-
[show abstract]
[hide abstract]
ABSTRACT: Retrograde amnesia following electroconvulsive therapy (ECT) is a major concern for both patients and clinicians. In contemporary ECT research, retrograde autobiographical amnesia (RAA) is commonly measured with instruments assessing autobiographical memory (AM) consistency over time. However, normal AM recall loses in consistency with the passage of time, and time has a differential effect on stability of personal memories. In addition, experiencing depression is associated with a decreased ability to recall specific AMs, and this difficulty may persist in the euthymic phase of recurrent depression. Despite these scientific facts, relatively few attempts have been made to accurately measure the specific effect of ECT on AM independent of both normal and mood-associated forgetting over time. This major gap in our knowledge prevents us at present from objectively quantifying the nature and extent of RAA associated with ECT. In turn, this hinders our identifying and implementing strategies for prevention or remediation of AM deficits. The present article aims to provide an up-to-date review and historical perspective of this major methodological conundrum for ECT research, highlight current issues in retrograde amnesia assessment following ECT, and propose directions for future studies. In conclusion, we suggest methods to reliably and specifically measure the extent and progression over time of ECT-associated RAA independently from persistent depressive symptoms' contribution and normal loss in AM consistency over time.
The journal of ECT 01/2013; · 1.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autobiographical amnesia assessments in depression need to account for normal changes in consistency over time, contribution of mood and type of memories measured. We report herein validation studies of the Columbia Autobiographical Memory Interview - Short Form (CAMI-SF), exclusively used in depressed patients receiving electroconvulsive therapy (ECT) but without previous published report of normative data. The CAMI-SF was administered twice with a 6-month interval to 44 healthy volunteers to obtain normative data for retrieval consistency of its Semantic, Episodic-Extended and Episodic-Specific components and assess their reliability and validity. Healthy volunteers showed significant large decreases in retrieval consistency on all components. The Semantic and Episodic-Specific components demonstrated substantial construct validity. We then assessed CAMI-SF retrieval consistencies over a 2-month interval in 30 severely depressed patients never treated with ECT compared with healthy controls (n=19). On initial assessment, depressed patients produced less episodic-specific memories than controls. Both groups showed equivalent amounts of consistency loss over a 2-month interval on all components. At reassessment, only patients with persisting depressive symptoms were distinguishable from controls on episodic-specific memories retrieved. Research quantifying retrograde amnesia following ECT for depression needs to control for normal loss in consistency over time and contribution of persisting depressive symptoms.
Psychiatry Research 03/2012; 197(1-2):41-8. · 2.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Overexpression of neuronal adaptor protein X11β has been shown to decrease the production of amyloid-β, a toxic peptide deposited in Alzheimer's disease brains. Therefore, manipulation of the X11β level may represent a potential therapeutic strategy for Alzheimer's disease. As X11β expression can be regulated at the transcription level, we determined the genomic organization and the promoter of the human X11β gene, amyloid β A4 precursor protein-binding family A member 2 (APBA2). By RNA ligase-mediated rapid amplification of cDNA ends, a single APBA2 transcription start site and the complete sequence of exon 1 were identified. The APBA2 promoter was located upstream of exon 1 and was more active in neurons. The core promoter contains several CpG dinucleotides, and was strongly suppressed by DNA methylation. In addition, mutagenesis analysis revealed a putative Pax5-binding site within the promoter. Together, APBA2 contains a potent neuronal promoter whose activity may be regulated by DNA methylation and Pax5.
