Effect of an attentional strategy on movement-related potentials recorded from subjects with Huntington's disease

Huntington's disease patients perform automatic movements in a bradykinetic manner, somewhat similar to patients with Parkinson's disease. Cortical activity relating to the preparation of movement in Parkinson's disease is significantly improved when a cognitive strategy is used. It is unknown whether patients with Huntington's disease can utilise an attentional strategy, and what effect this strategy would have on the premovement cortical activity. Movement-related potentials were recorded from 12 Huntington's disease patients and controls performing externally cued finger tapping movement, allowing an examination of cortical activity related to movement performance and bradykinesia in this disease. All subjects were tested in two conditions, which differed only by the presence or absence of the cognitive strategy. The Huntington's disease group, unlike controls, did not produce a rising premovement potential in the absence of the strategy. The Huntington's disease group did produce a rising premovement potential for the strategy condition, but the early slope of the potential was significantly reduced compared with the control group's early slope. These results are similar to those found previously with Parkinson's disease patients. The strategy may have put the task, which previously might have been under deficient automatic control, under attentional control. (C) 2002 Movement Disorder Society.

Movement-related potentials in Huntington's disease: movement preparation and execution

Movement-related potentials (MRPs) reflect increasing cortical activity related to the preparation and execution of voluntary movement. Execution and preparatory components may be separated by comparing MRPs recorded from actual and imagined movement. Imagined movement initiates preparatory processes, but not motor execution activity. MRPs are maximal over the supplementary motor area (SMA), an area of the cortex involved in the planning and preparation of movement. The SMA receives input from the basal ganglia, which are affected in Huntington's disease (HD), a hyperkinetic movement disorder. In order to further elucidate the effects of the disorder upon the cortical activity relating to movement, MRPs were recorded from ten HD patients, and ten age-matched controls, whilst they performed and imagined performing a sequential button-pressing task. HD patients produced MRPs of significantly reduced size both for performed and imagined movement. The component relating to movement execution was obtained by subtracting the MRP for imagined movement from the MRP for performed movement, and was found to be normal in HD. The movement preparation component was found by subtracting the MRP found for a control condition of watching the visual cues from the MRP for imagined movement. This preparation component in HD was reduced in early slope, peak amplitude, and post-peak slope. This study therefore reported abnormal MRPs in HD. particularly in terms of the components relating to movement preparation, and this finding may further explain the movement deficits reported in the disease.

Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins

Juvenile idiopathic arthritis reflects a group of clinically heterogeneous arthritides hallmarked by elevated concentrations of circulating immune complexes. In this study, the circulating immune complex proteome was examined to elucidate disease-associated proteins that are overexpressed in patients with an aggressive, and at times destructive, disease phenotype. To solve this proteome, circulating immune complexes were isolated from the sera of patients with chronic, erosive or early-onset, aggressive disease and from patients in medical remission or healthy controls subsequent to protein separation by 2-DE. Thirty-seven protein spots were overexpressed in the circulating immune complexes of the aggressive disease groups as compared to controls, 28 of which have been confidently identified to date. Proteolytic fragments of glyceraldehyde-3-phosphate dehydrogenase, serotransferrin, and a-1-antitrypsin have been identified among others. In total, these 28 putative disease-associated proteins most definitely contribute to immune complex formation and likely have a significant role in disease etiology and pathogenesis. Moreover, these proteins represent markers of aggressive disease, which could aid in diagnosis and management strategies, and potential therapeutic targets to prevent or control disease outcome. This is the first in-depth analysis of the circulating immune complex proteome in juvenile idiopathic arthritis.

Attention deficits in Alzheimer's disease and vascular dementia

OBJECTIVE:

To compare the performance of patients with mild-moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of information processing and attention.

METHOD:

Patients with AD (n=75) and VaD (n=46) were recruited from a memory clinic along with dementia-free participants (n=28). They underwent specific tests of attention from the Cognitive Drug Research battery, and pen and paper tests including Colour Trails A and B and Stroop. All patients had a CT brain scan that was independently scored for white-matter change/ischaemia.

RESULTS:

Attention was impaired in both AD and VaD patients. VaD patients had more impaired choice reaction times and were less accurate on a vigilance test measuring sustained attention. Deficits in selective and divided attention occurred in both patient groups and showed the strongest correlations with Mini Mental State Examination scores.

CONCLUSION:

This study demonstrates problems with the attentional network in mild-moderate AD and VaD. The authors propose that attention should be tested routinely in a memory clinic setting.

