Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Endocannabinoid system dysfunction in mood and related disorders.

OBJECTIVE: The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. METHOD: An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. RESULTS: We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. CONCLUSION: Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.

White matter lesions in euthymic patients with bipolar disorder.

OBJECTIVE: We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls. METHOD: Cerebral hyperintensities on T2, proton density and fluid-attenuated inversion recovery (FLAIR) MRI were compared between 48 bipolar and 47 control subjects using semi-quantitative rating scales. RESULTS: Bipolar subjects had more severe frontal deep white matter lesions (DWML). Hyperintensity load was independent of age in bipolar patients but increased with age in controls. Global prevalence and severity of hyperintensities did not differ between groups. Exploratory analysis showed DWML in excess in the left hemisphere in bipolar subjects but not in controls. CONCLUSION: Findings are consistent with clinical, particularly some neurocognitive, features of bipolar disorder and implicate fronto-subcortical circuits in its neurobiology. They more probably reflect a trait abnormality or illness scar rather than a mood state-dependent finding. Processes other than ageing and vascular factors may underlie their development.

The neurocognitive performance of drug-free and medicated euthymic bipolar patients do not differ.

OBJECTIVE: Although it is established that euthymic bipolar patients have neurocognitive deficits, the influence of medication on their cognitive performance is uncertain and requires investigation. METHOD: Neuropsychological tests of executive function, memory and attention were performed on 44 prospectively verified, euthymic bipolar I patients, 22 of whom were drug-free. Residual mood symptom effects were controlled statistically using ancova. RESULTS: Drug-free and medicated patients differed only in delayed verbal recall (Rey AVLT list A7, drug-free > medicated), and perseverations during the five-point test (drug-free > medicated). When residual mood symptoms were controlled statistically, differences between drug-free and medicated subjects became insignificant. Medication effect sizes were modest. Significant correlations were found between residual depression scores and measures of verbal learning. CONCLUSION: Medications did not have any significant influence on neurocognitive performance, suggesting that neurocognitive deficits are an integral part of bipolar disorder.

Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology.

BACKGROUND: The clinical and neuropathological features associated with dementia in Down's syndrome (DS) are not well established. Aims To examine clinico-pathological correlations and the incidence of cognitive decline in a cohort of adults with DS. METHOD: A total of 92 hospitalized persons with DS were followed up from 1985 to December 2000. At outset, 87 participants were dementia-free, with a median age of 38 years. Assessments included the Prudhoe Cognitive Function Test (PCFT) and the Adaptive Behavior Scale (ABS), to measure cognitive and behavioural deterioration. Dementia was diagnosed from case records and caregivers' reports. RESULTS: Eighteen (21%) patients developed dementia during follow-up, with a median age of onset 55.5 years (range 45-74). The PCFT demonstrated cognitive decline among those with a less severe intellectual disability (mild and moderate) but not among the profoundly disabled people (severe and profound). Clinical dementia was associated with neuropathological features of Alzheimer's disease, and correlated with neocortical neurofibrillary tangle densities. At the age of 60 years and above, a little more than 50% of patients still alive had clinical evidence of dementia. CONCLUSIONS: Clinical dementia associated with measurable cognitive and functional decline is frequent in people with DS after middle age, and can be readily diagnosed among less severely intellectually disabled persons using measures of cognitive function such as the PCFT and behavioural scales such as the ABS. In the more profoundly disabled people, the diagnosis of dementia is facilitated by the use of behavioural and neurological criteria. In this study, the largest prospective DS series including neuropathology on deceased patients, the density of neurofibrillary tangles related more closely to the dementia of DS than senile plaques. In people with DS surviving to middle and old age, the development of dementia of Alzheimer type is frequent but not inevitable, and some people with DS reach old age without clinical features of dementia.

The geometry of the ribosomal polypeptide exit tunnel.

The geometry of the polypeptide exit tunnel has been determined using the crystal structure of the large ribosomal subunit from Haloarcula marismortui. The tunnel is a component of a much larger, interconnected system of channels accessible to solvent that permeates the subunit and is connected to the exterior at many points. Since water and other small molecules can diffuse into and out of the tunnel along many different trajectories, the large subunit cannot be part of the seal that keeps ions from passing through the ribosome-translocon complex. The structure referred to as the tunnel is the only passage in the solvent channel system that is both large enough to accommodate nascent peptides, and that traverses the particle. For objects of that size, it is effectively an unbranched tube connecting the peptidyl transferase center of the large subunit and the site where nascent peptides emerge. At no point is the tunnel big enough to accommodate folded polypeptides larger than alpha-helices.

Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential.

Bipolar affective disorder is often poorly controlled by prescribed drugs. Cannabis use is common in patients with this disorder and anecdotal reports suggest that some patients take it to alleviate symptoms of both mania and depression. We undertook a literature review of cannabis use by patients with bipolar disorder and of the neuropharmacological properties of cannabinoids suggesting possible therapeutic effects in this condition. No systematic studies of cannabinoids in bipolar disorder were found to exist, although some patients claim that cannabis relieves symptoms of mania and/or depression. The cannabinoids Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) may exert sedative, hypnotic, anxiolytic, antidepressant, antipsychotic and anticonvulsant effects. Pure synthetic cannabinoids, such as dronabinol and nabilone and specific plant extracts containing THC, CBD, or a mixture of the two in known concentrations, are available and can be delivered sublingually. Controlled trials of these cannabinoids as adjunctive medication in bipolar disorder are now indicated.

The roles of ribosomal proteins in the structure assembly, and evolution of the large ribosomal subunit.

The structures of ribosomal proteins and their interactions with RNA have been examined in the refined crystal structure of the Haloarcula marismortui large ribosomal subunit. The protein structures fall into six groups based on their topology. The 50S subunit proteins function primarily to stabilize inter-domain interactions that are necessary to maintain the subunit's structural integrity. An extraordinary variety of protein-RNA interactions is observed. Electrostatic interactions between numerous arginine and lysine residues, particularly those in tail extensions, and the phosphate groups of the RNA backbone mediate many protein-RNA contacts. Base recognition occurs via both the minor groove and widened major groove of RNA helices, as well as through hydrophobic binding pockets that capture bulged nucleotides and through insertion of amino acid residues into hydrophobic crevices in the RNA. Primary binding sites on contiguous RNA are identified for 20 of the 50S ribosomal proteins, which along with few large protein-protein interfaces, suggest the order of assembly for some proteins and that the protein extensions fold cooperatively with RNA. The structure supports the hypothesis of co-transcriptional assembly, centered around L24 in domain I. Finally, comparing the structures and locations of the 50S ribosomal proteins from H.marismortui and D.radiodurans revealed striking examples of molecular mimicry. These comparisons illustrate that identical RNA structures can be stabilized by unrelated proteins.

The Prudhoe Cognitive Function Test, a scale to assess cognitive function in adults with Down's syndrome: inter-rater and test-retest reliability.

BACKGROUND: The Prudhoe Cognitive Function Test (PCFT) was designed to measure cognitive function in subjects with all degrees of intellectual disability (ID) and to be administered by non-specialist raters. The aim of the present study was to measure the test-retest and inter-rater reliability of the PCFT. METHODS: Three raters, one a specialist and two non-specialists, administered the PCFT to 14 subjects with Down's syndrome on two occasions separated by 4 weeks. RESULTS: The intra-class correlation coefficients (ICCs) between the rater pairs (n=3) were 0.99, 0.99 and 0.98 (P<0.01). Floor effects were recorded for two items. The ICC for test-retest reliability was 0.99 (P<0.01). CONCLUSIONS: The PCFT is a highly reliable instrument when used by either specialist or non-specialist raters. It has excellent temporal stability.

Preliminary evaluation of a scale to assess cognitive function in adults with Down's syndrome: the Prudhoe Cognitive Function Test.

BACKGROUND: In the clinical diagnosis of dementia in Down's syndrome (DS), it may be difficult to distinguish between cognitive deterioration and the various degrees of pre-existing intellectual disability (ID). Serial measurements of both cognitive function and behaviour are required. The aim of the present study was to evaluate the performance of non-demented adults with DS on a subject-directed instrument, the Prudhoe Cognitive Function Test (PCFT), preliminary to its serial use in a prospective study. METHODS: From 1985 to 1986, 85 non-demented hospitalized adults with DS were interviewed using the PCFT. The Adaptive Behavior Scale (ABS) was administered to the carers. The subjects' levels of ID (graded from mild through moderate, severe and profound to untestable) were based on their scores on the Stanford-Binet Intelligence Scale, as reported in the medical records, and the relationship between level of disability and performance on the PCFT and ABS, and their respective domains, was examined. RESULTS: Both scales produced a wide range of scores and the correlation between them was highly significant. Both scales correlated highly significantly with the degree of ID, but more subjects with high levels (i.e. profound to untestable) of disability obtained very low or zero scores on the PCFT and its domains than on the ABS. CONCLUSIONS: The PCFT provides a reliable quantitative measure of cognitive function in subjects with DS, and could be a useful adjunct to the diagnosis of dementia in prospective studies. However, the almost uniformly low scores obtained by those with high levels of ID suggests that its power to detect cognitive decline will be limited to those who are less disabled, while the ABS may be more useful than the PCFT in detecting deterioration in people with profound ID.

