Fabrication of a positional brain shift phantom through the utilization of the frozen intermediate hydrogel state.

Synthetic models (phantoms) of the brain-skull system are useful tools for the study of surgical events that are otherwise difficult to study directly in humans. To date, very few studies can be found which replicate the full anatomical brain-skull system. Such models are required to study the more global mechanical events that can occur in neurosurgery, such as positional brain shift. Presented in this work is a novel workflow for the fabrication of a biofidelic brain-skull phantom which features a full hydrogel brain with fluid-filled ventricle/fissure spaces, elastomer dural septa and fluid-filled skull. Central to this workflow is the utilization of the frozen intermediate curing state of an established brain tissue surrogate, which allows for a novel moulding and skull installation approach that permits a much fuller recreation of the anatomy. The mechanical realism of the phantom was validated through indentation testing of the phantom's brain and simulation of the supine to prone brain shift event, while the geometric realism was validated through magnetic resonance imaging. The developed phantom captured a novel measurement of the supine to prone brain shift event with a magnitude that accurately reproduces that seen in the literature.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

BACKGROUND: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. OBJECTIVE: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. METHODS: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. CONCLUSIONS: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease.

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma.

CONTEXT: Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB. OBJECTIVE: We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma. MATERIALS AND METHODS: The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O-arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI). RESULTS: All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition. CONCLUSION: Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy.

2013 Lush Science Prize.

The annual Lush Science Prize is designed to reward outstanding contributions to 21st Century Toxicology Research. A Background Paper is prepared each year prior to the judging process, in order to provide the judging panel with a brief overview of current developments in the field of Replacement alternatives, particularly those relevant to the concept of toxicity pathways. The Background Paper includes information on some key institutional developments in the area--such as the OECD's Adverse Outcome Pathway Project, the Hamner Institute's work, and the Human Toxome Project, and on the phenomenon of collaborative computer systems relevant to the field. From the literature review that was also performed as part of the background research, the two papers receiving the highest score were recommended for consideration by the judges for the 2013 Science Prize.

Nitrogen leaching from Douglas-fir forests after urea fertilization.

Leaching of nitrogen (N) after forest fertilization has the potential to pollute ground and surface water. The purpose of this study was to quantify N leaching through the primary rooting zone of N-limited Douglas-fir [Pseudotsuga menziesii (Mirb.) Franco] forests the year after fertilization (224 kg N ha(-1) as urea) and to calculate changes in the N pools of the overstory trees, understory vegetation, and soil. At six sites on production forests in the Hood Canal watershed, Washington, tension lysimeters and estimates of the soil water flux were used to quantify the mobilization and leaching of NO(3)-N, NH(4)-N, and dissolved organic nitrogen below the observed rooting depth. Soil and vegetation samples were collected before fertilization and 1 and 6 mo after fertilization. In the year after fertilization, the total leaching beyond the primary rooting zone in excess of control plots was 4.2 kg N ha(-1) (p = 0.03), which was equal to 2% of the total N applied. The peak NO(3)-N concentration that leached beyond the rooting zone of fertilized plots was 0.2 mg NO(3)-N L(-1). Six months after fertilization, 26% of the applied N was accounted for in the overstory, and 27% was accounted for in the O+A horizon of the soil. The results of this study indicate that forest fertilization can lead to small N leaching fluxes out of the primary rooting zone during the first year after urea application.

Inhibition of insulin-like growth factor I receptor tyrosine kinase by ethanol.

Ethanol inhibits insulin and insulin-like growth factor-I (IGF-I) signaling in a variety of cell types leading to reduced mitogenesis and impaired survival. This effect is associated with inhibition of insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) autophosphorylation, which implicates these receptors as direct targets for ethanol. It was demonstrated previously that ethanol inhibits the autophosphorylation and kinase activity of the purified cytoplasmic tyrosine kinase domain of the IR. We performed computer modeling of the ethanol interaction with the IR and IGF-IR kinases (IRK and IGF-IRK). The analysis predicted binding of alcohols within the hydrophobic pocket of the kinase activation cleft, with stabilization at specific polar residues. Using IGF-IRK purified from baculovirus-infected insect cells, ethanol inhibited peptide substrate phosphorylation by non-phosphorylated IGF-IRK, but had no effect on the autophosphorylated enzyme. In common with the IRK, ethanol inhibited IGF-IRK autophosphorylation. In cerebellar granule neurons, ethanol inhibited autophosphorylation of the apo-IGF-IR, but did not reverse IGF-IR phosphorylation after IGF-I stimulation. In summary, the findings demonstrate direct inhibition of IGF-IR tyrosine kinase by ethanol. The data are consistent with a model wherein ethanol prevents the initial phase of IRK and IGF-IRK activation, by inhibiting the engagement of the kinase activation loop.