Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma

Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n=29 low-grade intraepithelial neoplasia (LGIN) and n=27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.     

SMAGP, a new small trans-membrane glycoprotein altered in cancer

Using the Affymetrix array technology, we previously identified an EST strongly expressed in several metastatic cell lines. In the present study, we cloned the corresponding cDNA that encodes a new glycoprotein composed of 97 amino acids and containing a trans-membrane domain. Therefore, we named it SMAGP for Small trans-Membrane And Glycosylated Protein. SMAGP is strongly conserved during evolution. It is expressed by normal epithelia of various organs, the protein being notably localized to the lateral face of the plasma membrane of cohesive well-polarized epithelial cells. In addition, SMAGP contains binding domains for the protein 4.1 and the PDZ domain of MAGUK proteins. Similar protein features are observed in several cell-surface proteins involved via ternary complexes in intercellular processes leading to cytoskeleton assembly as well as intracellular signalling. Thus, SMAGP might similarly be involved in a scaffolding protein complex, and therefore participate in the epithelium organization or in subsequent functions. Immunohistochemical data obtained using human breast, colon and lung cancer samples sustain this hypothesis since they showed that, in both primary tumours and metastases, reduced expression and/or cytoplasmic redistribution of SMAGP is superimposable with low histological tumour differentiation features, namely a lack of epithelial cell polarity and disorganized tissue phenotype.     

Contrast dynamics during CT pulmonary angiogram: analysis of an inspiration associated artifact

OBJECTIVE: Several artifacts have been observed during contrast-enhanced CT of the pulmonary arteries. We describe a physiological artifact caused by a transient interruption of the contrast column in the pulmonary arteries associated with inspiration immediately prior to imaging. This results from a variable inflow of unopacified blood from the inferior vena cava (IVC). MATERIALS AND METHODS: From 327 consecutive pulmonary CT-angiograms, all performed on a single detector scanner at 3 mm collimation (1.5 mm incremental reconstruction), 50 positive studies, 46 indeterminate studies, and 33 negative studies (129 exams) were retrospectively reviewed by a blinded observer to determine the frequency of the described contrast interruption, its severity (mild, moderate, or severe), and its possible contribution to misinterpretation of studies. The numerical change in Hounsfield units was assigned within the right ventricular chamber for each examination to correlate with the subjective evaluation of severity. Statistical significance was determined with P = 0.05%. RESULTS: The artifact was present in 48 (37.2%) of the 129 evaluated studies. It was greater in frequency (50.0%) with the negative studies. The presence was 25% with positive studies and 36.7% with indeterminate exams. The interruption was more often mild (<100 HU change) in severity (45.8%). Three (6.6%) definite false positives were detected where the misinterpretation was directly attributed to the artifact. Three (6.6%) other examinations called positive were also directly related to the interrupted contrast column. However, since no further pulmonary vascular evaluation was performed, these examinations can only be considered indeterminate. Two of the latter 3 studies demonstrated a severe (>150 HU change) and the other study demonstrated a moderate (100-150 HU) interruption of contrast opacification. CONCLUSIONS: During inspiration, there is a variable increase in unopacified venous blood from the IVC, briefly diluting the contrast column entering from the SVC. This interruption is common, though usually mild in severity. However, a short severe interruption of vascular opacification can lead to misinterpretation as a pulmonary embolus or contribute to an indeterminate examination.     

Advances in in vivo imaging of serotonergic neurons in neuropsychiatric disorders

Alterations of central serotonergic neurotransmission, particularly changes in the presynaptically located serotonin transporter (SERT) availability, are thought to be one of the major pathomechanisms of neuropsychiatric symptoms. Modern neuroimaging techniques such as single-photon emission computed tomography and positron emission tomography employ radiolabeled tracers, which bind to SERT, and thus, allow detection of cerebral SERT availability in vivo. We review SERT imaging studies in patients with depression, anxiety disorders, eating disorders and patients with neurological diseases. We furthermore elucidate the potential of SERT imaging techniques in estimating the effect of selective serotonin reuptake-inhibitors.     

