Cognitive shifting and externalising problem behaviour in intellectual disability and autism spectrum disorder.

BACKGROUND: Behavioural problems are frequently reported in residential care for people with an intellectual disability (ID) in particular when they are additionally diagnosed with autism spectrum disorder (ASD). There are indications that impairment in cognitive shifting may be associated with problem behaviour. The objectives of this study were (1) to examine the relationship of cognitive shifting and severity of ASD symptoms with externalising problem behaviour in individuals with ID, with and without ASD, and (2) to examine whether a diagnosis based on shifting impairment is more predictive of externalising problem behaviour than an ASD diagnosis. METHOD: Participants consisted of adolescents and young adults with mild ID, with and without ASD (n = 41). Pearson intercorrelations were computed to explore the relationship between shifting impairment and severity of ASD symptoms on the one hand and ratings of externalising problem behaviour on the other hand. t-Tests were performed to analyse differences in externalising problem behaviour. RESULTS: Unlike ASD symptom severity, shifting scores were found to be associated with externalising problem behaviour, but only if shifting was measured using rating scales and not when using neuropsychological tasks. Externalising problem behaviour scores significantly differed when groups were classified according to shifting impairment (impaired vs. non-impaired) but not when they were classified according to ID and ASD diagnoses. CONCLUSIONS: It is proposed to use a cognition-based approach when analysing problem behaviour, thus concentrating not so much on ID and ASD diagnosis and their corresponding symptoms, but rather placing the focus on cognitive symptoms.

Executive functioning in individuals with intellectual disabilities and autism spectrum disorders.

BACKGROUND: Executive functioning (EF) is important for adequate behavioural functioning and crucial for explaining symptoms of autism spectrum disorders (ASD) in individuals with normal intelligence, but is scarcely studied in individuals with ASD and intellectual disabilities (ID). We therefore study EF in an ID population by comparing performances on three frequently studied executive functions (shifting, inhibition and updating) between individuals with ASD and individuals without ASD. When studying ID populations, one should be aware of Spearman's Law of Diminishing Returns (SLODR), as it questions the possibility of measuring separate cognitive functions in ID populations. METHODS: Six EF tasks were administered to 50 individuals with mild to borderline ID, of which half was diagnosed with ASD. In order to investigate the distinctness of the three executive functions in this ID sample, the results on the six EF tasks were subjected to principal components analysis (PCA). Subsequently, a multivariate analysis of variance (MANOVA) was performed to assess differences between the ASD and non-ASD group on shifting, inhibition and updating. RESULTS: The PCA revealed the hypothesised EF trichotomy. MANOVA analysis showed no significant group differences on EF-performance. CONCLUSIONS: Three separate executive functions were measured in this ID population, but despite much evidence that individuals with ASD display more behavioural problems and the proven relevance of EF in behavioural functioning, no significant group difference was found on shifting, inhibition or updating. After this first effort to achieve more insight into EF of individuals with ASD and ID the relation between behavioural problems and EF will require further study.

Role of transiently altered sarcolemmal membrane permeability and basic fibroblast growth factor release in the hypertrophic response of adult rat ventricular myocytes to increased mechanical activity in vitro.

One of the trophic factors that has been implicated in initiating or facilitating growth in response to increased mechanical stress in several tissues and cell types is basic fibroblast growth factor (bFGF; FGF-2). Although mammalian cardiac muscle cells express bFGF, it is not known whether it plays a role in mediating cardiac adaptation to increased load, nor how release of the cytosolic 18-kD isoform of bFGF would be regulated in response to increased mechanical stress. To test the hypothesis that increased mechanical activity induces transient alterations in sarcolemmal permeability that allow cytosolic bFGF to be released and subsequently to act as an autocrine and paracrine growth stimulus, we examined primary isolates of adult rat ventricular myocytes maintained in serum-free, defined medium that were continually paced at 3 Hz for up to 5 d. Paced myocytes, but not nonpaced control cells, exhibited a "hypertrophic" response, which was characterized by increases in the rate of phenylalanine incorporation, total cellular protein content, and cell size. These changes could be mimicked in control cells by exogenous recombinant bFGF and could be blocked in continually paced cells by a specific neutralizing anti-bFGF antibody. In addition, medium conditioned by continually paced myocytes contained significantly more bFGF measured by ELISA and more mitogenic activity for 3T3 cells, activity that could be reduced by a neutralizing anti-bFGF antibody. The hypothesis that transient membrane disruptions sufficient to allow release of cytosolic bFGF occur in paced myocytes was examined by monitoring the rate of uptake into myocytes from the medium of 10-kD dextran linked to fluorescein. Paced myocytes exhibited a significantly higher rate of fluoresceinlabeled dextran uptake. These data are consistent with the hypothesis that nonlethal, transient alterations in sarcolemmal membrane permeability with release of cytosolic bFGF is one mechanism by which increased mechanical activity could lead to a hypertrophic response in cardiac myocytes.

