[Child and adolescent psychiatric consultation encourages the transformation of youth care, but collaboration is not yet self-explanatory]. / Consultatie van de kinder- en jeugd­psychiater bevordert de transformatie van jeugdhulp, maar samenwerking gaat niet vanzelf.

BACKGROUND: The mission in Dutch youth care is to work together to help the child and its family in the best possible way. Child and adolescent psychiatric consultation seems a good way to contribute to this mission, but this is not self-explanatory. Many colleagues feel uncertain how to maintain their medical responsibility. AIM: To provide insight in the consultation process, which legislation to apply as well as its practical consequences in various settings. METHOD: The effect of legislation is worked out in various consultative settings. The consequences for the process of consultation are worked out as well as the consequences for the persons involved. RESULTS: Consultation is a good way to collaborate with adult psychiatry as well as youth care. It is important to realise the different roles as well as the different legislative consequences, because of its influence on the consultation process. CONCLUSION: While there is a need for psychiatric consultation in the field of youth care, it still is not an obvious method. In addition to political and financial limitations there is uncertainty in the field how to develop consultation the best way. The Dutch Society of Psychiatry published a supportive Guide on consultation, aiming to help in a practical way.

Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease.

Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/ß-catenin signaling and loss of CYLD sensitizes MM cells to NF-κB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFκB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF-κB and Wnt/ß-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity.

Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling.

A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.

The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis.

In multiple myeloma (MM), angiogenesis is strongly correlated to disease progression and unfavorable outcome, and may be promoted by bone marrow hypoxia. Employing gene-expression profiling, we here identified the pro-angiogenic factor adrenomedullin (AM) as the most highly upregulated gene in MM cells exposed to hypoxia. Malignant plasma cells from the majority of MM patients, belonging to distinct genetic subgroups, aberrantly express AM. Already under normoxic conditions, a subset of MM highly expressed and secreted AM, which could not be further enhanced by hypoxia or cobalt chloride-induced stabilization of hypoxia-inducible factor (HIF)1α. In line with this, expression of AM did not correlate with expression of a panel of established hypoxia-/HIF1α-target genes in MM patients. We demonstrate that MM-driven promotion of endothelial cell proliferation and tube formation is augmented by inducible expression of AM and strongly repressed by inhibition of endogenous and hypoxia-induced AM activity. Together, our results demonstrate that MM cells, both in a hypoxia-dependent and -independent fashion, aberrantly express and secrete AM, which can mediate MM-induced angiogenesis. Thus, AM secretion can be a major driving force for the angiogenic switch observed during MM evolution, which renders AM a putative target for MM therapy.

Performance of semiautomatic assessment of carotid artery stenosis on CT angiography: clarification of differences with manual assessment.

BACKGROUND AND PURPOSE: Semiautomated methods for ICA stenosis measurements have the potential to reduce interobserver variability and to speed up its analysis. In this study, we estimate the precision and accuracy of a semiautomated measurement for carotid artery stenosis degree and identify and explain differences compared with the manual method. MATERIALS AND METHODS: In this retrospective study involving 90 patients, 2 observers determined the stenosis degree twice, with both the semiautomated and the manual method. Intra- and interobserver correlations were calculated for both methods. The accuracy was estimated by comparing average semiautomated with manual measurements. The semiautomated stenosis calculations were performed using either the minimal or maximal intersection at the reference site. Individual cases with large differences in measurement were retrospectively inspected by 3 observers. RESULTS: Intra- (R = 0.93, 0.96) and interobserver (R = 0.98) correlations for the semiautomated method were excellent and exceeded the manual performance correlations (R = 0.87, 0.86). The semiautomated measurements correlated well with the manual measurements (R = 0.87), with high specificity of 96% and lower sensitivity of 63%. Large differences were caused by misinterpretations of the semiautomated method associated with calcified plaques, resulting in overestimations of the minimal diameter, underestimation of stenosis degree, and incorrect centerlines. The effect of using the minimal diameter at the reference position resulted in a small, but significant, underestimation of the stenosis degree by the semiautomated method. CONCLUSIONS: The semiautomated method showed an excellent reproducibility and good correlation with manual measurements with a high specificity and lower sensitivity for detecting a significant stenosis. Erroneous semiautomatic stenosis measurements were associated with the presence of calcium.

Quantitative multi-pinhole small-animal SPECT: uniform versus non-uniform Chang attenuation correction.

