Event related potential (ERP) evidence for selective impairment of verbal recollection in abstinent recreational methylenedioxymethamphetamine (“Ecstasy”)/polydrug users

Objectives Ecstasy is a recreational drug whose active ingredient, 3,4-methylenedioxymethamphetamine (MDMA), acts predominantly on the serotonergic system. Although MDMA is known to be neurotoxic in animals, the long-term effects of recreational Ecstasy use in humans remain controversial but one commonly reported consequence is mild cognitive impairment particularly affecting verbal episodic memory. Although event-related potentials (ERPs) have made significant contributions to our understanding of human memory processes, until now they have not been applied to study the long-term effects of Ecstasy. The aim of this study was to examine the effects of past Ecstasy use on recognition memory for both verbal and non-verbal stimuli using ERPs. Methods We compared the ERPs of 15 Ecstasy/polydrug users with those of 14 cannabis users and 13 non-illicit drug users as controls. Results Despite equivalent memory performance, Ecstasy/polydrug users showed an attenuated late positivity over left parietal scalp sites, a component associated with the specific memory process of recollection. Conlusions This effect was only found in the word recognition task which is consistent with evidence that left hemisphere cognitive functions are disproportionately affected by Ecstasy, probably because the serotonergic system is laterally asymmetrical. Experimentally, decreasing central serotonergic activity through acute tryptophan depletion also selectively impairs recollection, and this too suggests the importance of the serotonergic system. Overall, our results suggest that Ecstasy users, who also use a wide range of other drugs, show a durable abnormality in a specific ERP component thought to be associated with recollection.

Refractive error and visual impairment in school children in Northern Ireland

To describe the prevalence of refractive error (myopia and hyperopia) and visual impairment in a representative sample of white school children.

Patterns of phonological errors as a function of a phonological versus an articulatory locus of impairment

WWe present the case of two aphasic patients: one with fluent speech, MM, and one with dysfluent speech, DB. Both patients make similar proportions of phonological errors in speech production and the errors have similar characteristics. A closer analysis, however, shows a number of differences. DB's phonological errors involve, for the most part, simplifications of syllabic structure; they affect consonants more than vowels; and, among vowels, they show effects of sonority/complexity. This error pattern may reflect articulatory difficulties. MM's errors, instead, show little effect of syllable structure, affect vowels at least as much as consonants and, and affect all different vowels to a similar extent. This pattern is consistent with a more central impairment involving the selection of the right phoneme among competing alternatives. We propose that, at this level, vowel selection may be more difficult than consonant selection because vowels belong to a smaller set of repeatedly activated units.

Oxidative impairment of plasma and skeletal muscle sarcoplasmic reticulum in rats with adjuvant arthritis - effects of pyridoindole antioxidants

OBJECTIVES: To study possible oxidation of proteins and lipids in plasma and sarcoplasmic reticulum (SR) from skeletal muscles and to assess the effects of pyridoindole antioxidants in rats with adjuvant arthritis (AA) and to analyze modulation of Ca-ATPase activity from SR (SERCA). METHODS: SR was isolated by ultracentrifugation, protein carbonyls in plasma and SR were determined by ELISA. Lipid peroxidation was analyzed by TBARS determination and by mass spectrometry. ATPase activity of SERCA was measured by NADH-coupled enzyme assay. Tryptophan fluorescence was used to analyze conformational alterations. RESULTS: Increase of protein carbonyls and lipid peroxidation was observed in plasma of rats with adjuvant arthritis. Pyridoindole antioxidant stobadine and its methylated derivative SMe1 decreased protein carbonyl formation in plasma, effect of stobadine was significant. Lipid peroxidation of plasma was without any effect of pyridoindole derivatives. Neither protein oxidation nor lipid peroxidation was identified in SR from AA rats. SERCA activity from AA rats increased significantly, stobadine and SMe1 diminished enzyme activity. Ratio of tryptophan fluorescence intensity in SR of AA rats increased and was not influenced by antioxidants. CONCLUSION: Plasma proteins and lipids were oxidatively injured in rats with AA; antioxidants exerted protection only with respect to proteins. In SR, SERCA activity was altered, apparently induced by its conformational changes, as supported by study of tryptophan fluorescence. Stobadine and SMe1 induced a decrease of SERCA activity, elevated in AA rats, but they did not affect conformational changes associated with tryptophan fluorescence.