Neuroreport 02/2012; 23(3):146-51. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: X11α is a brain specific multi-modular protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). Aggregation of amyloid-β peptide (Aβ), an APP cleavage product, is believed to be central to the pathogenesis of Alzheimer's disease. Recently, overexpression of X11α has been shown to reduce Aβ generation and to ameliorate memory deficit in a transgenic mouse model of Alzheimer's disease. Therefore, manipulating the expression level of X11α may provide a novel route for the treatment of Alzheimer's disease. Human X11α is encoded by the gene APBA1. As evidence suggests that X11α expression can be regulated at transcription level, we have determined the gene structure and cloned the promoter of APBA1. APBA1 spans over 244 kb on chromosome 9 and is composed of 13 exons and has multiple transcription start sites. A putative APBA1 promoter has been identified upstream of exon 1 and functional analysis revealed that this is highly active in neurons. By deletion analysis, the minimal promoter was found to be located between -224 and +14, a GC-rich region that contains a functional Sp3 binding site. In neurons, overexpression of Sp3 stimulates the APBA1 promoter while an Sp3 inhibitor suppresses the promoter activity. Moreover, inhibition of Sp3 reduces endogenous X11α expression and promotes the generation of Aβ. Our findings reveal that Sp3 play an essential role in APBA1 transcription.
DNA and cell biology 12/2011; 31(5):651-9. · 2.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Our aim was to perform a meta-analysis of randomized controlled trials comparing efficacy and side effects of bifrontal (BF) ECT to bitemporal (BT) or unilateral (RUL) ECT in depression.
We performed a systematic review of randomized controlled trials comparing BF ECT with RUL or BT ECT in depression. Eight trials (n=617) reported some cognitive outcome. Efficacy was measured by reduction in Hamilton Depression Rating Scale score. Cognitive outcomes were limited to Mini-Mental State Examination (MMSE) in seven studies, with two studies measuring each of: Complex-figure delayed recall, Trail-making tests and verbal learning.
Efficacy was equal between BF and BT ECT (Hedges's g=0.102, P=0.345, confidence interval (CI): -0.110, 0.313) and BF and RUL ECT (standardized mean difference=-0.12, P=0.365, CI: -0.378, 0.139). Post-treatment MMSE score decline was less for BF than BT ECT (g=0.89, CI: 0.054, 1.724) but not RUL ECT. RUL ECT impaired Complex figure recall more than BF ECT (g=0.76, CI :0.487, 1.035), but BF ECT impaired word recall more than RUL ECT (g=-1.45, CI: -2.75, -0.15).
Bifrontal ECT is not more effective than BT or RUL ECT but may have modest short-term benefits for specific memory domains. BF ECT has potential advantages, but given longer experience with BT and RUL, bifrontal ECT requires better characterization.
The World Journal of Biological Psychiatry 11/2011; 13(4):248-58. · 2.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To compare electroconvulsive therapy (ECT) practice between London in the United Kingdom and Bengaluru in India.
A retrospective case note study was conducted to compare patterns of referrals for ECT in university teaching hospitals in London (n = 46) and Bengaluru (n = 345) during a 1-year period. Further comparison of ECT practice was made for a consecutive series of depressed patients between London (n = 104) and Bengaluru (n = 125).
The rates of ECT referral were 0.9% of total annual admissions at the London site and 8.2% at the Bengaluru site. At the Bengaluru site, a higher proportion of patients were referred for ECT with a diagnosis of schizophrenia (P < 0.0001). Compared to the Bengaluru sample, depressed patients treated with ECT in London (n = 104) were older with more treatment resistance (P < 0.0001), had longer inpatient stays, and were less responsive to ECT.
The practice of ECT differed substantially between the London and Bengaluru sites. The relatively limited use of ECT in London reflects local treatment guidelines and may reflect the stigma associated with ECT. Electroconvulsive therapy is more widely used in Bengaluru with good outcomes. Further cross-cultural research is required to study the reasons for such contrasting practices and what constitutes the optimal practice of ECT for health systems in different countries.
The journal of ECT 06/2011; 27(4):275-80. · 1.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To our knowledge, changes in steroid metabolism in subjects with anorexia nervosa (AN) after weight gain have not been elucidated.
We characterized urinary steroid excretion and metabolism in AN patients and investigated the effects of refeeding.