Attenuation of photon flux on trajectories between the source and pinhole apertures affects the quantitative accuracy of reconstructed single-photon emission computed tomography (SPECT) images. We propose a Chang-based non-uniform attenuation correction (NUA-CT) for small-animal SPECT/CT with focusing pinhole collimation, and compare the quantitative accuracy with uniform Chang correction based on (i) body outlines extracted from x-ray CT (UA-CT) and (ii) on hand drawn body contours on the images obtained with three integrated optical cameras (UA-BC). Measurements in phantoms and rats containing known activities of isotopes were conducted for evaluation. In (125)I, (201)Tl, (99m)Tc and (111)In phantom experiments, average relative errors comparing to the gold standards measured in a dose calibrator were reduced to 5.5%, 6.8%, 4.9% and 2.8%, respectively, with NUA-CT. In animal studies, these errors were 2.1%, 3.3%, 2.0% and 2.0%, respectively. Differences in accuracy on average between results of NUA-CT, UA-CT and UA-BC were less than 2.3% in phantom studies and 3.1% in animal studies except for (125)I (3.6% and 5.1%, respectively). All methods tested provide reasonable attenuation correction and result in high quantitative accuracy. NUA-CT shows superior accuracy except for (125)I, where other factors may have more impact on the quantitative accuracy than the selected attenuation correction.

The relation of carotid calcium volume with carotid artery stenosis in symptomatic patients.

BACKGROUND AND PURPOSE: Recent research showed a strong correlation of calcium volume scores with degree of stenosis, suggesting that calcium volume could be used in the diagnosis of carotid artery stenosis. We investigated the accuracy of the use of calcium volume scores to diagnose carotid artery stenosis in our target population of recently symptomatic patients. MATERIALS AND METHODS: Ninety symptomatic patients suspected of having carotid artery stenosis underwent CTA, resulting in images of 159 evaluable arteries. The correlation between calcium volume and degree of stenosis was calculated by using the Pearson correlation coefficient. With thresholds of 0.03 and 0.09 mL, we assessed the diagnostic performance of a calcium volume-based evaluation of stenosis for a previously reported stenosis cutoff of 40% and for the clinically important cutoffs of 50% and 70%. RESULTS: In our patients series, the calcium volume score was not related to the stenosis degree on the symptomatic side (R = 0.04, P = .7) and was weakly related on the asymptomatic side (R = 0.29, P = .005). The diagnostic accuracy of the calcium volume score to estimate 40% stenosis was relatively low: a sensitivity of 47% or 64% and a specificity of 52% or 82%, for the 0.09 and 0.03 mL thresholds, respectively. The diagnostic accuracy decreased with increasing degree of stenosis. CONCLUSIONS: We could not confirm the previously reported strong correlation of calcium volume with stenosis degree in our population of patients with recent neurologic symptoms. We conclude that in this particular domain, calcium volume cannot be used to estimate the degree of stenosis.

Patient-specific computational hemodynamics of intracranial aneurysms from 3D rotational angiography and CT angiography: an in vivo reproducibility study.

BACKGROUND AND PURPOSE: Patient-specific simulations of the hemodynamics in intracranial aneurysms can be constructed by using image-based vascular models and CFD techniques. This work evaluates the impact of the choice of imaging technique on these simulations. MATERIALS AND METHODS: Ten aneurysms, imaged with 3DRA and CTA, were analyzed to assess the reproducibility of geometric and hemodynamic variables across the 2 modalities. RESULTS: Compared with 3DRA models, we found that CTA models often had larger aneurysm necks (P = .05) and that most of the smallest vessels (between 0.7 and 1.0 mm in diameter) could not be reconstructed successfully with CTA. With respect to the values measured in the 3DRA models, the flow rate differed by 14.1 ± 2.8% (mean ± SE) just proximal to the aneurysm and 33.9 ± 7.6% at the aneurysm neck. The mean WSS on the aneurysm differed by 44.2 ± 6.0%. Even when normalized to the parent vessel WSS, a difference of 31.4 ± 9.9% remained, with the normalized WSS in most cases being larger in the CTA model (P = .04). Despite these substantial differences, excellent agreement (κ ≥ 0.9) was found for qualitative variables that describe the flow field, such as the structure of the flow pattern and the flow complexity. CONCLUSIONS: Although relatively large differences were found for all evaluated quantitative hemodynamic variables, the main flow characteristics were reproduced across imaging modalities.

