IMAGINER: improving accuracy with a mixed reality navigation system during placement of external ventricular drains. A feasibility study.

OBJECTIVE: The placement of a ventricular catheter, that is, an external ventricular drain (EVD), is a common and essential neurosurgical procedure. In addition, it is one of the first procedures performed by inexperienced neurosurgeons. With or without surgical experience, the placement of an EVD according to anatomical landmarks only can be difficult, with the potential risk for inaccurate catheter placement. Repeated corrections can lead to avoidable complications. The use of mixed reality could be a helpful guide and improve the accuracy of drain placement, especially in patients with acute pathology leading to the displacement of anatomical structures. Using a human cadaveric model in this feasibility study, the authors aimed to evaluate the accuracy of EVD placement by comparing two techniques: mixed reality and freehand placement. METHODS: Twenty medical students performed the EVD placement procedure with a Cushing's ventricular cannula on the right and left sides of the ventricular system. The cannula was placed according to landmarks on one side and with the assistance of mixed reality (Microsoft HoloLens 2) on the other side. With mixed reality, a planned trajectory was displayed in the field of view that guides the placement of the cannula. Subsequently, the actual position of the cannula was assessed with the help of a CT scan with a 1-mm slice thickness. The bony structure as well as the left and right cannula positions were registered to the CT scan with the planned target point before the placement procedure. CloudCompare software was applied for registration and evaluation of accuracy. RESULTS: EVD placement using mixed reality was easily performed by all medical students. The predefined target point (inside the lateral ventricle) was reached with both techniques. However, the scattering radius of the target point reached through the use of mixed reality (12 mm) was reduced by more than 54% compared with the puncture without mixed reality (26 mm), which represents a doubling of the puncture accuracy. CONCLUSIONS: This feasibility study specifically showed that the integration and use of mixed reality helps to achieve more than double the accuracy in the placement of ventricular catheters. Because of the easy availability of these new tools and their intuitive handling, we see great potential for mixed reality to improve accuracy.

Students' perspectives regarding needs for and opportunities with mixed-reality education in neurosurgery at German medical schools.

OBJECTIVE: Despite mixed reality being an emerging tool for tailored neurosurgical treatment and safety enhancement, the use of mixed reality in the education of German medical students is not established in the field of neurosurgery. The present study aimed to investigate medical students' perspectives on the use of mixed reality in neurosurgical medical education. METHODS: Between July 3, 2023, and August 31, 2023, an online survey was completed by German medical students through their affiliated student associations and educational institutions. The survey included 16 items related to mixed reality in neurosurgery, with participants providing ratings on a 4-point Likert scale to indicate their level of agreement with these statements. RESULTS: A total of 150 students from 27 medical schools in Germany took part in the survey. A significant majority comprising 131 (87.3%) students expressed strong to intense interest in mixed-reality courses in neurosurgery, and 108 (72%) reported an interest in incorporating mixed reality into their curriculum. Furthermore, 94.7% agreed that mixed reality may enhance their understanding of operative neuroanatomy and 72.7% agreed with the idea that teaching via mixed-reality methods may increase the probability of the use of mixed reality in their future career. The majority (116/150 [77.3%]) reported that the preferred optimum timepoint for teaching with mixed reality might be within the first 3 years of medical school. In particular, more students in the first 2 years preferred to start mixed-reality courses in the first 2 years of medical school compared to students in their 3rd to 6th years of medical school (71.9% vs 41.5%, p = 0.003). Residents and attending specialists were believed to be appropriate teachers by 118 students (78.7%). CONCLUSIONS: German medical students exhibited significant interest and willingness to engage in mixed reality in neurosurgery. Evidently, there is a high demand for medical schools to provide mixed-reality courses. Students seem to prefer the courses as early as possible in their medical school education in order to transfer preclinical neuroanatomical knowledge into operative neurosurgical anatomy by using this promising technique.

Mixed reality for spine surgery: a step into the future with a human cadaveric accuracy study.