In an intervention study, we recruited 7 women with life-threatening weight loss upon admission and after a median [interquartile range (IQR)] of 95 d (88-125 d) of intensive refeeding; 15 age-matched women were recruited as control subjects. The major urinary metabolites were quantified in 24-h collections by capillary gas chromatography. A single examiner measured weights, heights, and skinfold thicknesses.
The median (IQR) age of patients was 24 y (21-26 y), and the duration of AN was 4.0 y (3.3-8.0 y). Body mass index (BMI; in kg/m(2)) increased from 12.8 (12.7-13.1) to 18.6 (18.0-19.6) after refeeding (P < 0.0001). Steroid values [median pre-, post-refeeding (P value)] were as follows: androgen metabolites [472, 1017 μg/24 h (0.93)], cortisol metabolites [1960, 3912 μg/24 h (0.60)], and ratios of androsterone (5α)/etiocholanolone (5β) [0.28, 0.63 (<0.001)], 5α-/5β-tetrahydrocortisol [0.20, 0.48 (0.02)], tetrahydrocortisols/tetrahydrocortisone [0.87, 0.61 (0.09)], 20-hydroxy-/20-oxocortisol metabolites [0.29, 0.47 (0.01)], and 20α-/20β-reduced cortisol metabolites [1.18, 1.89 (≥1.00)]. BMI change was positively correlated with 5α-/5β-tetrahydrocortisol (r = 0.95, P < 0.001). Before refeeding, the following metabolites were lower in patients than in control subjects: androsterone, 5α-tetrahydrocortisol, α-cortolone and α-cortol, 5α-/5β-tetrahydrocortisol, androsterone/etiocholanolone, and 20-hydroxy/20-oxocortisol (all P < 0.05). After refeeding, all steroid metabolites in patients were at concentrations that were comparable with those in control subjects.
Significant changes in urine steroid-metabolite excretion occurred upon starvation, which were reversed upon refeeding. For cortisol, there were decreases in 5α-/5β-tetrahydrocortisol and 20-hydroxy-/20-oxometabolites; for androgen, there was a decrease in androsterone/etiocholanolone.
American Journal of Clinical Nutrition 03/2011; 93(5):911-7. · 6.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To clarify advantages of unilateral electrode placement as an optimisation technique for electroconvulsive therapy (ECT) for depression, aims were to meta-analyse unilateral ECT effects on cognitive performance relative to: (1) bitemporal electrode placement, (2) electrical dosage, and (3) time interval between final treatment and cognitive reassessment. Relevant electronic databases were systematically searched through May 2009, using the terms: "electroconvulsive therapy" and ["cogniti∗", "neuropsycholog∗", "memory", "attention", "executive", "spatial", or "intellectual"]. Inclusion criteria were: independent study of depressed patients receiving unilateral or bitemporal brief-pulse ECT; within-subjects design; use of objective cognitive assessments; available mean electrical dosage for unilateral samples. Standardized pre-post ECT weighted effect sizes were computed and pooled within 16 cognitive domains by a mixed-effects model. Thirty-nine studies (1415 patients) were meta-analysed. Up to three days after final treatment, unilateral ECT was associated with significantly smaller decreases in global cognition, delayed verbal memory retrieval, and autobiographical memory, compared to bitemporal ECT. Significant publication bias was found for autobiographical memory, favouring reporting of larger percentage loss. Higher unilateral ECT electrical dosage predicted larger decreases in verbal learning, delayed verbal memory retrieval, visual recognition, and semantic memory retrieval. When retested more than three days after completing ECT, no significant differences remained between the two electrode placements; for unilateral ECT, electrical dosage no longer predicted cognitive performance whereas increasing interval between final treatment and retesting predicted growing improvement in some variables. This interval is a more useful long-term predictor of cognitive function than electrode placement or electrical dosage following unilateral ECT.
Journal of psychiatric research 11/2010; 45(6):770-80. · 3.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Electroconvulsive therapy (ECT) is the most acutely effective treatment for depression, but is limited by cognitive side effects. However, research on their persistence, severity, and pattern is inconsistent. We aimed to quantify ECT-associated cognitive changes, specify their pattern, and determine progression.