Model-based measurements of the diameter of the internal carotid artery in CT angiography images.

PURPOSE: Computed tomography angiography (CTA) is often used to determine the degree of stenosis in patients that suffer from carotid artery occlusive disease. Accurate and precise measurements of the diameter of the stenosed internal carotid artery are required to make decisions on treatment of the patient. However, the inherent blurring of images hampers a straightforward measurement, especially for smaller vessels. The authors propose a model-based approach to perform diameter measurements in which explicit allowance is made for the blurring of structures in the images. Three features of the authors' approach are the use of prior knowledge in the fitting of the model at the site of the stenosis, the applicability to vessels both with circular and noncircular cross-section, and the ability to deal with additional structures close to the arteries such as calcifications. METHODS: Noncircular cross-sections of vessels were modeled with elliptic Fourier descriptors. When calcifications or other high-intensity structures are adjacent to the lumen, both the lumen and the high-intensity structures were modeled in order to improve the diameter estimates of the vessel. Measurements were performed in CT scans of a phantom mimicking stenosed carotids and in CTA scans of two patients with an internal carotid stenosis. In an attempt to validate the measurements in CTA images, measurements were also performed in three-dimensional rotational angiography (3DRA) images of the same patients. RESULTS: The validity of the approach for diameter measurements of cylindrical arteries in CTA images is evident from phantom measurements. When prior knowledge about the enhancement and the blurring parameter was used, accurate and precise diameter estimates were obtained down to a diameter of 0.4 mm. The potential of the presented approach, both with respect to the extension to noncircular cross-sections and the modeling of adjacent calcifications, appears from the patient data. The accuracy of the size estimates in the patient images could not be unambiguously established because no gold standard was available and the quality of the 3DRA images was often suboptimal. CONCLUSIONS: The authors have shown that the inclusion of a priori information results in accurate and precise diameter measurements of arteries with a small diameter. Furthermore, in patient data, the assumption of a circular cross-section often appears to be too simple. The extension to noncircular cross-sections and adjacent calcifications paves the way to realistic modeling of the carotid artery.

Intracranial CT angiography obtained from a cerebral CT perfusion examination.

CT perfusion (CTP) examinations of the brain are performed increasingly for the evaluation of cerebral blood flow in patients with stroke and vasospasm after subarachnoid hemorrhage. Of the same patient often also a CT angiography (CTA) examination is performed. This study investigates the possibility to obtain CTA images from the CTP examination, thereby possibly obviating the CTA examination. This would save the patient exposure to radiation, contrast, and time. Each CTP frame is a CTA image with a varying amount of contrast enhancement and with high noise. To improve the contrast-to-noise ratio (CNR) we combined all 3D images into one 3D image after registration to correct for patient motion between time frames. Image combination consists of weighted averaging in which the weighting factor of each frame is proportional to the arterial contrast. It can be shown that the arterial CNR is maximized in this procedure. An additional advantage of the use of the time series of CTP images is that automatic differentiation between arteries and veins is possible. This feature was used to mask veins in the resulting 3D images to enhance visibility of arteries in maximum intensity projection (MIP) images. With a Philips Brilliance 64 CT scanner (64 x 0.625 mm) CTP examinations of eight patients were performed on 80 mm of brain using the toggling table technique. The CTP examination consisted of a time series of 15 3D images (2 x 64 x 0.625 mm; 80 kV; 150 mAs each) with an interval of 4 s. The authors measured the CNR in images obtained with weighted averaging, images obtained with plain averaging, and images with maximal arterial enhancement. The authors also compared CNR and quality of the images with that of regular CTA examinations and examined the effectiveness of automatic vein masking in MIP images. The CNR of the weighted averaged images is, on the average, 1.73 times the CNR of an image at maximal arterial enhancement in the CTP series, where the use of plain averaging increases the CNR only with a factor of 1.49. The quality of the weighted averaged images approaches that of CTA images, although in the present study the image quality of CTA was not quite reached. The automatic masking of veins is effective and only small remnants of veins were sometimes present in the masked images. Weighted averaging makes it possible to create CTA images from a CTP examination with a CNR considerably higher than that of images with maximal arterial enhancement. The quality of the resulting images approaches that of CTA images and offers the additional advantages to automatically differentiate between arteries and veins.