[Cognitive predictors of social improvement in adolescents with autism spectrum-disorders]. / Cognitieve voorspellers van sociale vooruitgang bij jongeren met een autismespectrumstoornis.

BACKGROUND: In an earlier study published in this journal (Berger e.a. 2002) it was shown that the cognitive styles 'weak central coherence' and 'poor cognitive shifting' are common in autism spectrum disorders, but tests have revealed that the styles do not apply to every member of the patient group. This finding could have consequences for the course of treatment. AIM: To find out if the cognitive styles of autistic patients can predict whether their social functioning will improve after three years of treatment we conducted a follow-up study in which we examined 44 non-retarded adolescents with an autism spectrum disorder who were receiving residential treatment. METHOD: On the basis of factor scores awarded in an extensive battery of neuropsychological tests, we formed subgroups of patients with weak versus strong central coherence and cognitive shifting. Then analyses of variance were used to discover whether the subgroups were predictors of changes in three aspects of social functioning: autistic symptoms, social intelligence and social competence. RESULTS: We found a small but significant gain in all the social domains. However, there were clear individual differences in the degree of improvement. Cognitive shifting was found to be a predictor of a clinically meaningful improvement in social competence. CONCLUSION: The correlation found between cognitive shifting and social competence indicates that patients with an autism spectrum disorder should be given different forms of treatment that take differences in cognitive style into account.

Detection of thrombophlebitis with 111In-labeled anti-fibrin antibody: preliminary results.

Deep venous thrombosis remains a major medical problem, affecting a large segment of the population and resulting in significant mortality and morbidity. Current techniques available for detecting deep venous thrombosis present limitations that may mitigate their potential benefit to the patient. Invasive techniques, such as ascending contrast venography, carry risks to the patient with regard to complications such as an allergic reaction to an iodine dye, adverse effects to renal functions, and clot formation in a normal vein. Noninvasive techniques, such as Doppler ultrasound and impedance plethysmography, evaluate only a limited segment of the venous bed. The need remains for a diagnostic technique that is safe, accurate, and widely accessible. A readily available noninvasive scintigraphic technique utilizing radiolabeled monoclonal anti-fibrin antibody may overcome some of these shortcomings. This imaging examination is quite effective in detecting clots in the lower extremities. Compared to contrast venography, 111In-labeled anti-fibrin antibody imaging appears to be as sensitive in identifying acute venous thrombosis. In addition, the preliminary data indicate that anticoagulation with heparin may interfere with adequate visualization of the clots with this technique.

Incomplete redistribution in delayed thallium-201 single photon emission computed tomographic (SPECT) images: an overestimation of myocardial scarring.

