[Sleep-wake patterns in adults with autism spectrum disorders in a clinical setting: a pilot study]. / Slaap-waakstoornissen bij volwassenen met autisme in een klinische setting: een pilotstudie.

BACKGROUND: The negative consequences of sleep-wake disorders in the general population and in children with an autism spectrum disorder (ASD) are well-established. However, little is known about sleep-wake disorders in adults with ASD.
AIM: To study and measure sleep-wake disorders and sleep-wake patterns in adults in a clinical facility who have been diagnosed primarily as having ASD without any comorbid intellectual disability.
METHOD: We assessed the sleep patterns of 19 patients in a residential facility. We asked patients to provide their sleep history, answer questionnaires and keep a sleep diary (subjective measurement). We also asked patients to collect actigraphy data (objective measurement) for seven days and to provide information about comorbid symptoms of anxiety and depression and use of medication.
RESULTS: Nine patients (47%) had undiagnosed comorbid sleep-wake disorders. Patients in our study overrated their sleep efficiency (diary) compared to objective data (actigraphy). However, patients' subjective sleep quality did match patients' sleep efficiency. Only two out of 14 patients with symptoms of anxiety and/or depression were diagnosed with a comorbid depressive disorder, 15 patients were treated with medication.
CONCLUSION: Sleep-wake disorders and comorbid symptoms of anxiety and depression might be more prevalent in adults with ASD in a residential facility than reported so far. This possibility needs to be considered more carefully during the diagnostic process and during treatment.

Fine mapping of the 9q31 Hirschsprung's disease locus.

Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.

Radiologist experience and CT examination quality determine metastasis detection in patients with esophageal or gastric cardia cancer.

We aimed to separate the influence of radiologist experience from that of CT quality in the evaluation of CT examinations of patients with esophageal or gastric cardia cancer. Two radiologists from referral centers ('expert radiologists') and six radiologists from regional non-referral centers ('non-expert radiologists') performed 240 evaluations of 72 CT examinations of patients diagnosed with esophageal or gastric cardia cancer between 1994 and 2003. We used conditional logistic regression analysis to calculate odds ratios (OR) for the likelihood of a correct diagnosis. Expert radiologists made a correct diagnosis of the presence or absence of distant metastases according to the gold standard almost three times more frequently (OR 2.9; 95% CI 1.4-6.3) than non-expert radiologists. For the subgroup of CT examinations showing distant metastases, a statistically significant correlation (OR 3.5; 95% CI 1.4-9.1) was found between CT quality as judged by the radiologists and a correct diagnosis. Both radiologist experience and quality of the CT examination play a role in the detection of distant metastases in esophageal or gastric cardia cancer patients. Therefore, we suggest that staging procedures for esophageal and gastric cardia cancer should preferably be performed in centers with technically advanced equipment and experienced radiologists.

The epithelial cellular adhesion molecule (Ep-CAM) is a ligand for the leukocyte-associated immunoglobulin-like receptor (LAIR).

Human leukocyte-associated immunoglobulin-like receptor (LAIR)-1 is expressed on many cells of the immune system and is predicted to mediate inhibitory functions based on the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. Although the role of LAIR-1 in the regulation of immune responses in vivo is unknown, LAIR-1 cross-linking by monoclonal antibody inhibits various immune cell functions in vitro. Here, we identify the colon carcinoma-associated epithelial cellular adhesion molecule (Ep-CAM) as a ligand for LAIR-1 and LAIR-2, a related soluble LAIR-1 family member. Ep-CAM interacts with the LAIR molecules through its first epidermal growth factor domain; Ep-CAM--specific antibodies can abrogate the binding. Intraepithelial T lymphocytes express LAIR-1 and thus may interact with Ep-CAM present on human intestinal epithelium. We propose that LAIR-1--Ep-CAM interaction may contribute to mucosal tolerance and that LAIR-2 possibly modulates this function.

[Veterinarians:'Watch your affairs!']. / Dierenarts: 'let op uw saeck!'