OBJECTIVE: Current application of mixed reality as a navigation aid in the field of spinal navigation points to the potential of this technology in spine surgery. Crucial factors for acceptance include intuitive workflow, system stability, reliability, and accuracy of the method. The authors therefore aimed to investigate the accuracy of the system in visualization of anatomical structures using mixed reality in the example of pedicles of the thoracic spine in a human cadaveric study. Potential difficulties and limitations are discussed. METHODS: CT scans of a human cadaveric spinal column specimen were performed. After segmentation and import into the advanced HoloLens 2 software, the vertebrae were exposed. The vertebral arches were preserved on one side for a landmark-based surface registration, whereas pedicles were exposed on the other side in order to measure and evaluate deviation of the overlay holographs with regard to the exact anatomical structure. Accuracy was measured and statistically evaluated. RESULTS: In this work it was demonstrated that the overlay of the virtual 3D model pedicles with the real anatomical structures with anatomical landmark registration was within an acceptable surgical accuracy with the mean value of 2.1 mm (maximum 3.8 mm, minimum 1.2 mm). The highest accuracy was registered at the medial and lateral pedicle wall, and the measurement results were best in the region of the middle thoracic spine. CONCLUSIONS: The accuracy analysis for mixed reality (i.e., between the virtual and real anatomical situation of the thoracic spine) showed a very good agreement when focus was on the pedicles. This work is thus a rare proof of the precision of segmentation to the potential surgical area. The results encourage researchers to open up mixed reality technology in its development and application for spinal navigation.

Escherichia coli recombinant expression of SARS-CoV-2 protein fragments.

We have developed a method for the inexpensive, high-level expression of antigenic protein fragments of SARS-CoV-2 proteins in Escherichia coli. Our approach uses the thermophilic family 9 carbohydrate-binding module (CBM9) as an N-terminal carrier protein and affinity tag. The CBM9 module was joined to SARS-CoV-2 protein fragments via a flexible proline-threonine linker, which proved to be resistant to E. coli proteases. Two CBM9-spike protein fragment fusion proteins and one CBM9-nucleocapsid fragment fusion protein largely resisted protease degradation, while most of the CBM9 fusion proteins were degraded at some site in the SARS-CoV-2 protein fragment. All of the fusion proteins were highly expressed in E. coli and the CBM9-ID-H1 fusion protein was shown to yield 122 mg/L of purified product. Three purified CBM9-SARS-CoV-2 fusion proteins were tested and found to bind antibodies directed to the appropriate SARS-CoV-2 antigenic regions. The largest intact CBM9 fusion protein, CBM9-ID-H1, incorporates spike protein amino acids 540-588, which is a conserved region overlapping and C-terminal to the receptor binding domain that is widely recognized by human convalescent sera and contains a putative protective epitope.

[Need for and predictability of magnetic resonance imaging examinations in patients with implanted neurostimulators]. / Bedarf und Vorhersagbarkeit von Magnetresonanztomographieuntersuchungen bei Patienten mit implantiertem Neurostimulator.

BACKGROUND: With an increasing number of magnetic resonance imaging (MRI) examinations in the general population, there are no data available regarding the requirements of patients with implanted neurostimulators in Germany. Published data from the United States of America suggest a high need. The limited approval for MRI scans of implants are a common problem. OBJECTIVE: The focus is on the MRI needs of these pain patients and the predictability at the time of implantation. MATERIAL AND METHOD: We carried out a retrospective evaluation of the database of our hospital information system. We searched for all MRI requests for patients with an implanted neurostimulator between November 2011 and March 2019. In addition, we compared these data with the implantation of neurostimulators in the same period. RESULTS: We identified 171 MRI examinations and 22 requests without a subsequent examination. Out of 294 (28%) patients implanted in our center 83 had at least 1 MRI scan in our hospital. We observed a steadily increasing demand. In 111 of 171 (65%) performed examinations, there was no association between the indications leading to neurostimulator implantation and to MRI. A predictability could only be assumed for 43 of 193 (22%) MRI requests. CONCLUSION: In Germany, patients with an implanted neurostimulator have a high need for MRI diagnostics which cannot be predicted at the time of implantation. Therefore, only MRI-conditional systems should be implanted. The manufacturers need to adapt the implants and their approval to requirements.

Magnetic resonance imaging scans in patients with dorsal root ganglion stimulation.