To determine if incomplete redistribution at 4 h in exercise tomographic thallium-201 studies is always due to a myocardial scar, 141 patients were evaluated before and after a total of 160 successful percutaneous transluminal coronary angioplasty procedures. Thallium studies were analyzed using polar "bull's-eye" maps. For both immediate and delayed images, abnormalities were quantified as a thallium score by calculating a standard deviation-weighted sum of pixels greater than 2.5 SD below gender-matched normal limits. One hundred forty-four of 160 studies indicated abnormalities before angioplasty. Of these 144, incomplete redistribution occurred in 111 (77%): 16 (14%) in patients with and 95 (86%) in patients without prior Q wave myocardial infarction. After angioplasty, improvement in delayed image score occurred in 8 (50%) of 16 patients with prior infarction and 72 (76%) of 95 patients without prior infarction (p less than 0.05). After angioplasty, delayed images were normal in 1 (6%) of 16 patients with prior infarction and 32 (34%) of the 95 without (p less than 0.05). Before angioplasty, delayed image scores were positively correlated with scores in the immediate postexercise images in patients with (r = 0.84) and those without (r = 0.69) prior infarction. To determine if additional delayed images could help differentiate scar from ischemia, an 8 to 24 h delayed image was obtained in each of 40 other patients with incomplete redistribution at 4 h. Of 28 patients without prior infarction, 15 had no redistribution, and 13 had further redistribution at 8 to 24 h.

Gold-195m for serial first pass radionuclide angiocardiography during upright exercise in patients with coronary artery disease.

Sequential first pass radionuclide angiocardiography can be performed in rapid succession using gold-195m because of its low radiation dose and short half-life (30.5 seconds). In 25 patients with known or suspected coronary artery disease, first pass studies with gold-195m were obtained using a computerized multicrystal gamma camera at rest (n = 29), at the end of each 3 minute stage of exercise (n = 25) and immediately after exercise (n = 23). In 13 patients, assessment of left ventricular function during exercise with gold-195m was combined with thallium-201 stress scintigraphy. Left ventricular ejection fraction at rest assessed with technetium-99m and gold-195m correlated well (r = 0.93). In addition, repeat left ventricular ejection fractions at rest with gold-195m correlated closely (r = 0.96). Comparing peak exercise left ventricular ejection fraction with ejection fraction at rest, abnormal left ventricular reserve was found in 20 of 25 patients. Various abnormal patterns of left ventricular ejection fraction response were noted, showing the diagnostic potential of serial exercise angiocardiography. Thallium-201 myocardial images, obtained on a single crystal gamma camera after multiple gold-195m injections, were all of good diagnostic quality and were abnormal in 10 of 13 patients. Thus, multiple high count rate first pass studies can be obtained with gold-195m during and after exercise, allowing serial study of physiologic changes in left ventricular function during exercise. Thallium-201 myocardial imaging can be performed using the same exercise test, providing direct comparison of myocardial function and perfusion.

Cognitive evaluation in adult patients with Möbius syndrome.

OBJECTIVE: To establish the occurrence of mental retardation in a group of patients with Möbius syndrome and subsequently, if mental retardation is absent, to screen major aspects of memory and attention, in order to assess possible pervasive dysfunction in these cognitive domains which might be responsible for the current view that mental retardation occurs frequently in Möbius syndrome. METHODS: In a group of 12 Dutch Möbius patients, intellectual performance, memory function and attention were assessed using a number of standardized neuropsychological tests. RESULTS: The mean general intellectual performance did not differ significantly from that of the Dutch population. Screening of selective attention and memory did not provide indications of pervasive dysfunctions in these domains. CONCLUSION: The rate of occurrence of mental retardation in our group of Möbius patients did not differ from that in the normal Dutch population. Furthermore, there was no evidence of attention and memory dysfunction in our group of Möbius patients.

Impaired cognitive shifting in parkinsonian patients on anticholinergic therapy.

In this study we established that cognitive shifting, an ability that is known to be affected in PD, is more impaired in PD patients, treated with anticholinergics, than in de novo patients. Eleven PD patients on anticholinergic monotherapy were compared with 30 de novo patients. The groups did not differ with respect to age, duration and severity of PD, and depression, nor with respect to general intelligence or attention. We assessed cognitive shifting with three different card-sorting tests. The patients on anticholinergics showed a poorer performance on all card-sorting tests than the de novo patients did. The patients on anticholinergics needed significantly more trials in two card-sorting tests and discovered significantly less categories in total. There was also a significant difference in memory performance, but memory performance did not correlate with any score on the card-sorting tests. This indicates that the performance on card-sorting tests and the memory performance were independent.

Executive functions and disease characteristics in Parkinson's disease.