Dynamical properties of a hydrated lipid bilayer from a multinanosecond molecular dynamics simulation.

A fully hydrated dimiristoylphosphatidylcholine (DMPC) bilayer has been studied by a molecular dynamics simulation. The system, which consisted of 64 DMPC molecules and 1792 water molecules, was run in the NVE ensemble at a temperature of 333 K for a total of 10 ns. The resulting trajectory was used to analyze structural and dynamical quantities. The electron density, bilayer spacing, and order parameters (S(CD)), based on the AMBER forcefield and SPCE water model are in good agreement with previous calculations and experimental data. The simulation reveals evidence for two types of lateral diffusive behavior: cage hopping and that of a two-dimensional liquid. The lateral diffusion coefficient is 8 x 10(-8) cm(2)/s. We characterize the rotational motion, and find that the lipid tail rotation (D(rot_tail) = -0.04 rad(2)/ns) is slower then the head group rotation (D(rot_hg) = 2.2 rad(2)/ns), which is slower than the overall in plane (D(rot) = 3.2 rad(2)/ns) for the lipid molecule.

The structure of helix III in Xenopus oocyte 5 S rRNA: an RNA stem containing a two-nucleotide bulge.

The solution structure of an oligonucleotide containing the helix III sequence from Xenopus oocyte 5 S rRNA has been determined by NMR spectroscopy. Helix III includes two unpaired adenosine residues, flanked on either side by G:C base-pairs, that are required for binding of ribosomal protein L5. The consensus conformation of helix III in the context provided by this oligonucleotide has the two adenosine residues located in the minor groove and stacked upon the 3' flanking guanosine residue, consistent with biochemical studies of free 5 S rRNA in solution. A distinct break in stacking that occurs between the first adenosine residue of the bulge and the flanking 5' guanosine residue exposes the base of the adenosine residue in the minor groove and the base of the guanosine residue in the major groove. The major groove of the helix is widened at the site of the unpaired nucleotides and the helix is substantially bent; nonetheless, the G:C base-pairs flanking the bulge are intact. The data indicate that there may be conformational heterogeneity centered in the bulge region. The corresponding adenosine residues in the Haloarcula marismortui 50 S ribosomal subunit form a dinucleotide platform, which is quite different from the motif seen in solution. Thus, the conformation of helix III probably changes when 5 S rRNA is incorporated into the ribosome.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Application of dipolar coupling data to the refinement of the solution structure of the sarcin-ricin loop RNA.

Residual dipolar couplings can provide the long-range information that most NMR solution structures lack. The use of such data in protein structure determinations is now fairly routine, but even though these data should be much more useful for nucleic acids, their application to nucleic acid structure determination is still in its infancy. Here we present a method for producing accurate, dipolar-refined structures of nucleic acids that is more efficient than those used previously, and apply it to E73, a 29 nucleotide RNA that includes the sarcin-ricin loop from rat 28S rRNA. The results enable us to address the differences between the crystal structure of E73 and the solution structure proposed for it previously.

White matter lesions and season of birth of patients with bipolar affective disorder.

OBJECTIVE: It is established that patients with bipolar disorder have an excess of births in winter or early spring. The authors investigated a link between season of birth and white matter lesions with magnetic resonance imaging (MRI). METHOD: T(2)-weighted and proton density MRI scans were examined for 79 patients with bipolar disorder (DSM-IV) for the presence of deep subcortical and periventricular white matter lesions. The birth seasons of patients with white matter lesions were compared with those of the general population. RESULTS: Thirteen subjects exhibited deep subcortical white matter lesions, of whom nine (69.2%) were born in the winter months (January to March). Seven of these patients remained symptomatic, despite adequate treatment for more than 2 years. CONCLUSIONS: Birth season, illness outcome, and deep subcortical white matter lesions appear to be closely linked. Deep subcortical white matter lesions may be a marker of a toxic or infective insult in utero.