MEDLINE, EMBASE, PsycArticles, PsychINFO, PsychLIT, and reference lists were systematically searched through January 2009. We included all independent, within-subjects design studies of depressed patients receiving ECT where cognition was assessed using standardized tests. Main outcome was change in performance after ECT relative to pretreatment scores with respect to delay between finishing ECT and cognitive testing. We explored potential moderators' influence, e.g., electrode placement, stimulus waveform.
Twenty-four cognitive variables (84 studies, 2981 patients) were meta-analyzed. No standardized retrograde amnesia tests were identified. Significant decreases in cognitive performance were observed 0 to 3 days after ECT in 72% of variables: effect sizes (ES) ranging from -1.10 (95% confidence interval [CI], -1.53 to -.67) to -.21 (95% CI, -.40 to .01). Four to 15 days post-ECT, all but one CI included zero or showed positive ES. No negative ES were observed after 15 days, with 57% of variables showing positive ES, ranging from .35 (95% CI, .07-.63) to .75 (95% CI, .43-1.08). Moderators did not influence cognitive outcomes after 3 days post-ECT.
Cognitive abnormalities associated with ECT are mainly limited to the first 3 days posttreatment. Pretreatment functioning levels are subsequently recovered. After 15 days, processing speed, working memory, anterograde memory, and some aspects of executive function improve beyond baseline levels.
Biological psychiatry 09/2010; 68(6):568-77. · 8.93 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: X11alpha is a neuronal adaptor protein that interacts with the amyloid precursor protein (APP) through a centrally located phosphotyrosine binding domain to inhibit the production of Abeta peptide that is deposited in Alzheimer's disease brains. X11alpha also contains two C-terminal postsynaptic density-95, large discs, zona occludens 1 (PDZ) domains, and we show here that through its PDZ domains, X11alpha interacts with a novel transcription factor, fibrinogen silencer binding protein. Moreover, we show that an X11alpha/fibrinogen silencer binding protein complex signals to the nucleus to repress glycogen synthase kinase-3beta promoter activity. Glycogen synthase kinase-3beta is a favoured candidate kinase for phosphorylating tau in Alzheimer's disease. Our findings show a new function for X11alpha that may impact on Alzheimer's disease pathogenesis.
Neuroreport 08/2010; 21(11):761-6. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: X11alpha is a neuronal-specific adaptor protein that binds to the amyloid-beta protein precursor (AbetaPP). Overexpression of X11alpha reduces Abeta production but whether X11alpha also protects against Abeta-related memory dysfunction is not known. To test this possibility, we crossed X11alpha transgenic mice with AbetaPP-Tg2576 mice. AbetaPP-Tg2576 mice produce high levels of brain Abeta and develop age-related defects in memory function that correlate with increasing Abeta load. Overexpression of X11alpha alone had no detectable adverse effect upon behavior. However, X11alpha reduced brain Abeta levels and corrected spatial reference memory defects in aged X11alpha/AbetaPP double transgenics. Thus, X11alpha may be a therapeutic target for Alzheimer's disease.
Journal of Alzheimer's disease: JAD 04/2010; 20(1):31-6. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: FE65 is a neuronal-enriched adaptor protein that binds to the Alzheimer's disease amyloid precursor protein (APP). FE65 forms a transcriptionally active complex with the APP intracellular domain (AICD). The precise gene targets for this complex are unclear but several Alzheimer's disease-linked genes have been proposed. Additionally, evidence suggests that FE65 influences APP metabolism. The mechanism by which FE65 expression is regulated is as yet unknown. To gain insight into the regulatory mechanism, we cloned a 1.6 kb fragment upstream of the human FE65 gene and found that it possesses particularly strong promoter activity in neurones. To delineate essential regions in the human FE65 promoter, a series of deletion mutants were generated. The minimal FE65 promoter was located between -100 and +5, which contains a functional Sp1 site. Overexpression of the transcription factor Sp1 potentiates the FE65 promoter activity. Conversely, suppression of the FE65 promoter was observed in cells either treated with an Sp1 inhibitor or in which Sp1 was knocked down. Furthermore, reduced levels of Sp1 resulted in downregulation of endogenous FE65 mRNA and protein. These findings reveal that Sp1 plays a crucial role in transcriptional control of the human FE65 gene.