In the present study, we investigated the association of two executive functions with disease characteristics in Parkinson's disease (PD), especially with severity of motor symptoms. We operationalized two executive functions, viz. fluency and cognitive shifting, each in a number of tests with heterogeneous materials, but with an identical format. We calculated the correlations between test performance and disease characteristics, including the factor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). The results of this study show that only cognitive shifting was consistently associated with the severity of motor symptoms in PD, in particular with rigidity. None of the fluency tests had a significant association with severity of motor symptoms. The present study indicates that PD, as reflected by the severity of motor symptoms, is not associated with a general decrease in executive function. In spite of the fact that both are executive functions and both require generation of items, fluency and cognitive shifting are differentially related to PD.

Memory performance under varying cueing conditions in patients with Parkinson's disease.

The present study is a continuation of a previous study in memory performance which showed that Parkinson's disease (PD) patients increasingly relied on explicit cues which prompt the external strategy of serial clustering, in comparison to control subjects (CS), who profited increasingly from implicit cues which prompt the internal and more effective strategy of semantic clustering. In this study, we investigated whether the recall of PD patients can be affected by adding or removing explicit cues. We manipulated the California Verbal Learning Test in two ways. First, we told the subjects under study in advance from which categories the items to be recalled were derived, thus making the implicit cue to cluster semantically explicit (explicit condition). Next, we permuted the sequence of the items in each trial, thus preventing the subjects from adhering to the serial order, i.e. to explicit cues (permuted condition). We included the data of our previous study (mixed condition) in the analysis of memory and learning performance in the three conditions. Learning of PD patients, as reflected in the semantic ratio, proved to be more affected by the cueing conditions than that of CS. Total performance and the serial ratios did not show a significant interaction between group and cueing condition. The results are discussed in terms of external and internal generation of problem-solving strategies.

Haloperidol and cognitive shifting.

In this study haloperidol appeared to affect the performance on a selected category of cognitive tasks considered to represent shifting aptitude. A pretest--post-test design was used with two groups of subjects: 17 patients suffering from idiopathic spasmodic torticollis, and 17 controls who were matched for age and intelligence. The results are discussed in relation to previous findings on haloperidol and cognition, shifting disorder in Parkinson's disease and changes in behavioural organization found in animals with an experimentally induced dopaminergic hypoactivity.

Memory and learning strategies in patients with Parkinson's disease.

Parkinson's disease patients (PD) do not differ from control subjects (CS) when they have to execute a problem solving task in which external cues for solving the problem are given. However, when PD have to solve a problem by means of an internally generated strategy, they show a serious decrease in performance. We hypothesised that this distinction may also apply to the way PD and CS organize recall. In order to test our hypothesis the California Verbal Learning Test (CVLT) was administered to 59 PD and 30 CS. The test consists of five learning trials using a 16-word target list, composed of four items from each of four semantic categories. The fact that the word list was built on this implicit organization was not divulged in advance. The sequence in which the words were read is fixed; each subsequent word belongs to a category being different from the category to which the preceding word belongs. The organization in recall according to the semantic categories is considered to be the result of an unprompted, internally generated strategy. Recall according to the sequence in which the words are read by the experimenter, is viewed as an externally offered strategy. The results prove to be in line with our hypothesis: unlike CS who appeared to rely mainly and increasingly on an internally generated semantic organization, PD showed evidence of gradually adhering more to the externally imposed serial sequence.

Left ventricular systolic performance during upright bicycle exercise in patients with essential hypertension.

