Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).

The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.

Activation of the HIF pathway in childhood ALL, prognostic implications of VEGF.

Hypoxia-inducible factor 1 (HIF-1) controls angiogenesis and glycolysis, two leading characteristics of solid tumor invasion, metastasis, and lethality. Increased angiogenesis is also found in the bone marrow (BM) of leukemias. Less is known in leukemia about the role of HIF-1 and vascular endothelial growth factor (VEGF), the most important proangiogenic target gene of HIF-1. We show by immunohistochemistry that the oxygen-regulated component of HIF-1 (HIF-1alpha) is overexpressed in clusters of leukemic cells in BM specimens of childhood acute lymphoblastic leukemia (ALL) and absent in biopsies of normal BM. Half the HIF-1alpha-positive ALL biopsies exhibited VEGF coexpression. Among 96 children with relapsed ALL, diagnostic BM aspirates with high VEGF mRNA levels were associated with a significantly lower probability of event-free survival at 3 years (0.31+/-0.08 vs 0.65+/-0.07, P=0.003). Those with poor molecular response to therapy (evaluated by MRD assessment) had 2.2-fold higher VEGF levels than those responding well to chemotherapy (P=0.005). In conclusion, the data demonstrate activation of the HIF pathway in the BM of ALL patients and indicate that the expression of HIF target genes, such as VEGF, play an important role in leukemia progression, therapy response, and outcome.

Absence of mutations in the CDKN2 binding site of CDK4 in childhood acute lymphoblastic leukemia.

The cell cycle regulatory circuit resulting in phosphorylation of the retinoblastoma protein (pRB) is frequently altered in human cancers. Several mechanisms of disruption are known in that pathway. In childhood acute lymphoblastic leukemia (ALL), the main disrupting mechanism is the homozygous deletion of the CDKN2 (cyclin dependent kinase inhibitor 2) genes: p16CDKN2a, p15CDKN2b, and p19ARF. Another pRB pathway disturbance is a previously described point mutation in the exon 2 of CDK4, a pRB phosphorylating enzyme, which abrogates binding of the latter to its inhibitors, p16CDKN2a and p15CDKN2b. Here we report the absence of point mutations in the CDKN2-binding site of CDK4 in 100 cases of childhood ALL, 2 cases of childhood chronic myeloid leukemia and 9 hematologic cell lines screened by PCR-SSCP (polymerase chain reaction single stranded conformational polymorphism gel electrophoresis), thereby minimizing the possibility of the existence of these specific CDK4 mutations in childhood ALL.

[MR and CT patterns of neurocysticercosis]. / MR- und CT-Muster der Neurozystizerkose.

MRI and CT manifestations were studied in five cases of neurocysticercosis. As demonstrated by long-term follow-ups the disease usually causes multiple lesions the morphology of which depends on the life cycle of the parasite. Tissue lesions consist of three main types: 1) vital cysticerci, 2) inflammatory parenchymatous reactions following degenerating cysts and 3) calcified granulomas. MRI provides all information that is given by CT except for small calcifications which are usually missed. Morphological details of vital cysticerci like cyst wall and scolex are better outlined by MRI. When i.v. contrast medium is applied, it leads to nodular or annular enhancement of inflamed tissue. The sensitivity of MRI towards edema caused by parasite exceeds that of CT by several weeks. CT and MRI are complementary methods providing at the present time the highest degree of specificity in diagnosing neurocysticercosis.

DWI in transient global amnesia and TIA: proposal for an ischaemic origin of TGA.

There are conflicting reports concerning signal intensity changes in transient global amnesia (TGA) using diffusion weighted imaging (DWI). We prospectively analysed DWI signal intensity changes in TIA and TGA patients, and compared the clinical characteristics and risk factors of both groups. Using DWI and conventional T1 and T2 weighted turbo spin echo sequences, 28 patients with acute TGA (13 men, mean age 61.5 years) and 74 TIA patients (47 men, mean age 62.4 years) were studied within 48 hours after symptom onset. Every patient underwent an intensive diagnostic investigation. In 10/28 (36%) of the TGA patients and 21/74 (28%) of the TIA patients, DWI signal intensity changes occurred. The time to DWI and the duration of symptoms were comparable in TIA and TGA patients. Overall, TIA patients showed an increased prevalence of vascular risk factors compared with TGA patients. In the TGA group, patients with abnormal DWI showed carotid atherosclerosis significantly more frequently. Based on our data, we suggest that the aetiology of TGA could be explained by an ischaemic event; due to arterial thrombembolic ischaemia in one subgroup, particularly in those patients with increased vascular risk factors, and due to venous ischaemia in another subgroup with valsalva-like activities before symptom onset.

[The significance of leukoaraiosis. A current evaluation and differential diagnosis]. / Bedeutung der Leukoaraiosis. Eine Bestandsaufnahme und differentialdiagnostische Abgrenzung.

Bilateral symmetric changes in the cerebral hemispheric white matter are found with increasing frequency using CT and MRI techniques. These unspecific changes of the white matter signal are often called leukoaraiosis. They differ from the normal white matter signal. These changes are found with increasing frequency in persons older than 60 years and also patients with dementia and cerebrovascular diseases. The pathogenesis, clinical significance and morphological substrate are unclear. The aim of this review is to summarise the actual knowledge about the etiology and clinical signs and symptoms found in patients with leukoaraiosis. This term should not be used when white matter changes are found in patients younger than 35 years, with an unilateral onset, asymmetric distribution, and extensive changes all over the infra- and supratentorial white matter area. Neuroradiological and clinical criteria are given to differentiate between leukoaraiosis and diseases of the white matter, especially enlarged Virchow-Robin spaces, lacunar infarction, subcortical arteriosclerotic angiopathy (Binswanger's disease), leukoencephalopathy of different origin, and demyelinating diseases.