Journal of Cellular Biochemistry 03/2010; 109(4):782-93. · 2.87 Impact Factor
-
E L Tudor,
C M Galtrey,
M S Perkinton,
K-F Lau,
K J De Vos,
J C Mitchell,
S Ackerley,
T Hortobágyi,
E Vámos,
P N Leigh,
C Klasen, D M McLoughlin,
C E Shaw,
C C J Miller
[show abstract]
[hide abstract]
ABSTRACT: Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.
Neuroscience 02/2010; 167(3):774-85. · 3.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer's disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer's disease.
Human Molecular Genetics 10/2009; 18(23):4492-500. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport.
Neuroscience Letters 05/2009; 454(2):161-4. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Neurofilaments are the intermediate filaments of neurons and are synthesised in neuronal cell bodies and then transported through axons. Neurofilament light chain (NFL) is a principal component of neurofilaments, and phosphorylation of NFL head domain is believed to regulate the assembly of neurofilaments. However, the role that NFL phosphorylation has on transport of neurofilaments is poorly understood. To address this issue, we monitored axonal transport of phosphorylation mutants of NFL. We mutated four known phosphorylation sites in NFL head domain to either preclude phosphorylation, or mimic permanent phosphorylation. Mutation to preclude phosphorylation had no effect on transport but mutation of three sites to mimic permanent phosphorylation inhibited transport. Mutation of all four sites together to mimic permanent phosphorylation proved especially potent at inhibiting transport and also disrupted neurofilament assembly. Our results suggest that NFL head domain phosphorylation is a regulator of neurofilament axonal transport.
European journal of cell biology 02/2009; 88(4):193-202. · 3.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: FE65 is an adaptor protein that binds to and forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. The regulatory mechanisms of FE65-APP-mediated transcription are still not clear. In this report, we demonstrate that Dexras1, a Ras family small G protein, binds to FE65 PTB2 domain and potently suppresses the FE65-APP-mediated transcription. The suppression is not via competition for binding of FE65 between Dexras1 and APP because the two proteins can simultaneously bind to the FE65 PTB2 domain. Phosphorylation of FE65 tyrosine 547 within the PTB2 domain has been shown to enhance FE65-APP-mediated transcription but not to influence binding to APP. Here we find that this phosphorylation event reduces the binding between Dexras1 and FE65. We also demonstrate that Dexras1 inhibits the FE65-APP-mediated transcription of glycogen synthase kinase 3beta (GSK3 beta). Moreover, small interfering RNA knockdown of Dexras1 enhances GSK3 beta expression and increases phosphorylation of Tau, a GSK3 beta substrate. Thus, Dexras1 functions as a suppressor of FE65-APP-mediated transcription, and FE65 tyrosine 547 phosphorylation enhances FE65-APP-mediated transcription, at least in part, by modulating the interaction between FE65 and Dexras1. These findings reveal a novel regulatory mechanism for FE65-APP-mediated signaling.
Journal of Biological Chemistry 11/2008; 283(50):34728-37. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aberrant metabolism of the amyloid precursor protein (APP) is believed to be at least part of the pathogenic process in Alzheimer’s disease. The carboxy-terminus of APP has been shown to interact with the Mint/X11 family of phosphotyrosine binding (PTB) domain-bearing proteins. It is via their PTB domains that the Mints/X11s bind to APP. Here we report the cloning of full-length mouse Mint2 and demonstrate that in primary cortical neurons, Mint2 and APP share highly similar distributions. Mint2 also colocalizes with APP in transfected CHO cells. In Mint2/APP-cotransfected cells, Mint2 reorganizes the subcellular distribution of APP and also increases the steady-state levels of APP. Finally, we demonstrate that Mint2 is associated with the neuritic plaques found in Alzheimer’s disease but not with neurofibrillary tangles. These results are consistent with a role for Mint2 in APP metabolism and trafficking, and suggest a possible role for the Mints/X11s in the pathogenesis of Alzheimer’s disease.