Left ventricular performance was evaluated at rest and during maximal upright bicycle exercise in 51 patients with chronic essential hypertension. Twenty-eight of these patients had no clinical or electrocardiographic evidence of coronary artery disease and comprise the primary study population. The remaining 23 patients had coronary artery disease and represent a comparison group. First-pass radionuclide angiocardiograms were obtained at rest and during maximal upright bicycle exercise, allowing evaluation of global left ventricular ejection fraction and regional wall motion. At the time of the radionuclide studies, all patients were hypertensive, defined as a diastolic blood pressure 90 mm Hg or greater and/or a systolic blood pressure 140 mm Hg or greater with the patient at rest and sitting. In the primary study group, the left ventricular functional response to upright bicycle exercise was normal in 26 of 28 patients. Left ventricular ejection fraction averaged (+/- standard error) 65 +/- 2 percent at rest and increased significantly to 76 +/- 2 percent with exercise (p less than 0.001). Regional wall motion was normal both at rest and during exercise in all patients. Seventeen patients had electrocardiographic evidence of left ventricular hypertrophy, and 14 were receiving propranolol therapy. The left ventricular functional response also was normal in these subgroups. In contrast to the nearly uniform normal left ventricular responses noted in the patients with hypertension alone, the group with concomitant coronary artery disease had a markedly higher incidence of abnormal left ventricular reserve (19 of 23 versus two of 28, p less than 0.001) during exercise. Thus, in most patients with essential hypertension but without concomitant coronary artery disease, left ventricular reserve during exercise was normal. Hypertension, even with left ventricular hypertrophy, should not be viewed as the cause for an abnormal left ventricular response to exercise in a patient undergoing diagnostic exercise radionuclide angiocardiography.

Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography.

To impact on the development of clinical congestive heart failure as a complication of doxorubicin therapy, left ventricular ejection fraction was monitored with serial resting radionuclide angiocardiography in 1,487 patients with cancer over a seven-year period in both university and community hospital environments. A high-risk subset of 282 patients was selected for retrospective analysis of their clinical outcome. High-risk patients were identified by one or two of the following three criteria: decline of 10 percent or more in absolute left ventricular ejection fraction from a normal baseline to 50 percent or less; high cumulative dose of doxorubicin (more than 450 mg/m2); abnormal baseline left ventricular ejection fraction (less than 50 percent). Clinical congestive heart failure occurred in 46 (16 percent) during the treatment period, and in an additional three patients (1.3 percent) at last follow-up examination 11.8 +/- 14.2 months following discontinuation of doxorubicin. Total cumulative dosages of doxorubicin that precipitated congestive heart failure (75 to 1,095 mg/m2) and those that did not (30 to 880 mg/m2) varied widely. Decline of 10 percent or more in absolute left ventricular ejection fraction to a value of 50 percent or less preceded administration of the final dose of doxorubicin that precipitated clinical congestive heart failure in the majority of patients in whom congestive heart failure developed. Clinical congestive heart failure improved in 87 percent given routine therapy with digitalis, diuretics, and/or vasodilators. Criteria for monitoring left ventricular ejection fraction and discontinuing doxorubicin were formulated. The occurrence of clinical congestive heart failure was compared in those patients whose management was concordant with proposed criteria (Group A) and in those whose management was not (Group B). Group A had a lower incidence of congestive heart failure compared with Group B (2.9 percent versus 20.8 percent, p less than 0.001) and had only mild congestive heart failure that resolved with treatment (n = 2) and no deaths due to congestive heart failure. Multivariate analysis with proportional-hazards regression (Cox's model) demonstrated a fourfold reduction in the incidence of congestive heart failure independent of other clinical predictor variables in those patients whose management was concordant with proposed guideline criteria. The incidence, persistence, late development, predictability, and reversibility of clinical congestive heart failure were comparable in university and community hospital settings.(ABSTRACT TRUNCATED AT 400 WORDS)

An instant kit method for labeling antimyosin Fab' with technetium-99m: evaluation in an experimental myocardial infarct model.

An instant kit method for labeling antibody Fab' fragments was developed. The method utilizes a ligand exchange reaction between the intermediate complex 99mTc-D-glucarate and the free sulfhydryl groups on the antibody Fab' fragment. Radiolabeling of the Fab' using generator eluate achieves quantitative 99mTc incorporation in less than 30 min at room temperature. The radiolabel is stable in human plasma for at least 24 hr and stable to incubation with 10 mM diethylene-triaminepentaacetic acid (24 hr) and 1 mM diaminodithiol agent (up to 3 hr). Mouse biodistribution of 99mTc-antimyosin shows faster blood clearance and lower uptake in the lungs, liver, and spleen in comparison to 111In-antimyosin. Technetium-99m-antimyosin and 111In-antimyosin showed equivalent ability to detect myocardial infarct in a canine model.