OBJECTIVE: Patients fitted with a neurostimulator face a greater need to undergo magnetic resonance imaging (MRI) scans. Given the lack of literature in this regard, this study aims to review our experience with MRI examinations on patients implanted with a dorsal root ganglion stimulation (DRG-S) system and their potential adverse events. MATERIALS AND METHODS: We conducted a retrospective analysis of the prospective treatment documentation gathered from November 2011 to October 2020. We identified 259 MRI registrations for patients with an implanted neurostimulation system; the MRI examinations were performed using a 1.5 Tesla MRI system in accordance with a structured scheme. RESULTS: Among the 259 MRI registrations identified in this study, 28 corresponded to patients with an implanted DRG-S system. In 2 cases, no MRI scan was performed, and thus, only 26 MRI examinations were evaluated in detail. The DRG-S device was approved for the requested MRI scans in only 2 of these 26 cases (7.7%). In addition, 2 minor adverse events (syncopal episode and connection problem) were identified, and only the second problem (3.8%) was related to neurostimulator operation. CONCLUSIONS: Necessary MRI examinations in patients with DRG-S systems are rarely covered by the European CE/US Food and Drug Administration (CE/FDA) approval. Although the manufacturer recommendations are against the use of MRI in patients with implanted DRG-S in certain conditions, we performed these scans without causing injury to the patient or damaging the device. Given that data on safety are limited, MRIs should be conducted study related. We provide recommendations for the procedure that should be followed when an MRI is needed urgently.

A technical concept of a computer game for patients with Parkinson's disease - a new form of PC-based physiotherapy.

Background: At present, there are no meaningful and sophisticated computer games that simultaneously allow the treatment of movement disorders such as Parkinson's syndrome. In particular, there are no systems to consider the severity of the disease and the physical skills of the patient. Methods: A computer game using the Microsoft Kinect as markerless sensor for the 3 D recognition of the patient's movement was developed to support the rehabilitation. The scenario of a basketball game was created after determining that the movement like throwing a ball and the correct posture of the body are important. A study based on system usability was performed with 15 patients to evaluate the system. Results: The technical feasibility of a computer-assisted training system for supporting patients with Parkinson's disease has been demonstrated. No markers on the patient are required for movement detection and allow a user-friendly handling. Regarding the usability study, the patients were accepting of such a system and its at-home use and symptoms like 'freezing' and the Pisa syndrome can be treated. Conclusions: The physiotherapist can be assisted by the developed rehabilitation system. An objective measurement of the patient's training progress delivers valuable information to adjust the training sessions for every patient individually. Due to its modular character, the system can also be applied to other diseases or sports injuries and offers the basis for further development.

Subthalamic nucleus volumes are highly consistent but decrease age-dependently-a combined magnetic resonance imaging and stereology approach in humans.

The subthalamic nucleus (STN) is a main target structure of deep brain stimulation (DBS) in idiopathic Parkinson's disease. Nevertheless, there is an ongoing discussion regarding human STN volumes and neuron count, which could potentially have an impact on STN-DBS. Moreover, a suspected functional subdivision forms the basis of the tripartite hypothesis, which has not yet been morphologically substantiated. In this study, it was aimed to investigate the human STN by means of combined magnetic resonance imaging (MRI) and stereology. STN volumes were obtained from 14 individuals (ranging from 65 to 96 years, 25 hemispheres) in 3 T MRI and in luxol-stained histology slices. Neuron number and cell densities were investigated stereologically over the entire STN and in pre-defined subregions in anti-human neuronal protein HuC/D-stained slices. STN volumes measured with MRI were smaller than in stereology but appeared to be highly consistent, measuring on average 99 ± 6 mm3 (MRI) and 132 ± 20 mm3 (stereology). The neuron count was 431,088 ± 72,172. Both STN volumes and cell count decreased age-dependently. Neuron density was different for the dorsal, medial and ventral subregion with significantly higher values ventrally than dorsally. Small variations in STN volumes in both MRI and stereology contradict previous findings of large variations in STN size. Age-dependent decreases in STN volumes and neuron numbers might influence the efficacy of STN-DBS in a geriatric population. Though the study is limited in sample size, site-dependent differences for the STN subregions form a morphological basis for the tripartite theory. Hum Brain Mapp 38:909-922, 2017. © 2016 Wiley Periodicals, Inc.

Positional Relations of the Cervical Vagus Nerve Revisited.

