CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression.

Neuroblastoma (NB) is a common childhood malignant tumor of the neural crest-derived sympathetic nervous system. In NB the frequent loss of heterozygosity (LOH) on chromosome 1p raises the possibility that this region contains tumor-suppressor genes whose inactivation contributes to tumorigenesis. The human homolog of the Drosophila neural fate determination gene CASZ1, a zinc-finger transcription factor, maps to chromosome 1p36.22, a region implicated in NB tumorigenesis. Quantitative real-time PCR analysis showed that low-CASZ1 expression is significantly correlated with increased age (≥18 months), Children's Oncology Group high-risk classification, 1p LOH and MYCN amplification (all P<0.0002) and decreased survival probability (P=0.0009). CASZ1 was more highly expressed in NB with a differentiated histopathology (P<0.0001). Retinoids and epigenetic modification agents associated with regulation of differentiation induced CASZ1 expression. Expression profiling analysis revealed that CASZ1 regulates the expression of genes involved in regulation of cell growth and developmental processes. Specific restoration of CASZ1 in NB cells induced cell differentiation, enhanced cell adhesion, inhibited migration and suppressed tumorigenicity. These data are consistent with CASZ1 being a critical modulator of neural cell development, and that somatically acquired disruption of normal CASZ1 expression contributes to the malignant phenotype of human NB.

[Interferon-alpha treatment of the Churg-Strauss syndrome]. / Behandlung des Churg-Strauss-Syndromes mit Interferon-alpha.

HISTORY: Two patients, 60 (pat. 1; female) and 30 years of age (pat. 2; male), respectively, suffering from a histologically confirmed Churg-Strauss-syndrome and receiving immunosuppressive therapy were treated with Interferon-alpha. INVESTIGATIONS: Clinical complaints, disease activity, blood eosinophil counts, and lung function were monitored. In patient 1 the differential cell counts and immunocytology of bronchoalveolar lavage cells were assessed using flow cytometry. TREATMENT AND COURSE: Both patients were treated with interferon-alpha in dosages of 3 million units of IFN-alpha 2b or an equivalent dosage of interferon-acon thrice weekly subcutaneously. The patients were observed for a period of up to 24 months. Interferon-alpha induced remission of disease and allowed discontinuation of oral glucocorticoid therapy in both patients. Treatment also improved the peripheral polyneuropathia in patient 1 as well as the hemorrhagic cystitis and reduction of the Cushing syndrome (weight reduction of 19 kg) in patient 2. In addition, blood eosinophil counts normalised. After 12 months of treatment, the number of bronchoalveolar eosinophils decreased from 61,5% (5.7 x 106 cells/ml) to 7% (1.1 x 106 cells/ml). In addition, the proportion of CD4+ T-lymphocytes and B-cells increased, while CD8+ T-cells and NK cells decreased (pat. 1). CONCLUSION: Interferon-alpha may represent an effective alternative to the current treatment of Churg-Strauss syndrome consisting of corticosteroids and immunosuppressives.

Multiple tactile maps in the human cerebellum.

Functional imaging studies of the cerebellum have mostly investigated motor performance or have been limited to the anterior lobe and therefore the somatosensory representations in the human cerebellum have not been fully demonstrated. We used fMRI of the entire cerebellum during tactile stimulation of the hand and foot in six normal subjects. Our results demonstrate that the tactile projections to the cerebellum in humans are represented in both the anterior and posterior lobes. in agreement with previous functional imaging studies, our results show a large-scale, between-limb somatotopy comparable to that shown in early animal studies.

Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility.

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that included Cdkn2a, which encodes p16(INK4a) and p19(ARF), and the coding sequences for the BALB/c p16(INK4a) and p19(ARF) alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16(INK4a) and p19(ARF) alleles from BALB/c and DBA/2 indicated that the BALB/c p16(INK4a) allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19(ARF) alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16(INK4a) gene.

[Asthmatic airway inflammation]. / Die asthmatische Entzündung.