Peptide DV-28 amide: Prototype of a novel class of bradykinin receptor antagonist isolated from the defensive skin secretion of bombinid toads

Kinestatin, isolated from the skin of the Chinese toad, Bombina maxima, was the first bradykinin B2 receptor antagonist identified in amphibians. Molecular cloning established that it is co-encoded with the bradykinin-related peptide, maximakinin, within one of several skin kininogens. To examine other species within the genus Bombina for the presence of structural homologues of kinestatin, we subjected skin secretion of the toad, Bombina orientalis, to HPLC fractionation with subsequent bioassay of fractions for antagonism of bradykinin activity using an isolated rat tail artery smooth muscle preparation. A single fraction was located that inhibited bradykinin-induced relaxation of rat arterial smooth muscle and MALDI-TOF analysis of this fraction revealed that it contained a single peptide of molecular mass 3198.5 Da. Further primary structural analysis of this peptide showed that it was a 28-mer with an N-terminal Asp (D) residue and a C-terminal Val (V) residue that was amidated. The peptide was named DV-28 amide in accordance with these primary structural attributes. Synthetic DV-28 amide replicated the observed bradykinin antagonistic effect within the smooth muscle bioassay in a dose-dependent manner. In addition, it was observed to inhibit the proliferation of human microvessel endothelial cells (HMECs) as assessed by MTT assay. Bioinformatic analysis revealed that DV-28 amide was, like kinestatin, co-encoded with a bradykinin receptor agonist on one of two skin kininogens identified in B. orientalis. DV-28 amide thus represents a novel class of bradykinin antagonist from skin secretions of bombinid toads that appear to be a rich source of such novel peptides.

Executive functioning in Alzheimer's disease and vascular dementia

Objective: To compare performance of patients with mild-moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of executive functioning and working memory.

Methods: Patients with AD (n = 76) and VaD (n = 46) were recruited from a memory clinic along with dementia free participants (n = 28). They underwent specific tests of working memory from the Cognitive Drug Research (CDR) battery and pen and paper tests of executive function including CLOX 1 & 2, EXIT25 and a test of verbal fluency (COWAT). All patients had a CT brain scan which was independently scored for white matter change/ischaemia.

Results: The AD and VaD groups were significantly impaired on all measures of working memory and executive functioning compared to the disease free group. There were no significant differences between the AD and VaD groups on any measure. Z-scores confirmed the pattern of impairment in executive functioning and working memory was largely equivalent in both patient groups. Small to moderate correlations were seen between the MMSE and the neurocognitive scores in both patient groups and the pattern of correlations was also very similar in both patient groups.

Conclusions: This study demonstrates sizeable executive functioning and working memory impairments in patients with mild-moderate AD and VaD but no significant differences between the disease groups. Copyright (C) 2009 John Wiley & Sons, Ltd.

Maternal Glucose at 28 Weeks of Gestation Is Not Associated With Obesity in 2-Year-Old Offspring:The Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Family Study

OBJECTIVE:Diabetes during pregnancy is a strong risk factor for obesity in the offspring, but the age at which this association becomes apparent is unknown. The purpose of this study was to examine the relation of glycemia during pregnancy with anthropometry in offspring of nondiabetic pregnant women from the Belfast U.K. center of the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.
RESEARCH DESIGN AND METHODS: Women from the HAPO Study were invited to participate in follow-up of their offspring aged 2 years. Measurements included height, weight, and thickness of triceps, subscapular, and suprailiac skinfolds. RESULTS: A total of 1,165 offspring (73% of eligible children; 598 boys and 567 girls) were seen from ages 22-30 completed months. The only association that reached statistical significance was between categories of maternal 1-h glucose and BMI Z score =85th percentile at 2 years (P = 0.017). Overall the correlations between maternal glucose during pregnancy and BMI Z score at age 2 years were weak (fasting glucose r = 0.05, P = 0.08; 1-h glucose r = 0.04, P = 0.22; 2-h glucose r = 0.03, P = 0.36; and area under the curve for glucose r = 0.04, P = 0.18).
CONCLUSIONS: This study found little association between maternal glucose during pregnancy and obesity in the offspring at this young age. These findings are not unexpected given that study results for young offspring whose mothers had diabetes during pregnancy were indistinguishable from those for normal offspring at this age. It will be interesting to see whether, as these children age, maternal glucose during pregnancy in the ranges included in the HAPO Study will be associated with obesity in their children. © 2010 by the American Diabetes Association.

A novel reciprocal and biphasic relationship between membrane cholesterol and beta-secretase activity in SH-SY5Y cells and in human platelets.

Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the A beta peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane beta-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane beta-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y beta-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane beta-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment.

Melanism and disease resistance in insects

There is growing evidence that insects in high-density populations invest relatively more in pathogen resistance than those in low-density populations (i.e. density-dependent prophylaxis). Such increases in resistance are often accompanied by cuticular melanism, which is characteristic of the high-density form of many phase polyphenic insects. Both melanism and pathogen resistance involve the prophenoloxidase enzyme system. In this paper the link between resistance, melanism and phenoloxidase activity is examined in Spodoptera lanae. In S. exempta, cuticular melanism was positively correlated with phenoloxidase activity in the cuticle, haemolymph and midgut. Melanic S. exempta larvae were found to melanize a greater proportion of eggs of the ectoparasitoid Euplectrus laphygmae than non-melanic larvae, and melanic S. littoralis were more resistant to the entomopathogenic fungus Beauveria bassiana (in S. exempta the association between melanism and fungal resistance was non-signficant). These results strengthen the link between melanism and disease resistance and implicate the involvement of phenoloxidase.