OBJECTIVES: The cervical part of the vagus nerve (CVN) has become an important target for stimulation therapy to treat epilepsy and psychiatric conditions. For this purpose, the CVN is visualized in the carotid sheath, assuming it to be localized dorsomedially between the carotid artery (CA) and the internal jugular vein (JV). The aim of our morphological study was therefore to revisit the CVN relationships to the CA and JV, hypothesizing it to have common variations to this classical textbook anatomy. MATERIALS AND METHODS: Positional relations of the CVN, CA and JV were investigated in the carotid sheath of 35 cadavers at the C3 to C6 level. Positional relations of the CVN, CA and JV were documented on the basis of a 3 × 3 chart. RESULTS: Eighteen different arrangements of the CVN, CA and JV were observed. The typical topographic relationship of the CVN dorsomedially between the CA and JV was only found in 42% of all cases. The CVN was located dorsally or (dorso-)laterally to the CA in 80% and dorsally or (dorso-)medially of the JV in 96% of all cases. CONCLUSIONS: Classical textbook anatomy of the CVN is only present in a minority of cases. Positional variations in contrast to textbook anatomy are considerably more frequent than previously described, which might be a hypothetical morphological explanation for the lack of efficacy or side effects of CVN stimulation. Furthermore, the position of the CVN relative to the internal jugular vein is more consistent than to the CA.

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, ß2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG.

We studied the incidences, associations, and prognostic roles of NOTCH1 and SF3B1 mutations (NOTCH1(mut), SF3B1(mut)) as compared with TP53(mut) in fludarabine-refractory chronic lymphocytic leukemia (CLL) patients treated with alemtuzumab in the CLL2H trial. We found NOTCH1(mut), SF3B1(mut), and TP53(mut) in 13.4%, 17.5%, and 37.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) were mutually exclusive, whereas TP53(mut) were evenly distributed within both subgroups. Apart from correlation of SF3B1(mut) with 11q deletion (P = .029), there were no other significant associations of the mutations with any baseline characteristics or response rates. However, NOTCH1(mut) cases had a significantly longer progression-free survival (PFS) compared with wild-type cases (15.47 vs 6.74 months; P = .025), although there was no significant difference with overall survival (OS). SF3B1(mut) had no significant impact on PFS and OS. In multivariable analyses, NOTCH1(mut) was identified as an independent favorable marker for PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00274976.

Investigation of the automated solid-phase synthesis of a 38mer peptide with difficult sequence pattern under different synthesis strategies.

Difficult peptides are a constant challenge in solid-phase peptide synthesis. In particular, hydroxyl amino acids such as serine can cause severe breakdowns in coupling yields even several amino acids after the insertion of the critical amino acid. This paper investigates several methods of improving synthesis yields of difficult peptides including the use of different resins, activators and the incorporation of a structure-breaking pseudoproline dipeptide building block both alone and in combination with each other.

Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial.

The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.

High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.

To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism-array analysis using Affymetrix Version 6.0 on 353 samples from untreated patients entered in the CLL8 treatment trial. Based on paired-sample analysis (n = 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.21 (5% of patients) to a segment 486 kb proximal to the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4% of patients), with the smallest deletion (70.48 kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one CLL patient lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also deleted recurrently.

Analysis of the Technical Accuracy of a Patient-Specific Stereotaxy Platform for Brain Biopsy.

The use of stereotactic frames is a common practice in neurosurgical interventions such as brain biopsy and deep brain stimulation. However, conventional stereotactic frames have been shown to require modification and adaptation regarding patient and surgeon comfort as well as the increasing demand for individualized medical treatment. To meet these requirements for carrying out state-of-the-art neurosurgery, a 3D print-based, patient-specific stereotactic system was developed and examined for technical accuracy. Sixteen patient-specific frames, each with two target points, were additively manufactured from PA12 using the Multi Jet Fusion process. The 32 target points aim to maximize the variability of biopsy targets and depths for tissue sample retrieval in the brain. Following manufacturing, the frames were measured three-dimensionally using an optical scanner. The frames underwent an autoclave sterilization process prior to rescanning. The scan-generated models were compared with the planned CAD models and the deviation of the planned target points in the XY-plane, Z-direction and in the resulting direction were determined. Significantly lower (p < 0.01) deviations were observed when comparing CAD vs. print and print vs. sterile in the Z-direction (0.17 mm and 0.06 mm, respectively) than in the XY-plane (0.46 mm and 0.16 mm, respectively). The resulting target point deviation (0.51 mm) and the XY-plane (0.46 mm) are significantly higher (p < 0.01) in the CAD vs. print comparison than in the print vs. sterile comparison (0.18 mm and 0.16 mm, respectively). On average, the results from the 32 target positions examined exceeded the clinically required accuracy for a brain biopsy (2 mm) by more than four times. The patient-specific stereotaxic frames meet the requirements of modern neurosurgical navigation and make no compromises when it comes to accuracy. In addition, the material is suitable for autoclave sterilization due to resistance to distortion.

