Maturation of luminance- and motion-defined form perception beyond adolescence: a combined ERP and fMRI study

Abilities to discriminate forms defined by motion continue to develop throughout childhood. To investigate late development of the visual motion system, we measured brain activity with event-related EEG potentials (ERPs) and functional magnetic resonance imaging (fMRI) in groups of adolescents (15-17 years) and adults (20-30 years) during a visual form discrimination task--with forms being either defined by motion or luminance contrast. We further explored whether possible developmental changes varied with the degree of motion coherence reflecting maturation specific to global motion processing. Both the fMRI activation patterns and ERP topographies were very similar between adolescents and adults, suggesting that the basic visual networks for processing motion and form are established by the age of 15-17. The ERP response to luminance- and motion-defined forms was dominated by a posterior negativity (N1: 120-270 ms). The N1 of the motion contrast was delayed in adolescents, whereas the N1 of the static condition did not differ between groups. Since the motion-evoked N1 is thought to arise in the middle temporal area MT/V5, our results indicate that visual motion processing in MT continues to get faster, becoming still more efficient during late development. Neither the ERP nor the fMRI results revealed maturation effects specific to motion coherence. This indicates that the specific mechanisms to process global dot motion are already mature in adolescence. The present findings support the view that static perception matures earlier than dynamic perception, and that these visual systems have different developmental courses.     

Evidence for developmental changes in the visual word processing network beyond adolescence

Late development of specialization in the visual word processing system was examined using event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) of word and symbol string processing in groups of adolescents (15.2-17.3 years) and adults (19.8-30.8 years). We focused our ERP analyses on fast visual activity: the occipital P1 (82-131 ms) modulated by physical stimulus characteristics and the occipito-temporal N1 (132-256 ms) reflecting visual tuning for print. Our fMRI analyses concentrated on basal occipito-temporal activations in the visual word form area VWFA. For words, the correlation of fMRI activation in the VWFA and N1 amplitude confirmed the close relationship of the electrophysiological N1 with metabolic activity in the VWFA. Further support for this relationship came from low resolution electromagnetic tomography localizing the word-specific N1 near the VWFA. Both imaging techniques revealed age-independent differences between words and symbol strings. Late development, however, was preferentially detected with ERPs. Decreases of P1 and N1 amplitudes with age were not limited to words and suggested further maturation of the underlying brain microstructure and function. Following adolescence, decreasing N1 latencies specific to words point to continued specialization of the visual word processing system. Both N1 and fMRI measures correlated with reading performance. In summary, the similarity of global fMRI activation patterns between groups suggests a fully established distribution of the reading network in adolescence, while the decreasing N1 latencies for words indicate protracted fine tuning after adolescence.     

Inhibition of angiogenesis and tumor growth in the brain. Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor.

Microvascular proliferation, a hallmark of malignant brain tumors, represents an attractive target of anticancer research, especially because of the quiescent nonproliferative endothelium of the normal brain. Cerebral neoplasms sequester copper, a trace metal that modulates angiogenesis. Using a rabbit brain tumor model, normocupremic animals developed large vascularized VX2 carcinomas. By contrast, small, circumscribed, relatively avascular tumors were found in the brains of rabbits copper-depleted by diet and penicillamine treatment (CDPT). The CDPT rabbits showed a significant decrease in serum copper, copper staining of tumor cell nuclei, microvascular density, the tumor volume, endothelial cell turnover, and an increase in the vascular permeability (breakdown of the blood-brain barrier), as well as peritumoral brain edema. In non-tumor-bearing animals, CDPT did not alter the vascular permeability or the brain water content. CDPT also inhibited the intracerebral growth of the 9L gliosarcoma in F-344 rats, with a similar increase of the peritumoral vascular permeability and the brain water content. CDPT failed to inhibit tumor growth and the vascularization of the VX2 carcinoma in the thigh muscle or the metastases to the lung, findings that may reflect regional differences in the responsiveness of the endothelium, the distribution of copper, or the activity of cuproenzymes. Metabolic and pharmacologic withdrawal of copper suppresses intracerebral tumor angiogenesis; angiosuppression is a novel biologic response modifier for the in situ control of tumor growth in the brain.     

Brain biocompatibility of a biodegradable, controlled-release polymer in rats

We report the biocompatibility in the rat brain of a controlled-release, biodegradable polymer, the polyanhydride poly-[bis(p-carboxyphenoxy)propane-sebacic acid] copolymer (PCPP-SA) in a 20:80 formulation. The biodegradable polyanhydride can be used for drug delivery directly into the brain, circumventing the difficulties posed by the blood-brain barrier and avoiding the consequences of having to administer toxic doses systematically to reach therapeutic doses in the central nervous system. The tissue reaction in the presence of PCPP-SA was compared to that seen with other standard neurosurgical implants. Fifty-six adult Sprague-Dawley rats were assigned to one of seven groups and underwent bilateral frontal lobe implantation of PCPP-SA (42 hemispheres), Surgicel (oxidized regenerated cellulose) (35 hemispheres), or Gelfoam (absorbable gelatin sponge) (35 hemispheres). None of the animals showed any behavioral changes or neurological deficits suggestive of either systemic or localized toxicity from the biodegradable polyanhydride, all surviving to the scheduled data of sacrifice. PCPP-SA evoked a well localized inflammatory reaction, comparable to that of Surgicel, which resolved as the PCPP-SA polymer degraded over five weeks. The biodegradable polyanhydride has been shown in this study to be nontoxic and biocompatible in the rat brain, when compared to standard neurosurgical implants.     

Primary laparoscopic placement of peritoneal dialysis catheters in children and young adults

Background: Primary placement of peritoneal dialysis catheters in children often requires suturing of the catheter into the pelvis. We describe our experience with a gasless laparoscopy technique in children and young adults. Methods: During an 18-month period, 12 patients (mean age, 14 years) underwent primary laparoscopic placement of peritoneal dialysis catheters. A single umbilical port was used for abdominal wall elevation, telescope, and catheter. A needleholder was introduced via an accessory port at the future catheter exit site or through the umbilical port. Omentectomy was performed through the umbilical incision. The catheter was tunneled to the lateral abdominal wall. Follow-up data (≥15 months) included time to initiation of dialysis, hospitalization, and outcome. End points were cure, transplantation, or death. Results: Diet was started on the day of surgery and dialysis on the following day. Four patients had seven complications, including leakage and entanglement of the catheter in tubal fimbriae. Long-term revision-free catheter survival was 67% at 24 months. Conclusions: This minimal access technique for primary placement of peritoneal dialysis catheters includes securing of the catheter tip in a dependent location and omentectomy. It allows nearly immediate use of the catheter, leads to a minimal hospital stay, and has acceptable long-term patency. Received: 24 December 1998/Accepted: 3 March 1999     

Xenotransplantation. Possibilities of animal breeding]

The pig is the most likely donor organism for xenotransplantation of organs to humans. However, since this constellation is discordant, hyperacute rejection needs to be overcome. This review summarises current strategies of genetically modifying pigs for xenotransplantation. Limitations of the classical method of DNA-microinjection and new perspectives arising from the possibility of cloning animals from cultured cells are discussed.     

Polymer Delivery of Camptothecin against 9L Gliosarcoma: Release,Distribution, and Efficacy

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11–45g of camptothecin-sodium/mg brain tissue was within a 3mm radius of the polymer disc, with levels of 0.1g at the outermost margin of the rat brain, 7mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P=0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P=0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P<0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000h in vitro. We conclude that the biodegradable polymer p(CPP:SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.