, even when flankers appeared in the neglected field. Patient G.M. demonstrated reduced interference effects for contralesional flankers. Results are discussed in terms of goal-directed selective attention and response competition monitoring.

Age differences in explicit and implicit memory for pictures.

In the present study, the authors examined age effects in memory for nonverbal material. A picture fragment completion task was used to test explicit and implicit memory in a younger and an older group. Explicit memory was indexed by free recall of pictures, whereas implicit memory was indexed by perceptual learning (priming). Both free recall and perceptual learning performance were found to be impaired in the older group. A measure of executive functioning was found to be predictive of both explicit and implicit memory.

Attentional modulation of implicit processing of information in spatial neglect.

Patients with parietal lesions often fail to identify stimuli in the contralesional field (i.e. neglect) but may nevertheless demonstrate implicit processing of neglected stimuli. Explanations of implicit processing in neglect range from intact preattentive mechanisms, to intact higher level categorical processing. Such theories assume implicit processing in neglect is passive and not subject to attentional modulation. We investigated implicit processing in a neglect patient US) using a flanker task in which targets differed on two dimensions simultaneously (i.e. coloured letters). Controls demonstrated interference effects only from goal-relevant dimensions of flankers. JS showed a similar pattern of results even when flankers appeared in his neglected field, suggesting that implicit processing of neglected stimuli can be modulated by behavioural goals.

Prediction of gait velocity in ambulatory stroke patients during rehabilitation.

OBJECTIVE: To quantify prediction of gait velocity in ambulatory stroke patients during rehabilitation. DESIGN: Single group (n = 42) at the beginning of rehabilitation (Test 1) and 8 weeks later (Test 2). SETTING: Inpatient rehabilitation. PATIENTS: Unilateral first stroke; informed consent; able to walk 10 meters. INDEPENDENT VARIABLES: Gait velocity at Test 1, age, time from stroke to Test 1, side of lesion, neglect. DEPENDENT VARIABLES: Gait velocity at Test 2, gait velocity change. RESULTS: The correlation between initial gait velocity and gait velocity outcome at Test 2 was of moderate strength (r2 = .62, p<.05). However, even at its lowest, the standard error of prediction for an individual patient was 9.4 m/min, with 95% confidence intervals extending over a range of 36.8 m/min. Age was a weak predictor of gait velocity at Test 2 (r2 = -.10, p<.05). Gait velocity change was poorly predicted. The only significant correlations were initial gait velocity (r2 = .10, p<.05) and age (r2 = .10, p<.05). CONCLUSION: While the prediction of gait velocity at Test 2 was of moderate strength on a group basis, the error surrounding predicted values of gait velocity for a single patient was relatively high, indicating that this simple approach was imprecise on an individual basis. The prediction of gait velocity change was poor. A wide range of change scores was possible for patients, irrespective of their gait velocity score on admission to rehabilitation.

The role of the family for behavioral outcome in children and adolescents following traumatic brain injury.

This study assessed the behavioral outcome of 51 children with traumatic brain injury (TBI) up to 2 years following injury. Children with severe injuries, but not those with mild or moderate injuries, were reported by parents to have a greater incidence of behavior problems following TBI. Regression analyses indicated that the presence of a partner for the primary caregiver of the child and the acute emotional reaction of the parent to the injury were both predictive of child behavioral outcome, although not by 2-year follow-up. These findings suggest that parental coping resources may impact on the development of child behavioral sequelae following TBI, emphasizing the role of the family in the child's response and the importance of supportive intervention.

Investigating form and colour perception in blindsight using an interference task.

Patients with striate cortical damage causing a hemianopic field defect can nevertheless demonstrate residual visual capacities in their blind field. Previous research investigating blindsight required patients to respond explicitly to stimuli appearing in the blind field by making forced choice judgements. We present data from a patient with a left occipital lesion resulting in a homonymous hemianopia, using the flanker task. This patient displayed a significant flanker congruency effect (FCE) for colour and letter stimuli even when they appeared in the blind field. A control patient with a lesion of the right thalamus showed no FCE in the blind field. This suggests that thalamo-extrastriate neural pathways are necessary for residual functioning in blindsight.

Predictors and indicators of academic outcome in children 2 years following traumatic brain injury.

Within the context of a longitudinal study investigating outcome for children following traumatic brain injury, this paper reports on the utility of neuropsychological testing in predicting academic outcome in children 2 years following traumatic brain injury (TBI). Twenty-nine school-age children who were admitted to hospital after TBI were assessed with a battery of neuropsychological and academic measures at 3 and 24 months postinjury. The neuropsychological battery included measures of memory, learning, and speed of information processing. Academic outcome was assessed in terms of post-TBI change in school placement. According to logistic regression analysis, change in placement from regular to special education at 2 years post-TBI was predicted by injury severity and by neuropsychological performance at 3 months post-TBI. Findings suggest that neuropsychological testing is useful in identifying children with special educational needs subsequent to TBI.