The most relevant results of a written questionnaire among veterinarians in the Netherlands are presented and discussed. The inquiry was performed by MarketResponse Nederland BV. The objective was to get an overview of the current perception and the future view of the profession. The response was 37%. Most respondents (66%) were practitioners, 7% were active in research or teaching institutions, 5% were governmental employees, 5% were employed in industry, and 17% did not belong to any of these categories (retired, unemployed etc.). Forty-seven per cent of the veterinarians practised mainly small animal medicine, 24% large animal medicine (cattle 15%, swine 8%, and poultry 1%), and 4% equine medicine; 24% worked in mixed practices. This division reflects the real-life situation. The percentage of female respondents was considerably higher in the group of recent graduates than in the other groups of graduates (increasing from 27% in the graduation period 1980-1989 to 56% in the period 1990-1999). Sixty per cent of the veterinarians worked more than 40 hours a week. Veterinarians considered themselves reliable, honest, professional, client-minded, and animal-friendly. According to them, the public perceived veterinarians as being animal-friendly, professional, and reliable. Veterinarians were less satisfied in their current position than other professional groups, particularly with regard to their income. Their current market position was considered indifferent or good. This position was influenced negatively by the decrease in the number of animals and competition from non-veterinarians and others. The situation could be improved by collaboration and practice fusions, specialization, and differentiation. More demanding and price-conscious clients and governmental regulations were considered important trends. Social, management, and marketing skills, increased knowledge and cooperation, and a vision of future developments were considered essential in order to be able react to developments on the market. About 60% of the practitioners and 50% of the other veterinarians felt that they lacked the right skills, and especially management and marketing skills, to react to these developments adequately. Most veterinarians (77%) considered that their training did not provide them with the skills needed for their current position. During training, more time should be spent on management, communication, marketing, and social skills. Based on the results, veterinary medicine in the Netherlands seems to be an introspective but good profession; however, the interesting aspects of the profession appear to be over-shadowed by less appreciated aspects and the income is moderate. Entrepreneuship is poorly developed, in part because this is considered taboo. The importance of skills that are not an integral part of veterinary medicine, such as management, marketing, and communication, is recognized, as is the lack of these skills. Despite this, emphasis is put on continuing professional education, species specialization, modernization, accreditation, and expansion of facilities and treatment possibilities as ways to respond to the market situation.

A phage antibody identifying an 80-kDa membrane glycoprotein exclusively expressed on a subpopulation of activated B cells and hairy cell leukemia B cells.

We have isolated a phage display library-derived monoclonal antibody, phab V-3, that identifies a membrane glycoprotein of approximately 80 kDa which is expressed on a subpopulation of activated B lymphocytes in secondary lymphoid organs. In agreement with their activated phenotype, phab V-3(+) B cells display a blast-like morphology, and are prone to spontaneous apoptosis in vitro, unless rescued by stimulation with CD40 ligand (CD40L). The expression of the phab V-3 molecule coincides with B cells that produce high levels of IgM, IgG and IgA in vitro upon stimulation with CD40L in combination with IL-2 and IL-10. Immunofluorescent analysis of B cell malignancies unveiled that the phab V-3 molecule was uniquely expressed on hairy cell leukemia (HCL) B cells. Similar to phab V-3(+) tonsils B cells, HCL B cells have been reported to express CD11c, CD95 and CD27, which might indicate that the phab V-3(+) B cells in HCL are the malignant counterpart of the phab V-3(+) B cell subpopulation.

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling.

Leukocyte-associated Ig-like receptor-1 (LAIR-1) belongs to the growing family of immunoreceptor tyrosine-based inhibitory motif-bearing receptors and is expressed on the majority of peripheral mononuclear cells, including NK cells, T cells, B cells, monocytes, and dendritic cells. In this study, we investigated the distribution and the capacity of LAIR-1 to function as an inhibitory receptor on human B cells. LAIR-1 is expressed from early on during B cell differentiation, but is absent on approximately half of the memory B cells, and all germinal center B cells, plasmablasts, and terminally differentiated plasma cells. In vitro stimulation of naive B cells via the B cell receptor (BCR) or CD40, triggering proliferation and differentiation into Ig-producing plasma cells, is accompanied by loss of LAIR-1 expression. We previously reported that LAIR-1 can function as an inhibitory receptor on NK cells and T cells. Here, we demonstrate that it can also function as a negative regulator of BCR-mediated signaling, since simultaneous cross-linking of LAIR-1 and the BCR reduces the increase of intracellular Ca(2+) evoked by BCR ligation. Taken together, this suggests that the inhibitory mechanism of LAIR-1 is functional in multiple components of the hematopoietic system.

A recombinant, fully human monoclonal antibody with antitumor activity constructed from phage-displayed antibody fragments.

A single-chain Fv antibody fragment specific for the tumor-associated Ep-CAM molecule was isolated from a semisynthetic phage display library and converted into an intact, fully human IgG1 monoclonal antibody (huMab). The purified huMab had an affinity of 5 nM and effectively mediated tumor cell killing in in vitro and in vivo assays. These experiments show that nonimmunized phage antibody display libraries can be used to obtain high-affinity, functional, and clinically applicable huMabs directed against a tumor-associated antigen.

Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid, euthyroid, and hyperthyroid subjects.