Diagnostic accuracy of CT angiography with matched mask bone elimination for detection of intracranial aneurysms: comparison with digital subtraction angiography and 3D rotational angiography.

BACKGROUND AND PURPOSE: Our aim was to determine the diagnostic accuracy of multisection CT angiography combined with matched mask bone elimination (CTA-MMBE) for detection of intracranial aneurysms compared with digital subtraction angiography (DSA) and 3D rotational angiography (3DRA). MATERIALS AND METHODS: Between January 2004 and February 2006, 108 patients who presented with clinically suspected subarachnoid hemorrhage underwent both CTA-MMBE and DSA for diagnosis of an intracranial aneurysm. Two neuroradiologists, independently, evaluated 27 predefined vessel locations in the CTA-MMBE images for the presence of an aneurysm. After consensus, diagnostic accuracy of CTA was calculated per predefined location and per patient. Interobserver agreement was calculated with kappa statistics. RESULTS: In 88 patients (81%), 117 aneurysms (82 ruptured, 35 unruptured) were present on DSA. CTA-MMBE detected all ruptured aneurysms except 1. Overall specificity, sensitivity, positive predictive value, and negative predictive value of CTA-MMBE were 0.99, 0.90, 0.98, and 0.95 per patient and 0.91, 1.00, 0.97, and 0.99 per location, respectively. Sensitivity was 0.99 for aneurysms >/=3 mm and 0.38 for aneurysms <3 mm. Interobserver agreement for aneurysm detection was excellent (kappa value of 0.92 per location and 0.80 per patient). CONCLUSION: CTA-MMBE is accurate in detecting intracranial aneurysms in any projection without overprojecting bone. CTA-MMBE has limited sensitivity in detecting very small aneurysms. Our data suggest that DSA and 3DRA can be limited to the vessel harboring the ruptured aneurysm before endovascular treatment, after detection of a ruptured aneurysm with CTA.

Removal of bone in CT angiography by multiscale matched mask bone elimination.

For clear visualization of vessels in CT angiography (CTA) images of the head and neck using maximum intensity projection (MIP) or volume rendering (VR) bone has to be removed. In the past we presented a fully automatic method to mask the bone [matched mask bone elimination (MMBE)] for this purpose. A drawback is that vessels adjacent to bone may be partly masked as well. We propose a modification, multiscale MMBE, which reduces this problem by using images at two scales: a higher resolution than usual for image processing and a lower resolution to which the processed images are transformed for use in the diagnostic process. A higher in-plane resolution is obtained by the use of a sharper reconstruction kernel. The out-of-plane resolution is improved by deconvolution or by scanning with narrower collimation. The quality of the mask that is used to remove bone is improved by using images at both scales. After masking, the desired resolution for the normal clinical use of the images is obtained by blurring with Gaussian kernels of appropriate widths. Both methods (multiscale and original) were compared in a phantom study and with clinical CTA data sets. With the multiscale approach the width of the strip of soft tissue adjacent to the bone that is masked can be reduced from 1.0 to 0.2 mm without reducing the quality of the bone removal. The clinical examples show that vessels adjacent to bone are less affected and therefore better visible. Images processed with multiscale MMBE have a slightly higher noise level or slightly reduced resolution compared with images processed by the original method and the reconstruction and processing time is also somewhat increased. Nevertheless, multiscale MMBE offers a way to remove bone automatically from CT angiography images without affecting the integrity of the blood vessels. The overall image quality of MIP or VR images is substantially improved relative to images processed with the original MMBE method.

Depressive and anxiety disorders in adolescence: a follow-up study of adolescents with school refusal.

Twenty-five adolescents referred to an outpatient clinic because of school refusal in 1985-1986 were followed up after an average of 5 years. DSM-III diagnoses and scores on the Maudsley Symptom Checklist were obtained at initial contact and a follow-up. At follow-up, information was also gathered on psychosocial adjustment, and subjects completed self-ratings of anxiety and depression. At initial contact, school refusal was associated mainly with anxiety symptoms, and to a lesser extent with depressive and somatoform disorders. No specific relationships were found between diagnoses at baseline and at follow-up. About half of the sample still had a psychiatric disorder at follow-up. Outcome was negatively associated with a history of previous psychosocial or psychiatric treatment and a small family size, and positively with a history of frequent somatic complaints.