BACE1 mRNA Expression in Alzheimer's Disease Postmortem Brain Tissue

ß-site AßPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-ß (Aß) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD.

A20 Regulation of NF-{kappa}B: Perspectives for Inflammatory Lung Disease.

Persistent activation of NF-B is central to the pathogenesis of many inflammatory lung disorders including Cystic Fibrosis, Asthma and Chronic Obstructive Pulmonary Disease. A20 is an endogenous negative regulator of NF-B signalling which has been widely described in autoimmune and inflammatory disorders including Diabetes and Crohn’s disease, but which has received little attention in terms of chronic lung disorders. This review examines the existing body of research on A20 regulation of NF-B signalling and details the mechanism and regulation of A20 action focusing, where possible, on pulmonary inflammation. A20 and its associated signalling molecules are highlighted as being of potential therapeutic interest for the treatment of inflammatory disorders and a proposed model of A20 activity in inflammatory lung disease is provided.

Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia

Background: This is an update of a previous review (McGuinness 2006). Hypertension and cognitive impairment are prevalent in older people. Hypertension is a direct risk factor for vascular dementia (VaD) and recent studies have suggested hypertension impacts upon prevalence of Alzheimer's disease (AD). Therefore does treatment of hypertension prevent cognitive decline?
Objectives: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease.
Search strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 13 February 2008 using the terms: hypertens$ OR anti-hypertens$. Selection criteria: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months.
Data collection and analysis: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life.
Main results: Four trials including 15,936 hypertensive subjects were identified. Average age was 75.4 years. Mean blood pressure at entry across the studies was 171/86 mmHg. The combined result of the four trials reporting incidence of dementia indicated no significant difference between treatment and placebo (236/7767 versus 259/7660, Odds Ratio (OR) = 0.89, 95% CI 0.74, 1.07) and there was considerable heterogeneity between the trials. The combined results from the three trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.42, 95%CI 0.30, 0.53). Both systolic and diastolic blood pressure levels were reduced significantly in the three trials assessing this outcome (WMD = -10.22, 95% CI -10.78, -9.66 for systolic blood pressure, WMD = -4.28, 95% CI -4.58, -3.98 for diastolic blood pressure). Three trials reported adverse effects requiring discontinuation of treatment and the combined results indicated no significant difference (OR = 1.01, 95% CI 0.92, 1.11). When analysed separately, however, more patients on placebo in Syst Eur 1997 were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the four studies. Analysis of the included studies in this review was problematic as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen.
Authors' conclusions: There is no convincing evidence fromthe trials identified that blood pressure lowering in late-life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients who received active treatment. This introduced bias. More robust results may be obtained by conducting a meta-analysis using individual patient data.

Age-related changes in energy efficiency of gait, activity, and participation in children with cerebral palsy

Aim
The aim of this study was to use a prospective longitudinal study to describe age-related trends in energy efficiency during gait, activity, and participation in ambulatory children with cerebral palsy (CP).

Method
Gross Motor Function Measure (GMFM), Paediatric Evaluation of Disability Inventory (PEDI), and Lifestyle Assessment Questionnaire-Cerebral Palsy (LAQ-CP) scores, and energy efficiency (oxygen cost) during gait were assessed in representative sample of 184 children (112 male; 72 female; mean age 10y 9mo; range 4–16y) with CP. Ninety-four children had unilateral spastic CP, 84 bilateral spastic CP, and six had other forms of CP. Fifty-seven were classified as Gross Motor Function Classification System (GMFCS) level I, 91 as level II, 22 as level III, and 14 as level IV). Assessments were carried out on two occasions (visit 1 and visit 2) separated by an interval of 2 years and 7 months. A total of 157 participants returned for reassessment.

Results
Significant improvements in mean raw scores for GMFM, PEDI, and LAQ-CP were recorded; however, mean raw oxygen cost deteriorated over time. Age-related trends revealed gait to be most inefficient at the age of 12 years, but GMFM scores continued to improve until the age of 13 years, and two PEDI subscales to age 14 years, before deteriorating (p<0.05). Baseline score was consistently the single greatest predictor of visit 2 score. Substantial agreement in GMFCS ratings over time was achieved (?lw=0.74–0.76).

Interpretation
These findings have implications in terms of optimal provision and delivery of services for young people with CP to maximize physical capabilities and maintain functional skills into adulthood.