A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Background

In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive.

Methods

Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry.

Results

Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age.

Conclusions

Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field.

Electronic supplementary material

The online version of this article (doi:10.1186/1866-1955-7-3) contains supplementary material, which is available to authorized users.     

Laser-induced interstitial thermotherapy of liver metastases in an interventional 0.5 Tesla MRI system: technique and first clinical experiences

Laser-induced interstitial thermotherapy (LITT) surveyed by magnetic resonance imaging (MRI) has been shown to be effective in various applications. The laser treatment of colorectal liver metastases usually requires a separate device (e.g., ultrasound or CT) to position the laser applicator. In this study, we used an interventional 0.5 T MRI system, allowing both the navigation to the target tissue and on-line thermometry. Laser irradiation was performed using a near-infrared laser source combined with a cooled laser light guide. We treated 20 patients exhibiting a total of 58 colorectal liver metastases. Clinically relevant complications did not occur. No residual tumor was observed after laser irradiation in all metastases with a diameter below 2 cm. Metastases with a mean diameter between 2 and 3 cm demonstrated total necrosis in 71%, while in larger tumors this proportion decreased to 46% (diameter, 3-4 cm) and 30% (diameter, >4 cm), respectively. We conclude that LITT, guided by the employed interventional MRI system, is feasible and safe. The results suggest a more aggressive treatment, especially for larger metastases. J. Magn. Reson. Imaging 2001;13:729-737.     

Technic for implantation of the Oreopoulos-Zellerman catheter in peritoneal dialysis

The continuous ambulatory peritoneal dialysis is a routine measurement under certain circumstances in nephrological units, which is preferentially performed in patients who cannot be adapted to haemodialysis. Certain risks are inherent in this method. They are dependent on the patient himself as well as on measurement used. Typical complications are canalicular infections along the catheter loop, intra- and extraabdominal dislocations of the catheter tube, abdominal wall leaking and the CAPD-peritonitis. Our own patients are analyzed according to this aspect; the value of a standardized technique of implantation of the Oreopoulos-Zellermann-Catheter is described with regard to the reduction of surgical risks.     

Prinzipien des chirurgischen Vorgehens beim Stromatumor

Zusammenfassung. Gastrointestinale Stromatumoren (GIST) als seltene Tumormanifestation der mesenchymalen Gewebsfraktion des intestinalen Bauprinzips, wurden aufgrund eigenst?ndiger immunhistochemischer und ultrastruktureller Eigenschaften als selbst?ndige Tumorentit?t etabliert. Trotz zunehmend tiefergehender Erkenntnisse über ihr biologisches Verhalten und dessen molekularbiologische Grundlagen bleibt bei vielen dieser Tumoren die Beurteilung ihrer Dignit?t nicht nur pr?operativ, sondern auch postoperativ offen, so da? die aus der Carcinomchirurgie weitgehend standardisierte Radikalit?t des chirurgischen Eingriffs hier nicht einheitlich vorgegeben wird. Die bis heute verfügbare Literatur erm?glicht aufgrund kleiner Fallzahlen und der Heterogenit?t der klinischen und pathologischen Variablen keine valide analytische Schlu?folgerung, so da? Empfehlungen zur onkologisch-chirurgischen Radikalit?t derzeit empirischen Charakter haben und wegen der Seltenheit des Tumors wahrscheinlich auch weiter haben werden. Adjuvante Therapiema?nahmen von relevanter Wirksamkeit existieren nicht, so da? der operativen Therapie, deren Radikalit?t sich an organspezifischen, tumorspezifischen und tumorbiologischen Kriterien orientiert, die zentrale Rolle zukommt.      

Stellenwert der Gastrektomie im multimodalen Therapiekonzept des primären Non-Hodgkin-Lymphoms des Magens

Zusammenfassung Daten von 41 Patienten mit einem Non-Hodgkin-Lymphom des Magens werden in einer retrospektiven Analyse im Hinblick auf das notwendige Resektionsausmaß im Rahmen der multimodalen Therapie dargestellt. Dreißig Magenlymphome von niedrigem, 2 von intermediärem und 9 von hohem Malignitätsgrad verteilen sich auf die klinischen Stadien Ie in 44%, IIe in 15%, IIIe in 12% and IV in 29%. Die kumulative Überlebensrate betrug nach 5 Jahren im Stadium Ie 85%, in den Stadien IIe and IIIe 55% und nach 3 Jahren im Stadium IV 10%. Es bestand ein Befall des proximalen Magens in 73%, eine polytope Tumormanifestation im Magen in 15%, überwiegend infiltrierende Wuchsformen in 71%, eine Infiltration von Ösophagus und/oder Duodenum in 20% und das synchrone Vorliegen eines Magenkarzinoms in 12% der Fälle. In Anbetracht der ermittelten morphologischen und topographischen Tumoreigenschaften scheint das kurative Ziel einer Operation beim primaren Magenlymphom nur durch eine Gastrektomie erreichbar zu sein.

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Value of total gastrectomy in interdisciplinary therapy of primary gastric lymphoma

Summary Retrospectively analyzed data of 41 patients with gastric Non-Hodgkin lymphoma are presented with special regard to the required extent of gastric resection in multimodality treatment. Thirty lymphomas of low, 2 of intermediate and 9 of high grade malignancy were distributed on stage Ie in 44%, stage Ile in 15%, stage IIIe in 12% and stage IV in 29%. The cumulative 5 years survival rate was 85% for stage Ie and 55% for the stages Ile and IIIe. Stage IV showed a 3 years survival of 10%. The proximal part of the stomach was involved in 73%, polycentric lesions were found in 15%. The majority (71%) of the tumours showed an infiltrating growth, an invasion of the oesophagus and/or the duodenum was seen in 20%. Five patients (12%) had synchronous adenocarcinoma as second gastric tumour. Regarding our morphological and topographical data curative surgery for primary gastric lymphoma required total gastric resection.

     

Expression of Bax,a pro-apoptotic member of the Bcl-2 family,in esophageal squamous cell carcinoma

Samples of normal esophageal squamous epithelium (n = 10), severe squamous cell dyplasia (n = 22), carcinoma in situ (n = 15), invasive squamous cell carcinoma (n = 172), lymph-node metastasis (n = 21) and 2 permanent esophageal squamous cell carcinoma cell lines were analyzed immunohistochemically for Bax expression using a polyclonal anti-Bax antibody. Immunostaining was evaluated according to a score system (0–8 points) based on the percentage of positive tumor cells and the relative immunostaining intensity. Cytoplasmatic staining for Bax protein was found uniformly in all cell layers of the normal esophageal squamous epithelium. In contrast, a gradual loss of immunoreactivity for Bax was found in a fraction of pre-neoplastic and neoplastic lesions. Upon comparison of the amount of Bax expression between the different types of lesion, however, no significant differences were found between severe squamous cell dysplasias, carcinomas in situ, invasive carcinomas and lymph-node metastases. In both esophageal carcinoma cell lines, immunoreactivity for Bax was found and confirmed by means of Northern blot analysis. In invasive carcinomas, Bax immunoreactivity was inversely correlated with Bcl-2 expression (p = 0.0243) and decreased continuously with decreasing tumor differentiation (p = 0.0011). No correlation was found between Bax expression and the following parameters: depth of invasion, nodal status and tumor size. Bax expression had no influence on the post-operative survival of esophageal cancer patients. Int. J. Cancer 73:508–513, 1997. © 1997 Wiley-Liss, Inc.     

The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.