Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory.

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Cognitive effects of methylphenidate and levodopa in healthy volunteers.

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory.

The effects and costs of a hearing screening and rehabilitation program in residential care homes for the elderly in the Netherlands1.

PURPOSE: This study describes the effects and costs of hearing screening and rehabilitation in residential care homes for the elderly. It was hypothesized that offering an in-house hearing screening and rehabilitation program would be an effective strategy to increase hearing aid ownership among the residents. METHOD: All 705 residents of 8 residential care homes in the Netherlands were invited to participate in a hearing screening (pure-tone audiometry) and rehabilitation (hearing aids) program. Resident participation was analyzed, and the costs were calculated. RESULTS: A total of 243 residents (34%) participated in the screening, 222 (91%) of whom had hearing loss. Ninety-one (41%) of the screening participants with hearing loss started rehabilitation, which was successful for 50 (55%) of them. Hearing aid ownership among the residents with hearing loss increased from 28% at the start of the program to 33% at the end. The costs were €1,896 (US $2,480) per successfully rehabilitated resident. Hearing aid trials and hearing aids together accounted for 83% of the total costs. CONCLUSION: The effectiveness of the program was limited, as hearing aid ownership increased only slightly. Cost reduction measures should focus on decreasing the number of unsuccessful hearing aid trials.

Higher, faster, stronger: the effect of dynamic stimuli on response preparation and CNV amplitude.

The contingent negative variation (CNV) is a slow negative shift in the electroencephalogram (EEG), observed during response preparation. To optimalize the CNV paradigm, this study developed a task using dynamic stimuli and next combined this task with a Go/No-go test. In the first experiment, 19 healthy volunteers were subjected to the classic Traffic light (TL) task and the new dynamic Lines task. In the Lines task, response time was faster and CNV amplitude was larger compared to the TL task. In the second experiment, 20 healthy participants were tested on a Go/No-go version of the Lines task. Response times increased as the probability of response requirement decreased. CNV amplitude was larger when probability of response requirement was higher. In conclusion, the dynamic task promotes response preparation. The new tasks may be especially valuable in groups with attention difficulties (i.e. elderly or ADHD patients).

Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers.

RATIONALE: Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate. OBJECTIVE: In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers. METHODS: In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test. RESULTS: Declarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning. CONCLUSIONS: To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.

Rhemulatologists' performance in dailiy practice.

OBJECTIVE: To assess rheumatologists' performance for 8 rheumatologic conditions and to explore possible explanatory factors. METHODS: After written informed consent was obtained, 27 rheumatologists (21% of all Dutch rheumatologists) practicing in 16 outpatient departments were each visited by 8 incognito "standardized patients" (SPs). The diagnoses of these 8 cases account for about 23% of all new referred patients in the Netherlands. Results for ordered lab tests as well as real radiographs with corresponding results from a radiologist were simulated. Information from the visits was obtained from the SPs, who completed predefined case-specific checklists, and by collecting data on resource utilization. Feedback was provided. RESULTS: Altogether 254 encounters took place, of which 201 were first visits and 53 were followup visits. SPs were unmasked twice during a visit. There was considerable variation in resource utilization (lab tests and imaging) between cases and between rheumatologists. Mean costs per rheumatologist ranged from US $ 4.67 to $ 65.36 per visit for lab tests and from US $ 33.15 to $ 226.84 per visit for imaging tests. No significant correlations were seen between resource utilization costs and number of years of clinical experience or performance on checklist scores. Rheumatologists with longer experience had lower total item checklist scores (r = -0.47; P < 0.05). CONCLUSION: A considerable variation in resource utilization was found among 27 Dutch rheumatologists. The information obtained is an excellent source for discussion on the appropriateness of care.

Coping with depression and anxiety: preliminary results of a standardized course for elderly depressed women.

The experiences of 51 elderly depressed female patients with a standardized course "Coping with Depression and Anxiety" were investigated. Preliminary findings concerning the effectiveness of this course in 34 patients who completed the course will also be presented. This course consisted of psychoeducation and skills training. Depressive symptoms were scored by using the SCL-90 depression scale and the Geriatric Depression Scale. Results indicate that patients were very enthusiastic about the course and that there was no need to make major changes in its structure and content. Also, depressive symptoms were significantly reduced after completion of the course, which emphasizes the importance of this psychoeducational program in the treatment of depression in elderly female patients.

An efficient method for sampling the essential subspace of proteins.