Overt hypothyroidism is associated with premature coronary artery disease, and this is assumed to be due to a deteriorated metabolism of atherogenic lipoproteins. The effect of thyroid status on plasma concentrations of lipoprotein(a) [Lp(a)], a recently recognized highly atherogenic lipoprotein in man, is unknown. In a cross-sectional study, plasma Lp(a) concentrations were higher in overtly hypothyroid subjects [255 +/- 28 (+/- SD) mg/L; n = 19] and lower in hyperthyroid subjects (75 +/- 28 mg/L; n = 27) compared to those in 54 euthyroid subjects (150 +/- 36 mg/L) and a reference population of local blood bank donors (155 +/- 31 mg/L; n = 114). These findings were confirmed in a follow-up study of 19 hypothyroid and 8 hyperthyroid individuals. In the hypothyroid subjects, initial levo-T4 substitution therapy (25 micrograms daily) caused a 55% decrease in plasma Lp(a) concentrations and a 27% decrease in total plasma apolipoprotein B (apo B). Good agreement was found between the decrease in Lp(a) and apo B at a normal free T4 index. Follow-up of 8 hyperthyroid subjects revealed that their plasma Lp(a) and apo B concentrations significantly increased with return of euthyroidism. In conclusion, good agreement was found between the direction and magnitude of the responses of apo B and Lp(a) to changes in thyroid status. The following findings suggest that different thyroid hormone-dependent mechanisms modulate plasma Lp(a) concentrations in man, in part analogous to modulation of apo B: 1) impaired catabolism in the hypothyroid state, and 2) a combination of suppressed secretion of apoB and Lp(a) with increased catabolism in hyperthyroid subjects. Increased plasma Lp(a) concentrations may contribute to the increased risk of premature coronary artery disease in the hypothyroid state.

Digital subtraction angiography of the carotid bifurcation.

This report described the results of digital subtraction angiography (DSA) in the diagnosis of arteriosclerotic disease of the extracranial arteries, especially the distal part of the common- and proximal part of the internal carotid arteries compared to the catheter angiography. 50 patients underwent DSA and conventional angiography. In 85% of the patients, the quality of the DSA examination was good. For the internal carotid arteries the standard sensitivity was 91% and the standard specificity 93%. In all patients both vertebral arteries were visualized on DSA. All patients underwent the non-invasive tests (OPG, Doppler, Duplex). These tests and the DSA together cannot always replace the catheter-angiography in case of carotid pathology. We started an investigation to assess in which cases the catheter-angiography can be replaced by DSA to arrive at the same diagnosis. The preliminary results indicate that replacement of the conventional angiography by DSA is possible in 80% of this patients group.

Interobserver variability in assessing renal artery stenosis by digital subtraction angiography.

Four experienced observers independently assessed digital subtraction angiograms (DSA) of 134 renal arteries in 67 patients. Only the main renal arteries were evaluated. All patients were hypertensive and were screened for the existence of renal artery stenosis. The findings were classified in four categories: 0-49% stenosis; 50-99% stenosis; total occlusion, and fibromuscular dysplasia (FMD). As a measure of interobserver agreement, the kappa-statistic, which corrects for agreement by chance alone, was used. A kappa-value of 0.65 +/- 0.06 (kappa +/- SE) resulted for all observers and all categories. For category I a conditional kappa = 0.74 and for category II a conditional kappa = 0.69 was found. In cases of total occlusion (2 patients) or FMD (3 patients), all observers agreed upon diagnosis. We conclude that DSA is a reliable method for assessing renal artery stenosis if images of sufficient diagnostic quality can be obtained (93% of observations). It can be used as a screening method for renovascular hypertension and possibly for follow-up studies after surgical correction or after percutaneous dilatation of renal artery stenosis.

Digital video subtraction angiography and duplex scanning in assessment of carotid artery disease: comparison with conventional angiography.

Digital video subtraction angiography (DVSA) and duplex scanning were compared to conventional angiography with regard to their accuracy in quantifying internal carotid artery disease. A classification of 108 carotid arteries available for comparison was made into five groups: normal (14), stenosis to 20% (15), stenosis from 20% to 49% (19), stenosis from 50% to 99% (44), and occlusion (16). The overall agreement corrected for chance (K) for DVSA was 0.738 +/- (SE) 0.049, which was better than for duplex scanning (K = 0.610 +/- 0.055). For hemodynamically significant disease (greater than or equal to 50% diameter reduction), both techniques were highly accurate: DVSA had a sensitivity of 95% (57/60) and a specificity of 92% (44/48); the sensitivity of duplex scanning was also 95% (57/60) and the specificity 85% (41/48). The accuracy in differentiating between high-grade stenosis and occlusion was 98% (59/60) for duplex scanning and 100% (60/60) for DVSA. The most prominent limitation of duplex scanning was its overestimation of disease in normal and minimally diseased arteries. Its specificity for ruling out any degree of disease was only 21% (3/14). DVSA had a poor predictive value of a normal test, 55% (12/22), and was more than one category wrong seven times, while this occurred only three times for duplex scanning. At the present time carotid endarterectomy without conventional angiography is only advocated when there is complete agreement between DVSA and duplex scanning.

The accuracy of ultrasonic duplex scanning in carotid artery disease.

Ultrasonic duplex scanning of the internal carotid artery is highly accurate in the detection of disease as expressed in its sensitivity of 0.97 and specificity of 0.82 for haemodynamic significant lesions. For the detection of obstructions of 20% or over, these parameters are 0.94 and 0.77 respectively. The most striking problem is the poor classification of normal vessels and those with minor lesions. The duplex scanning overestimates the degree of disease in these cases. For the external carotid artery the method differentiates reasonably well between non-haemodynamic and haemodynamic significant lesions.