Asthma is an inflammatory disease of the airways even in its clinically mildest manifestation. The pathogenesis is based on complex interactions between inflammatory cells, soluble signal molecules (mediators) and structural cells as well as extracellular components of the airways. Bronchial inflammation is closely associated with bronchial hyperreactivity, airways obstruction and asthmatic symptoms. Airways inflammation causes airflow limitation via (1) acute muscular bronchoconstriction, (2) formation of mucous plugs, (3) thickening of the airway wall, and (4) fibrotic remodelling of the airways ("Remodelling"). The insights into bronchial inflammation as the basis of asthma is of principle significance for the diagnosis, prevention, and treatment of the condition.

[Asthma therapy for adults]. / Therapie des Asthma bronchiale im Erwachsenenalter.

The goal of asthma management is to achieve control of the condition. This essentially requires environmental control measures (allergen avoidance) and patient training and education. Drug treatment comprises anti-inflammatory (corticosteroids), and bronchodilatory controller therapy (long-acting beta 2-sympathomimetics, leukotriene receptor antagonists, retarded theophylline) as well as bronchodilatory medication as required (short-acting beta 2-sympathomimetics). The number and frequency of pharmacologic therapy relates to the severity of the clinical presentation. The combination of certain controller drugs (corticosteroids with long-acting beta 2-agonists, corticosteroids with leukotriene receptor antagonists, and beta 2-agonists with leukotriene receptor antagonists) yields a synergistic therapeutic effect as well as a compliance advantage.

High-b-value diffusion-weighted MR imaging of suspected brain infarction.

BACKGROUND AND PURPOSE: Recent technological advances in MR instrumentation allow acquisition of whole-brain diffusion-weighted MR scans to be obtained with b values greater than 1,000. Our purpose was to determine whether high-b-value diffusion-weighted MR imaging improved contrast and detection of signal changes in acute and chronic brain infarction. METHODS: We prospectively evaluated the MR scans of 30 subjects with a history of possible brain infarction on a 1.5-T MR imager with 40 mT/meter gradients (slew rate 150 T/m/s) by use of the following single-shot echo-planar diffusion-weighted MR sequences: 1) 7,999/ 71.4/1 (TR/TE/excitations, b = 1,000; 2) 999/ 88.1/3, b = 2,500; and 3) 7,999/ 92.1/4, b = 3,000. Diffusion-weighted MR imaging was performed in three orthogonal directions during all sequences. All subjects were scanned with fast fluid-attenuated inversion recovery (FLAIR) (10,006/145/2,200/1 [TR/TE/TI/excitations]) and fast spin-echo T2-weighted (3,650/95/3 [TR/TE/excitations], echo train length, 8). The diagnosis of brain infarction was established by clinical criteria. RESULTS: Twenty women and 10 men with a mean age of 67.7 years were enrolled in the study. One subject was excluded owing to poor image quality. Twelve of 29 subjects had a clinical diagnosis of acute infarction. All 12 had lesions that were hyperintense on diffusion-weighted images at all three b values; five were cortical and seven subcortical. There was increased contrast of all lesions on high-b-value scans (b = 2,500 and 3,000). Lesions that were hypointense on diffusion-weighted images were identified and evaluated at the three different b values. At b = 1,000, there were 19 hypointense lesions, whereas at b = 2,500 and 3,000 there were 48 and 55 lesions, respectively. On FLAIR and T2-weighted images, these low-signal lesions were predominantly chronic, subcortical, ischemic lesions and lacunar infarcts, but four chronic cortical infarcts, one porencephalic cyst, and one primary brain tumor were also found. Low-signal lesions were also noted to have increased contrast on high-b-value diffusion-weighted scans. CONCLUSION: High-b-value diffusion-weighted MR imaging (b = 2,500 or b = 3,000) had no impact on diagnosis of acute infarction. High-b-value diffusion-weighted MR imaging (b = 2,500) combined with diffusion-weighted MR imaging at b = 1,000 improves tissue characterization by increasing the spectrum of observed imaging abnormalities in patients with suspected brain infarction.