A method is presented for a more efficient sampling of the configurational space of proteins as compared to conventional sampling techniques such as molecular dynamics. The method is based on the large conformational changes in proteins revealed by the "essential dynamics" analysis. A form of constrained dynamics is performed, forcing the system to move along some of the essential coordinates. This results in a broader sampling of the essential subspace than in a comparable conventional molecular dynamics simulation without constraints. The new sampling method (essential dynamics sampling) was applied to the histidine-containing phosphocarrier protein HPr. The results indicate that the essential dynamics sampling method produces physically allowed structures, as estimated by the evaluation of many geometrical properties. In addition, a study of the motions in the essential subspace reveals a diffusion-like behavior.

Responders and nonresponders to autogenic training and cognitive self-hypnosis: prediction of short- and long-term success in tension-type headache patients.

The present study was conducted to determine whether demographic variables, medical status variables, and psychological measures at pretreatment were related to pain reduction immediately following behavioral treatment for headache and at a 6-month follow-up. The study sample consisted of 156 subjects, who were selected for participation in a behavioral outcome study on the efficacy of autogenic training and cognitive self-hypnosis training. A Headache Index based on pain diaries constituted the main outcome measure. Psychological measures included the Symptom Checklist-90, Dutch Personality Questionnaire, Coping Strategy Questionnaire, Multidimensional Locus of Pain Control Questionnaire, and treatment expectations. Subjects who expected more pain reduction at pretreatment achieved a lower level of pain at posttreatment, independent of pretreatment pain levels. None of the other pretreatment variables were related with pain reduction at posttreatment or at the follow-up. Finally, at the 6-month follow-up, 43 subjects were classified as responders (more than 50% pain reduction) and 113 as nonresponders (less than 50% pain reduction and dropouts). At pretreatment, the responders perceived more pain control than the nonresponders. None of the other pretreatment differences between responders and nonresponders proved to be significant. The main conclusion that could be drawn from this study was that pain reduction, in the short- and long-term, cannot be predicted with any accuracy by demographic and medical status variables or scores for psychological distress, personality traits, coping strategy use, and pain appraisals.

Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis.

PURPOSE: Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis were assessed after a mean follow-up of nine years. Rheumatologic complications, in particular the presence and course of ankylosing spondylitis, were examined during the same period. METHODS: A hospital-based prospective study of 119 patients with HLA-B27-positive and 35 patients with HLA-B27-negative acute anterior uveitis was performed. All patients underwent a complete ophthalmologic and rheumatologic examination, including sacroiliac x-rays, and were examined again nine years later. RESULTS: No statistically significant differences in ocular complications and visual outcome were found between both patient groups with acute anterior uveitis after nine years. Posterior synechiae were observed in one half of the affected eyes. Blindness was infrequent. Rheumatologic complications, including ankylosing spondylitis, originally seen in one half of the HLA-B27-positive patients, were observed in two thirds of the patients nine years later, compared to only two of 35 HLA-B27-negative patients. When ankylosing spondylitis was evident at first examination no clinically significant deterioration was observed nine years later. CONCLUSIONS: After nine years we observed an ocular outcome equal for both patient groups. A small percentage of affected eyes became blind. Rheumatologic complications occurred in 55 (72%) of 76 HLA-B27-positive males and in 24 (56%) of 43 HLA-B27-positive females with acute anterior uveitis. The rheumatologic complications had a good prognosis.

The essential dynamics of thermolysin: confirmation of the hinge-bending motion and comparison of simulations in vacuum and water.

Comparisons of the crystal structures of thermolysin and the thermolysin-like protease produced by B. cereus have recently led to the hypothesis that neutral proteases undergo a hinge-bending motion. We have investigated this hypothesis by analyzing molecular dynamics simulations of thermolysin in vacuum and water, using the essential dynamics method. This method is able to extract large concerted atomic motions of biological importance from a molecular dynamics trajectory. The analysis of the thermolysin trajectories indeed revealed a large rigid body hinge-bending motion of the N-terminal and C-terminal domains, similar to the motion hypothesized from the crystal structure comparisons. In addition, it appeared that the essential dynamics properties derived from the vacuum simulation were similar to those derived from the solvent simulation.

Spondylarthropathy and selective IgA deficiency.

No serum IgA was detected in a young male patient suffering from spondylarthropathy (SpA) with bilateral sacroiliitis arthritis, enthesopathy and inflammatory low back pain, whose symptoms occurred in reaction to a sexually induced urethritis. After a period of several months in which the spondylarthropathy was active, disease activity came to a rest. Three years later no progression of the SpA was observed. This finding might be an indication that IgA is not involved in the pathogenesis of spondylarthropathy.

Essential dynamics of proteins.