European Journal of Neuroscience 10/2008; 11(6):1988 - 1994. · 3.63 Impact Factor
-
Martin Knapp,
Renee Romeo,
Andrew Mogg,
Savitha Eranti,
Graham Pluck,
Rick Purvis,
Richard G Brown,
Robert Howard,
Michael Philpot,
John Rothwell,
Denzil Edwards, Declan M McLoughlin
[show abstract]
[hide abstract]
ABSTRACT: Electroconvulsive therapy (ECT) has a long history of use in treating depression. Repetitive transcranial magnetic stimulation (rTMS) has been introduced more recently to the treatment spectrum. Its cost-effectiveness has not been explored.
Forty-six right-handed people with severe depressive episodes referred for ECT were randomised to receive either ECT twice weekly or rTMS on consecutive weekdays. Health and other service use were recorded for retrospective periods of 3 months prior to initiation of treatment and during the 6 months following the end of allocated treatment. Costs were calculated for the treatment period and the subsequent 6 months, and comparisons made between groups after adjustment for any baseline differences. Cost-effectiveness analysis was conducted with incremental change on the 17-item Hamilton Rating Scale for Depression (HRSD) as the primary outcome measure, and quality-adjusted life years (based on SF6D-generated utility scores with societal weights) as secondary outcome, cost-effectiveness acceptability curves plotted.
Based on the HRSD scores and other outcome measures, rTMS was not as effective as ECT. The cost of a single session of rTMS was lower than the cost of a session of ECT, but overall there were no treatment cost differences. In the treatment and 6-month follow-up periods combined, health and other service costs were not significantly different between the two groups. Informal care costs were higher for the rTMS group. Total treatment, service and informal care costs were also higher for the rTMS group. The cost-effectiveness acceptability curves indicated a very small probability that decision-makers would view rTMS as more cost-effective than ECT.
Small sample size, some sample attrition and a relatively short follow-up period of 6 months for a chronic illness. Productivity losses could not be calculated.
ECT is more cost-effective than rTMS in the treatment of severe depression.
Journal of Affective Disorders 09/2008; 109(3):273-85. · 3.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The neuronal cyclin-dependent kinase p35/cdk5 comprises a catalytic subunit (cdk5) and an activator subunit (p35). To identify novel p35/cdk5 substrates, we utilized the yeast two-hybrid system to screen for human p35 binding partners. From one such screen, we identified β-catenin as an interacting protein. Confirmation that p35 binds to β-catenin was obtained by using glutathione S-transferase (GST)–β-catenin fusion proteins that interacted with both endogenous and transfected p35, and by showing that β-catenin was present in p35 immunoprecipitates. p35 and β-catenin also displayed overlapping subcellular distribution patterns in cells including neurons. Finally, we demonstrated that p35/cdk5 phosphorylates β-catenin. β-catenin also binds to presenilin-1 and altered β-catenin/presenilin-1 interactions may be mechanistic in Alzheimer's disease (AD). Abnormal p35/cdk5 activity has also been suggested to contribute to AD. We therefore investigated how modulation of p35/cdk5 activity influenced β-catenin/presenilin-1 interactions. Inhibition of p35/cdk5 with roscovitine did not alter the steady state levels of either β-catenin or presenilin-1 but reduced the amount of presenilin-1 bound to β-catenin. Thus, p35/cdk5 binds and phosphorylates β-catenin and regulates its binding to presenilin-1. The findings reported here therefore provide a novel molecular framework to connect p35/cdk5 with β-catenin and presenilin-1 in AD.
European Journal of Neuroscience 07/2008; 13(2):241 - 247. · 3.63 Impact Factor