Bilateral symmetrical upper-lobe opacities: an unusual presentation of bronchiolitis obliterans organizing pneumonia.

A 45-year-old man was admitted with nonresolving fever, cough, and dyspnea 2 months after a common cold. His chest radiograph demonstrated bilateral symmetrical upper-lobe opacities reminiscent of tuberculosis. Transbronchial biopsy revealed inflammatory nonspecific alveolar lesions suggestive of bronchiolitis obliterans organizing pneumonia, which responded well clinically and radiologically to oral corticosteroids. Here, the case of a previously unreported radiographic manifestation of bronchiolitis obliterans organizing pneumonia is presented.

[Specific immunotherapy (hyposensitization) with insect venom in pregnancy]. / Spezifische Immuntherapie (Hyposensibilisierung) mit Insektengift in der Schwangerschaft.

BACKGROUND: Pregnancy typically prohibits the specific immunotherapy (SIT) of various allergic conditions, with the exception of pre-existing Hymenoptera venom allergies. International consensus currently recommends the continuation of a well-tolerated SIT with insect venom during pregnancy, since there is a significant risk of anaphylaxis after insect stings with potentially dismal outcomes for mother and fetus. CASE REPORT: We report on a 28-year old woman, becoming pregnant during specific immunotherapy with Hymenoptera venom. SIT was continued during pregnancy and a premature birth occurred at the 24th week. DISCUSSION AND CONCLUSION: Unfortunately, there are still conflicting opinions in Germany regarding SIT during pregnancy, and the decision to perform such therapy is entirely based on knowledge and/or level of comfort of the primary physician. Thus, obstetricians should closely work together with an allergologist in cases of pregnant women with insect sting allergies.

Structure and localization of mouse Pmscl1 and Pmscl2 genes.

Sera from some patients with polymyositis-scleoderma overlap syndrome (PM-SCL) recognize two antigenically unrelated proteins, PMSCL1 and PMSCL2. Complete mouse Pmscl1 and Pmscl2 cDNA sequences, chromosomal localizations, exon/intron structure, and promoter region sequences of the mouse Pmscl2 gene are presented. The PMSCL1 gene was found to overlap significantly with cyclin A2 in both human and mouse. As such, it may be deduced that PMSCL1 sequences map to human chromosome 4q27 and the proximal portion of mouse chromosome (Chr) 3 where human and mouse cyclin A2 genes reside. Analysis of human and mouse PMSCL1 cDNA sequences provides evidence that the PMSCL1 protein is 68 amino acids longer than previously thought. A BAC containing mouse Pmscl2 was localized to distal mouse Chr 4 by FISH. This BAC contains the microsatellite D4Mit310. D4Mit310 colocalizes with a number of genes that map to human 1p36. In fact, a STS (G25404) located 54.6 cR from the top of human chromosome 1 was found to contain PMSCL2 sequence upon BLAST search.

Mapping of the SWAP70 gene to mouse chromosome 7 and human chromosome 11p15.

The protein SWAP-70 was isolated as part of a DNA recombination complex in B lymphocytes, where it is predominantly expressed. In resting B cells, SWAP-70 is found in the cytoplasm; upon B-cell activation, it is transported both into the nucleus and to the cell membrane, where it is associated with the B-cell receptor complex and may play a role in signal transduction. In the nucleus, its involvement in heavy-chain class switch recombination has been suggested. In this report, using restriction fragment length polymorphism, simple sequence length polymorphism, and fluorescence in situ hybridization, we map the chromosomal localization of the mouse and the human genes to syntenic regions of mouse mid Chromosome (Chr) 7 and human Chr 11p15.

Functional neuroanatomy of the cognitive process of mapping during discourse comprehension.