Analysis of extended molecular dynamics (MD) simulations of lysozyme in vacuo and in aqueous solution reveals that it is possible to separate the configurational space into two subspaces: (1) an "essential" subspace containing only a few degrees of freedom in which anharmonic motion occurs that comprises most of the positional fluctuations; and (2) the remaining space in which the motion has a narrow Gaussian distribution and which can be considered as "physically constrained." If overall translation and rotation are eliminated, the two spaces can be constructed by a simple linear transformation in Cartesian coordinate space, which remains valid over several hundred picoseconds. The transformation follows from the covariance matrix of the positional deviations. The essential degrees of freedom seem to describe motions which are relevant for the function of the protein, while the physically constrained subspace merely describes irrelevant local fluctuations. The near-constraint behavior of the latter subspace allows the separation of equations of motion and promises the possibility of investigating independently the essential space and performing dynamic simulations only in this reduced space.

Autogenic training and self-hypnosis in the control of tension headache.

This study compares autogenic training and training in multiple self-hypnosis strategies in a sample of 56 patients diagnosed as having chronic tension headache on the basis of medical evaluation by a neurologist. At posttreatment and follow-up, no differences between the two treatment regimens in the reduction of headache and psychological distress were observed. During treatment, patients reduced their headache activity and level of psychological distress significantly in contrast to the waiting-list period (p < 0.05). Follow-up measurements indicated that therapeutic improvement was maintained (p < 0.05). Short-term and long-term pain reduction was accompanied by an increase in perceived pain control (p < 0.003). Moreover, those patients who attributed the pain reduction obtained during therapy to their own efforts manifested long-term pain reduction (p < 0.003).

Hypnosis and autogenic training in the treatment of tension headaches: a two-phase constructive design study with follow-up.

Tension headaches can form a chronic (very long duration) condition. EMG biofeedback, relaxation training and analgesia by hypnotic suggestion can reduce the pain. So far, no differences have been demonstrated between the effects of various psychological treatments. In a constructively designed study, we firstly compared an abbreviated form of autogenic training to a form of hypnotherapy (future oriented hypnotic imagery) which was not presented as hypnosis and secondly we compared both treatments to the same future oriented hypnotic imagery, but this time explicitly presented as hypnosis. The three treatments were equally effective at post-treatment, but after a 6-month follow-up period, the future oriented hypnotic imagery which had been explicitly presented as hypnosis was superior to autogenic training. Contrary to common belief, it could be demonstrated that the therapists were as effective with the treatment modality they preferred as with the treatment modality they felt to be less remedial.

Biochemical measures in patients with a somatoform pain disorder, before, during, and after treatment with amitriptyline with or without flupentixol.

The possible relationship between a number of biochemical parameters and measures of pain and depression was studied in chronic pain patients without a major depression. In a double-blind crossover study, patients were treated with amitriptyline combined with a low dose of flupentixol or placebo. We investigated whether pretreatment biochemical values correlated with initial data on pain and/or depression, or whether they had predictive value for treatment outcome. We also studied systematically the effect of both treatment regimes on the biochemical parameters themselves and their relation to the plasma levels of amitriptyline. From our results, the possible involvement of the serotonin system in somatoform pain disorder is confirmed and no direct relation with the noradrenergic system could be inferred. The lack of involvement of a number of putative, depression-related, biochemical parameters suggests that affective disorders and pain syndromes do not share all mechanisms in common.

Multimodal treatment programmes for chronic pain: a quantitative analysis of existing research data.

This article reviews the empirical data obtained in existing studies on the multimodal treatment of chronic pain. The majority of these 'treatment packages' are based on a cognitive/behavioural perspective. The articles for review were selected from the scientific literature on this subject which has appeared since the first publication of Fordyce in 1973. The following aspects have been analysed: the goal and structure of the treatment programmes; the method of evaluating treatment results; and the indications for treatment. Programmes for in-patients and out-patients have been compared because it is very likely that there are differences between the treatment methods and study populations. The interval validity and clinical relevance of the available research are discussed in the conclusion.

Uveitis and systemic disease.

A prospective study was conducted of 865 patients with uveitis to determine the frequency of associated systemic diseases and to assess the value of limited laboratory screening of these patients. All patients underwent a standard diagnostic protocol followed--when indicated--by special tests and procedures performed in order of likelihood ('tailored approach'). For 628 patients (73%) a specific diagnosis was established based on history, ophthalmologic examination, and laboratory and radiographic studies. A definite association with systemic disease was determined for 220 patients (26%). A relationship with a subclinical systemic disorder could be presumed in 201 cases (23%) and a well-established clinical uveitis entity without a recognisable systemic disorder was present in 207 cases (24%). For 237 patients (27%) a diagnosis could not be determined. The most frequently observed systemic diseases were sarcoidosis (7%) and HLA-B27-associated seronegative spondylarthropathies (6%). Presumed or definite toxoplasmosis was encountered in 10% of cases. HLA-B27-associated acute anterior uveitis was the most common clinical entity (17%). In the majority of cases the presence of a systemic disease was not suspected prior to eye involvement and was only recognised after the subsequent diagnostic procedures.