Multiple progressive intracerebral hemorrhages due to an angiosarcoma: a case report.

Identification of intracerebral hemorrhage (ICH) and the underlying cause is a common clinical problem. Rare causes of ICH can be particularly difficult to diagnose. We describe a man on oral anticoagulation with multiple progressive ICHs, who initially showed no signs of a malignant disease. After normalisation of all coagulation tests, the ICHs continued to spread. Autopsy examination revealed an angiosarcoma. Multiple progressive ICHs caused by an angiosarcoma that mainly affects the brain have not yet been described. In the presence of normal coagulation tests, further progression of ICH should raise questions about common causes of ICH such as oral anticoagulation in our case.

Hemolytic-uremic syndrome with involvement of basal ganglia and cerebellum.

Hemolytic-uremic syndrome is a microangiopathy often associated with neurologic symptoms. Several patients with persistent lesions in cerebrum and basal ganglia have been reported. We present two children with bilateral basal ganglia and additional unilateral cerebellar lesions in magnetic resonance imaging. These resolved completely in one child. In the other child there were still residuals after 11 weeks. The neurologic symptoms of both improved after several therapeutic plasma exchanges and disappeared after months.

Correlation between quantitative EMG and muscle MRI in patients with axonal neuropathy.

The aim of the study was to investigate whether there are correlations between electromyography (EMG) data and findings in muscle magnetic resonance imaging (MRI). Quantitative EMG data and the amount of pathologic spontaneous activity (PSA) were compared with MRI signal intensities of the tibialis anterior muscles of 20 patients with axonal polyneuropathy and 14 healthy subjects. Using hierarchical regression analysis, the mean motor unit action potential (MUAP) size index (SI) and the amount of PSA were accurate predictors of T1-weighted signal intensity in MRI, an expression of fatty degeneration. The MUAP SI was superior to MUAP amplitude in explaining the variance of T1 signal intensity. Age was not a relevant factor. A high correlation was found between the amount of PSA and the T2-weighted signal intensity in short tau inversion recovery sequence. Magnetic resonance imaging demonstrates the structural changes and thus visualizes the outcome of the functional changes of denervation and reinnervation detected by EMG.

Time-resolved fMRI of activation patterns in M1 and SMA during complex voluntary movement.

The aim of this study was to use time-resolved functional magnetic resonance imaging (fMRI) to investigate temporal differences in the activation of the supplementary motor area (SMA) and the primary motor cortex (M1). We report data from eight human volunteers who underwent fMRI examinations in a 1.5T Philips Gyroscan ACS-NT MRI scanner. While wearing a contact glove, subjects executed a complex automated sequence of finger movements either spontaneously or in response to external auditory cues. Based on the result of a functional scout scan, a single slice that included the M1 and the SMA was selected for image acquisition (echo planar imaging, repetition time 100 ms, echo time 50 ms, 64 x 64 matrix, 1,000 images). Data were analyzed with a shifting cross-correlation approach using the STIMULATE program and in-house programs written in Interactive Data Language (IDL(TM)). Time-course data were generated for regions of interest in the M1 as well as in the rostral and caudal SMA. Mean time between onset of the finger movement sequence and half-maximum of the signal change in M1 was 3.6 s for the externally cued execution (SD 0.5) and 3.5 s for the spontaneous execution (SD 0.6). Activation in the rostral section of the SMA occurred 0.7 s earlier than it did in the M1 during the externally cued execution and 2.0 s earlier during the spontaneous execution, a difference significant at the P < 0.01 level. Our results indicate that rostral SMA activation precedes M1 activation by varying time intervals in the sub-second range that are determined by the mode of movement initialization. By applying a paradigm that exerts a differential influence on temporal activation, we could ensure that the observed timing differences were not the result of differences in hemodynamic response function.

Neural correlates associated with impaired disgust processing in pre-symptomatic Huntington's disease.

Disturbances in recognizing facial expressions of disgust have been reported previously in pre-symptomatic and manifest Huntington's disease. Given the substantial role of the insula and basal ganglia in the perception of disgust as revealed by functional imaging, lesion studies and intracerebral recordings, we propose dysfunction within the insula and/or basal ganglia as the underlying neural substrate. Using functional MRI (fMRI), we studied a group of nine pre-symptomatic Huntington's disease gene carriers and nine healthy controls, matched for age, gender, intelligence and years of education, while they were viewing disgusted facial expressions. As control conditions, surprised and neutral expressions were presented. Compared with healthy controls, Huntington's disease gene carriers showed reduced responses within the left dorsal anterior insula during processing of disgusted facial expressions. Moreover, processing of disgust was associated with significant activation of the left dorsal anterior insula and putamen in healthy controls, but not in Huntington's disease gene carriers. Furthermore, behavioural assessment revealed a selective impairment in recognizing facial expressions displaying disgust in Huntington's disease gene carriers. Our finding of dysfunctional decreased insula activation in pre-symptomatic Huntington's disease provides an explanation for the clinical deficit in recognizing facial expression of disgust. Furthermore, it underscores the role of the insula in the emotion of disgust.