We used functional magnetic resonance imaging (fMRI) to identify brain regions involved in the process of mapping coherent discourse onto a developing mental representation. We manipulated discourse coherence by presenting sentences with definite articles (which lead to more coherent discourse) or indefinite articles (which lead to less coherent discourse). Comprehending connected discourse, compared with reading unrelated sentences, produced more neural activity in the right than left hemisphere of the frontal lobe. Thus, the right hemisphere of the frontal lobe is involved in some of the processes underlying mapping. In contrast, left-hemisphere structures were associated with lower-level processes in reading (such as word recognition and syntactic processing). Our results demonstrate the utility of using fMRI to investigate the neural substrates of higher-level cognitive processes such as discourse comprehension.

PET imaging of oxidative metabolism abnormalities in sympathetically denervated canine myocardium.

UNLABELLED: This study was designed to test the hypothesis that regional sympathetic denervation produces perfusion and metabolic alterations in myocardial tissue under resting conditions. METHODS: PET studies of myocardial sympathetic innervation, myocardial perfusion and oxygen utilization using [11C]hydroxyephedrine (HED), [13N]ammonia and 1-[11C]acetate, respectively, were performed before and approximately 2 and 8 wk after surgical left thoracotomy and regional chemical sympathetic denervation (n = 5). A second group of animals underwent the same surgical procedure but, so that they could serve as a sham control group, were not sympathetically denervated (n = 5). The second group of animals was imaged before and 2 wk after surgery. Images of the retention of [11C]HED taken from 50 to 60 min postinjection were used to differentiate sympathetically innervated and denervated regions of the left ventricle. Regions of interest were defined on polar plots of the [11C]HED retention, including the sympathetically denervated territory and normally innervated regions. Regions defined on the HED polar plots were then transferred to the [13N]ammonia and 1-[11C]acetate image data, and tracer kinetic models were fit to the regional time-activity curves to generate estimates of myocardial perfusion and oxidative metabolism. RESULTS: The average percentage of the left ventricle denervated in the group I animals was 13.1% +/- 7.3%. Significant reductions in oxidative metabolism were observed in the sympathectomized tissue both at 2 and 8 wk after surgery (22% and 15% reductions, respectively). Significant alterations in regional perfusion were not observed. No significant changes in oxidative metabolism or perfusion were observed in the sham control group. CONCLUSION: Regional sympathetic denervation alters oxidative metabolism but not perfusion in the denervated region of the heart.

[Recurrent panuveitis. First manifestation of Behçet disease in childhood]. / Rezidivierende Panuveitis. Erstmanifestation eines Morbus Behçet im Kindesalter.

BACKGROUND: Behçet's disease is a rare systemic vasculitis of unknown etiology. The typical symptoms include recurrent oral and/or genital aphthous lesions, iridocyclitis (historically with hypopyon) and various skin lessions. The number of young adults and children which are diagnosed with Behçet-syndrome is increasing in recent years and the mean age of manifestation has decreased to 25 years in German patients. The disease is generally diagnosed later in German (48.5 months) than in Turkish patients (25.5 months). Ocular manifestation has been confirmed as a marker of severe prognosis. In 15-25% of affected patients it leads to blindness. PATIENT: We describe a 19-year-old Caucasian woman who has suffered from the typical symptoms (oral aphthous lesions, recurrent uveitis posterior, various skin lesions) since the 16th year of age. RESULTS: After three years the patient was finally be diagnosed with Behçet's disease (using the criteria of the "International Study Group for Behçet's Disease"). Visual acuity was stabilized with an immunosuppressive therapy, although there was no complete remission in disease activity. In addition a cerebral vasculitis was manifested. CONCLUSIONS: Ophthalmologists should be familiar with Behçet's disease. In cases of recurrent uveitis Behçet's disease should be included in the differential diagnosis because timely immunosuppressive therapy can prevent irrevocable changes in the corpus vitreum and retina and preserve complete visual acuity.

Basic concepts of functional magnetic resonance imaging and arteriovenous malformations

Cortical mapping is an important adjunct to the workup of patients with arteriovenous malformation (AVMs) near eloquent cortical regions. Task activation imaging can be performed that clearly identifies primary cortical regions. Although current methods require considerable postprocessing, advances in hardware and software will likely make functional MR imaging a routing examination before surgical resection of AVMs in the near future.