Anticholinergic medication use and cognitive impairment in the older population:the Medical Research Council cognitive function and ageing study

OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative. DESIGN: A 2-year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993. SETTING: Community-dwelling and institutionalized participants. PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini-Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33-point greater decline in MMSE score (95% confidence interval (CI)=0.03–0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=-0.14–0.11, P=.79). Two-year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30–2.16; P<.001) and possible (OR=1.56; 95% CI=1.36–1.79; P<.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality.

Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Background - Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. Objectives - To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and cognitive impairment in Parkinson’s disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). Search methods - The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly. Reference lists of relevant studies were searched for additional trials. Selection criteria - Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson’s disease (CIND-PD). Data collection and analysis - Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Main results - Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000). For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001). For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial. For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01). For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03). For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). Authors' conclusions - The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

MAP detection for impairment compensation in coherent WDM systems

We propose a novel recursive-algorithm based maximum a posteriori probability (MAP) detector in spectrally-efficient coherent wavelength division multiplexing (CoWDM) systems, and investigate its performance in a 1-bit/s/Hz on-off keyed (OOK) system limited by optical-signal-to-noise ratio. The proposed method decodes each sub-channel using the signal levels not only of the particular sub-channel but also of its adjacent sub-channels, and therefore can effectively compensate deterministic inter-sub-channel crosstalk as well as inter-symbol interference arising from narrow-band filtering and chromatic dispersion (CD). Numerical simulation of a five-channel OOK-based CoWDM system with 10Gbit/s per channel using either direct or coherent detection shows that the MAP decoder can eliminate the need for phase control of each optical carrier (which is necessarily required in a conventional CoWDM system), and greatly relaxes the spectral design of the demultiplexing filter at the receiver. It also significantly improves back-to-back sensitivity and CD tolerance of the system.

Diabetes therapies in renal impairment

Depending on age, duration of diabetes and glycaemic control, 20-40% of patients with type 2 diabetes will incur a moderate or severe deterioration of renal function. This will impact the choice of blood glucose-lowering therapy and require more frequent monitoring of both renal function and glycaemic control. Moderate renal impairment (glomerular filtration rate 30-<60 ml/min) requires consideration of dose reduction or treatment cessation for metformin, glucagon-like peptide-1 receptor agonists, some sulphonylureas and some dipeptidyl peptidase-4 inhibitors. At lower rates of glomerular filtration down to about 15 ml/min it may be appropriate to use a meglitinide, pioglitazone or certain sulphonylureas with careful consideration of dose and co-morbidities. Dipeptidyl peptidase-4 inhibitors can be used at reduced dose in patients with very low rates of glomerular filtration, and linagliptin can be used without dose reduction, and has been used in patients on dialysis. Insulin can be used at any stage of renal impairment, but the regimen and the dose must be suitably adjusted and accompanied by adequate monitoring. © The Author(s), 2012.

Childhood abuse is associated with structural impairment in the ventrolateral prefrontal cortex and aggressiveness in patients with borderline personality disorder

Volume reduction and functional impairment in areas of the prefrontal cortex (PFC) have been found in borderline personality disorder (BPD), particularly in patients with a history of childhood abuse. These abnormalities may contribute to the expression of emotion dysregulation and aggressiveness. In this study we investigated whether the volume of the PFC is reduced in BPD patients and whether a history of childhood abuse would be associated with greater PFC structural changes. Structural MRI data were obtained from 18 BPD patients and 19 healthy individuals matched for age, sex, handedness, and education and were analyzed using voxel based morphometry. The Child Abuse Scale was used to elicit a past history of abuse; aggression was evaluated using the Buss-Durkee Hostility Inventory (BDHI). The volume of the right ventrolateral PFC (VLPFC) was significantly reduced in BPD subjects with a history of childhood abuse compared to those without this risk factor. Additionally, right VLPFC gray matter volume significantly correlated with the BDHI total score and with BDHI irritability and negativism subscale scores in patients with a history of childhood abuse. Our results suggest that a history of childhood abuse may lead to increased aggression mediated by an impairment of the right VLPFC. © 2013 Elsevier Ireland Ltd.