Use of brief depression screening tools in primary care: consideration of heterogeneity in performance in different patient groups

Heterogeneity of performance of screening tools in different patient groups has rarely been considered in the literature on depression screening in primary care. The objectives of the present study were to assess and to compare diagnostic accuracy of three screening questionnaires (Brief Patient Health Questionnaire, General Health Questionnaire-12, WHO-5) in identifying depression across various patient subpopulations and to assess the accuracy of the unaided clinical assessment of primary care physicians in the same subgroups. We conducted a cross-sectional validation study in 448 primary care patients. Two-by-two tables as well as receiver operating characteristics were applied. Results indicated that diagnostic accuracy (sensitivity, specificity) of the three screening instruments as well as of the clinical diagnoses differed in the various patient groups. Superiority of one screening tool over the other depends on the subgroup considered. Gender, age, form (subtype), and severity of depression influence the test characteristics of a screening tool. This should be considered if routine depression screening should be widely introduced. Of course, the benefit of routine screening also depends on efforts made for treatment and monitoring of patients in whom depression was diagnosed.     

Magical ideation -- defense mechanism or neuropathology? A study with multiple sclerosis patients

BACKGROUND: The major psychological stress factor in multiple sclerosis (MS) is loss of control of life. In MS patients with impaired cognition, magical ideation might be a characteristic way of thinking. Proof for this may be the high frequency of alternative treatments used by individuals with MS. The study investigates whether the level of magical ideation in MS patients is higher compared to healthy control subjects and, in case of positive confirmation, with which somatic and psychological features it is associated. Moreover, it is aimed to discuss the modalities of magical ideation in general. SAMPLING AND METHODS: A German version of the Magical Ideation Scale was validated with a group of 69 healthy subjects. Ninety-four MS patients were additionally assessed with the Dissociative Experience Scale, the Symptom-Check-List-90-Revised and 5 neuropsychological tests. RESULTS: The Magical Ideation Scale did not reveal a significant difference between MS patients and healthy controls (p = 0.968). Among the MS patients, magical ideation shows a correlation neither with age nor with disability, but a positive correlation (p = 0.007; r = 0.329) with the grade of neuropsychological deficiency. Among the psychological parameters, the highest positive correlation with magical ideation was found in dissociation (p = 0.000; r = 0.520). DISCUSSION: Magical ideation, sharing common features with dissociation, can be viewed as an early defense mechanism when perceiving a loss of control of life, particularly in early stages of MS. In late stages, when developing neuropsychological deficits, it may occur as a substitute for cognitive coping. The data may encourage clinicians to identify magical ideation. In young and previously diagnosed patients, it is important to acknowledge helplessness and support a rather rational way of coping. Training cognitive skills could be crucial to prevent older patients from losing touch with reality. More generally, the occurrence of a significant amount of magical ideation is discussed both as a psychological and a neurophysiologic regression of thinking.     

Consequences of a single short lasting cerebral oligemia and the influence of iron injected into the substantia nigra or in the ventrolateral striatum of the rat. Trigger of Parkinson’s disease pathogenesis?

Summary. One BCCA-phase (bilateral clamping of carotid arteria) leads to an extensive release of striatal dopamine with a subsequent formation of free radicals (Heim et al., 200b). Early investigations did not show histological damage to cerebral structures after 24 and 60min duration of a BCCA phase (Melzacka et al., 1994). The study here turned out that oligemic damage and an increase in iron (FeCl₃) concentration in the ventral striatum was responsible for most of the defective performance of the animals investigated. Striatal damaged animals were unable to correct their deficient performance to the same extent as was possible for animals which had been damaged through BCCA and FeCl₃ in the substantia nigra. Furthermore it turn out that with the use of a comprehensive behaviour profile which was able to gather 22 parameters simultaneously, 15 of these parameters did not correspond in the performance of the controls already after BCCA alone. Since during the ageing process, pathological effects may occur in vulnerable structures not only from disturbances to cerebral blood-perfusion but also from enrichment of iron in vulnerable structures (Connor, 1992) the question arose whether this situation did not reveal pathological mechanisms that might triggered the early symptoms of Parkinsons disease.