The kink-turn: a new RNA secondary structure motif.

Analysis of the Haloarcula marismortui large ribosomal subunit has revealed a common RNA structure that we call the kink-turn, or K-turn. The six K-turns in H.marismortui 23S rRNA superimpose with an r.m.s.d. of 1.7 A. There are two K-turns in the structure of Thermus thermophilus 16S rRNA, and the structures of U4 snRNA and L30e mRNA fragments form K-turns. The structure has a kink in the phosphodiester backbone that causes a sharp turn in the RNA helix. Its asymmetric internal loop is flanked by C-G base pairs on one side and sheared G-A base pairs on the other, with an A-minor interaction between these two helical stems. A derived consensus secondary structure for the K-turn includes 10 consensus nucleotides out of 15, and predicts its presence in the 5'-UTR of L10 mRNA, helix 78 in Escherichia coli 23S rRNA and human RNase MRP. Five K-turns in 23S rRNA interact with nine proteins. While the observed K-turns interact with proteins of unrelated structures in different ways, they interact with L7Ae and two homologous proteins in the same way.

Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder.

OBJECTIVES: EEG abnormalities and neurocognitive deficits have been reported in patients with bipolar affective disorder. The aim of this study was to ascertain whether brain function remains impaired in young bipolar patients who have become euthymic in response to treatment. METHODS: Brain function was assessed by quantitative electroencephalographic (EEG) power-spectral mapping and by a battery of neuropsychological tests. The subjects were 29 euthymic bipolar patients aged 18-40 years and 26 healthy volunteers of similar age, IQ and socioeconomic status. RESULTS: Grand means of spectral power of the resting EEG showed significantly (from p < 0.01 to p < 0.0001) greater power in all wave bands (delta, theta, alpha and beta) in patients compared with controls. The most marked increases were in right temporal theta and left occipital beta power (with eyes open) encompassing brain areas concerned in visuospatial processing. Neurocognitive performance was significantly impaired in the patients compared with controls in a range of visuospatial tasks. CONCLUSIONS: The findings show significant disturbance of EEG activity and deficits in visuospatial processing in young bipolar patients despite clinical euthymia. The abnormalities were not related to age of onset or duration of illness and do not appear to be attributable to medication. The cognitive impairments were associated with the number of previous affective episodes.

Atomic structures at last: the ribosome in 2000.

Last year, atomic structures of the 50S ribosomal subunit from Haloarcula marismortui and of the 30S ribosomal subunit from Thermus thermophilus were published. A year before that, a 7.8 A resolution electron density map of the 70S ribosome from T. thermophilus appeared. This information is revolutionizing our understanding of protein synthesis.

A maximum likelihood method for determining D(a)(PQ) and R for sets of dipolar coupling data.

The algorithms available today that use dipolar coupling data for macromolecular structure determination require the independent determination of two parameters, D(a)(PQ) and R. Methods exist for obtaining these parameters when the set of dipolar couplings available is large and the orientations of the interatomic vectors on which they report is isotropically distributed. These methods are less satisfactory when the set is small and anisotropic. Described here is a maximum likelihood method that extracts accurate values for D(a)(PQ) and R from small, anisotropic data sets. Also demonstrated is a procedure for estimating the errors associated with the values of D(a)(PQ) and R obtained and for incorporating these errors into refinement protocols.

RNA tertiary interactions in the large ribosomal subunit: the A-minor motif.

Analysis of the 2.4-A resolution crystal structure of the large ribosomal subunit from Haloarcula marismortui reveals the existence of an abundant and ubiquitous structural motif that stabilizes RNA tertiary and quaternary structures. This motif is termed the A-minor motif, because it involves the insertion of the smooth, minor groove edges of adenines into the minor groove of neighboring helices, preferentially at C-G base pairs, where they form hydrogen bonds with one or both of the 2' OHs of those pairs. A-minor motifs stabilize contacts between RNA helices, interactions between loops and helices, and the conformations of junctions and tight turns. The interactions between the 3' terminal adenine of tRNAs bound in either the A site or the P site with 23S rRNA are examples of functionally significant A-minor interactions. The A-minor motif is by far the most abundant tertiary structure interaction in the large ribosomal subunit; 186 adenines in 23S and 5S rRNA participate, 68 of which are conserved. It may prove to be the universally most important long-range interaction in large RNA structures.