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia

Aim: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Method: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). Results: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. Interpretation: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals. © 2013 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

Gene delivery of the elastase inhibitor elafin protects macrophages from neutrophil elastase-mediated impairment of apoptotic cell recognition

The resolution of inflammation is dependent on recognition and phagocytic removal of apoptotic cells by macrophages. Receptors for apoptotic cells are sensitive to degradation by human neutrophil elastase (HNE). We show in the present study that HNE cleaves macrophage cell surface CD14 and in so doing, reduces phagocytic recognition of apoptotic lymphocytic cells (Mutu 1). Using an improved method of adenovirus-mediated transfection of macrophages with the HNE inbibitor elafin, we demonstrate that elafin overexpression prevents CD14 cleavage and restores apoptotic cell recognition by macrophages. This approach of genetic modification of macrophages could be used to restore apoptotic cell recognition in inflammatory conditions. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Normative contrast sensitivity values for the back-lit Melbourne Edge Test and the effect of visual impairment

Background: The Melbourne Edge Test (MET) is a portable forced-choice edge detection contrast sensitivity (CS) test. The original externally illuminated paper test has been superseded by a backlit version. The aim of this study was to establish normative values for age and to assess change with visual impairment. Method: The MET was administered to 168 people with normal vision (18-93 years old) and 93 patients with visual impairment (39-97 years old). Distance visual acuity (VA) was measured with a log MAR chart. Results: In those eyes without disease, MET CS was stable until the age of 50 years (23.8 ± .7 dB) after which it decreased at a rate of ≈1.5 dB per decade. Compared with normative values, people with low vision were found to have significantly reduced CS, which could not be totally accounted for by reduced VA. Conclusions: The MET provides a quick and easy measure of CS, which highlights a reduction in visual function that may not be detectable using VA measurements. © 2004 The College of Optometrists.

Severe visual impairment due to diabetes mellitus:can this be influenced by community & hospital retinal screening and formal hospital diabetic annual review?

Purpose: Diabetes is a leading cause of visual impairment in working age population in the UK. This study looked at the causes of Severe Visual Impairment(SVI) in the patients attending diabetic eye clinic and influence on the rate of SVI, over a 12 year period, after introducing retinal screening programmes in the hospital and the community in 1993 (review in 1992, 1998 & 2004). Methods: Medical records of all the patients attending the diabetic eye clinic over a period of 5months(April to August) in 1992, 1998 and 2004 were reviewed. The data collected for each patient included age, sex, ethnic origin, diabetes (type,duration &treatment), the best corrected visual acuity (present and at time of presentation), type and duration of retinopathy and attendance record to both diabetic clinic and diabetic eye clinic. In this study, SVI is defined as a visual acuity of 6/36 or worse in at least one eye. Results: In 1992, of a total 245 patients, 58patients(23.6%) had SVI {38 (15.5% of total) due to diabetic retinopathy [31(12.6%) maculopathy, 2(0.8%) vitreous haemorrhage and 5(2%) retinal detachment] and 20(8.1%) due to non–diabetic retinopathy causes}. In 1998, of a total 297, 77patients(25.9%) had SVI {33(11.1% of total) due to diabetic retinopathy [19(6.4%) maculopathy, 9(3%) proliferative retinopathy, 8(2.7%) vitreous haemorrhage and 3(1%) retinal detachment]and 44(14.8%)due to non–diabetic retinopathy}. In 2004, of a total 471, 72patients(15.2%) had SVI{46(9.7%of total) due to diabetic retinopathy [37(7.8%) maculopathy, 1(0.2%) proliferative retinopathy, 6(1.8%) vitreous haemorrhage and 2(0.4%) retinal detachment]and 26(5.5%) due to non– diabetic retinopathy causes}. Conclusions: Introduction of formalised annual diabetic review including retinal screening and a community retinal screening programme has reduced the rate of severe visual impairment due to diabetic retinopathy, in patients attending diabetic eye clinic, from 15.5% in1992 to 9.7% in2004. Keywords: diabetic retinopathy