Evaluation of indium-111-labeled antifibrin monoclonal antibody for the diagnosis of venous thrombotic disease.

The potential advantage of using 111In-antifibrin (111In-AF) monoclonal antibody for the diagnosis of deep venous thrombosis (DVT) was studied in 44 patients with suspected DVT (27 underwent heparin therapy before 111In-AF injection). All patients had contrast venography (considered as the gold standard) and 111In-AF scintigraphy within 24 hr. Two to 3 mCi of 111In-AF were injected intravenously, and planar scintigraphy of the limbs was recorded within 10 min (17 times), 3 hr (44 times), and 18 hr (39 times). Indium-111-AF images were then interpreted without knowledge of the results of the other examinations. The DVT diagnostic accuracy of 111In-AF was greater when interpretation was based on images recorded at different time periods after injection. Indium-111-AF sensitivity for diagnosis of DVT was 85% (29/34) and was not apparently decreased by heparin therapy. None of the 10 patients with negative contrast venography had a positive 111In-AF scan. The results demonstrate the importance of recording serial images and the excellent accuracy of 111In-AF for diagnosing DVT.

Effect of patient positioning on left lateral thallium-201 myocardial images.

The effect of patient positioning on thallium-201 images in the left lateral projection was evaluated in 28 patients. The left lateral image was performed with the patient on his right side (LLrs) and also supine (LLsup). False-positive inferoposterior defects were reported in five patients (18%) in the LLsup view, but not in the LLrs view. Image quality was better in the LLrs view. The false-positive results in the LLsup view may result from two factors: a) overlap of the left hemidiaphragm and myocardium; or b) changes in orientation of the heart in the two lateral positions. Therefore, thallium-201 images in the LL position should be performed with the patient lying on his right side.

Quantitative analysis of stress thallium-201 myocardial scintigrams: a multicenter trial.

Previously we validated a method for quantification of 201TI myocardial stress distribution and washout in which the patient's stress and washout circumferential profiles are compared with observed normal limits. The present study reports the results of a multicenter trial in which this method, utilizing normal limits from our institution, was employed to evaluate the presence, location, and extent of coronary artery disease (CAD). The normal limits utilized were generated from 49 patients having a low likelihood of CAD. The study population included 157 patients from four centers in the United States and Canada as well as a comparative prospective population from Cedars-Sinai Medical Center (CSMC) of 51 patients with CAD, 30 patients with normal coronary arteriograms, and 30 additional low-likelihood normals. The results in the combined centers regarding overall detection of CAD revealed a sensitivity of 84% and a frequency of test normality in the patients with low likelihood of CAD of 88%, compared to a sensitivity of 82% and true normalcy rate of 83% obtained in the prospective CSMC population. The sensitivity for detecting disease increased according to the extent of angiographic CAD in both the multicenter sites and the prospective CSMC group. Regarding localization of disease, similar sensitivities and specificities for detecting disease in individual coronary arteries were found in the multicenter sites and the prospective CSMC population. The results indicate that our method for quantifying 201TI stress-redistribution scintigrams utilizing standard normal limits can be applied at other institutions using a variety of scintillation cameras with similar accuracy to that currently obtained at our institution.

Noninvasive radiographic assessment of cardiovascular function in acute and chronic respiratory failure.

Noninvasive radiographic techniques have provided a means of studying the natural history and pathogenesis of cardiovascular performance in acute and chronic respiratory failure. Chest radiography, radionuclide angiocardiography and thallium-201 imaging, and M mode and cross-sectional echocardiography have been employed. Each of these techniques has specific uses, attributes and limitations. For example, measurement of descending pulmonary arterial diameters on the plain chest radiograph allows determination of the presence or absence of pulmonary arterial hypertension. Right and left ventricular performance can be evaluated at rest and during exercise using radionuclide angiocardiography. The biventricular response to exercise and to therapeutic interventions also can be assessed with this approach. Evaluation of the pulmonary valve echogram and echocardiographic right ventricular dimensions have been shown to reflect right ventricular hemodynamics and size. Each of these noninvasive techniques has been applied to the study of patients with respiratory failure and has provided important physiologic data.