NextLens-The Next Generation of Surgical Navigation: Proof of Concept of an Augmented Reality System for Surgical Navigation.

Objective The aim of this work was the development of an augmented reality system including the functionality of conventional surgical navigation systems. Methods An application software for the Augmented Reality System HoloLens 2 from Microsoft was developed. It detects the position of the patient as well as position of surgical instruments in real time and displays it within the two-dimensional (2D) magnetic resonance imaging or computed tomography (CT) images. The surgical pointer instrument, including a pattern that is recognized by the HoloLens 2 sensors, was created with three-dimensional (3D) printing. The technical concept was demonstrated at a cadaver skull to identify anatomical landmarks. Results With the help of the HoloLens 2 and its sensors, the real-time position of the surgical pointer instrument could be shown. The position of the 3D-printed pointer with colored pattern could be recognized within 2D-CT images when stationary and in motion at a cadaver skull. Feasibility could be demonstrated for the clinical application of transsphenoidal pituitary surgery. Conclusion The HoloLens 2 has a high potential for use as a surgical navigation system. With subsequent studies, a further accuracy evaluation will be performed receiving valid data for comparison with conventional surgical navigation systems. In addition to transsphenoidal pituitary surgery, it could be also applied for other surgical disciplines.

Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell prolymphocytic leukemia.

BACKGROUND: Scarce systematic trial data have prevented uniform therapeutic guidelines for T-cell prolymphocytic leukemia (T-PLL). A central need in this historically refractory tumor is the controlled evaluation of multiagent chemotherapy and its combination with the currently most active single agent, alemtuzumab. METHODS: This prospective multicenter phase 2 trial assessed response, survival, and toxicity of a novel regimen in previously treated (n = 9) and treatment-naive (n = 16) patients with T-PLL. Induction by fludarabine, mitoxantrone, and cyclophosphamide (FMC), for up to 4 cycles, was followed by alemtuzumab (A) consolidation, up to 12 weeks. RESULTS: Of the 25 patients treated with FMC, 21 subsequently received alemtuzumab. Overall response rate to FMC was 68%, comprising 6 complete remissions (all bone-marrow confirmed) and 11 partial remissions. Alemtuzumab consolidation increased the intent-to-treat overall response rate to 92% (12 complete remissions; 11 partial remissions). Median overall survival after FMC-A was 17.1 months and median progression-free survival was 11.9 months. Progression-free survival tended to be shorter for patients with high-level T-cell leukemia 1 oncoprotein expression. Hematologic toxicities were the most frequent grade 3/4 side effects under FMC-A. Exclusively in the 21 alemtuzumab-consolidated patients, 13 cytomegalovirus reactivations were observed; 9 of these 13 represented a clinically relevant infection. CONCLUSIONS: FMC-A is a safe and efficient protocol in T-PLL, which compares favorably to published data.

DNA damage-induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing.

The DNA damage pathway plays a central role in chemoresistance in chronic lymphocytic leukemia (CLL), as indicated by the prognostic impact of TP53 and ATM loss/mutations. We investigated the function of the p53 axis in primary CLL samples by studying p53 and p21 responses to irradiation by FACS and RT-PCR. We observed a distinct response pattern for most cases with a 17p deletion (n = 16) or a sole TP53 mutation (n = 8), but not all cases with a p53 aberration were detected based on a number of different assays used. Samples with a small clone with a TP53 mutation remained undetected in all assays. Only 1 of 123 cases showed high expression of p53, which is suggestive of p53 aberration without proof of mutation of TP53. Samples with an 11q deletion showed a heterogeneous response, with only 13 of 30 showing an abnormal response based on cutoff. Nevertheless, the overall induction of p53 and p21 was impaired, suggesting a gene-dosage effect for ATM in the 11q-deleted samples. The detectability of p53 defects is influenced by clonal heterogeneity and sample purity. Functional assays of p53 defects will detect a small number of cases not detectable by FISH or TP53 mutational analysis. The clinical utility of functional p53 testing will need to be derived from clinical trials.

Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.

Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.

Implementing conventional Zamorano Dujovny frames versus individually manufactured microTargeting platforms--a comparative study on deep brain stimulation in Parkinson patients.

BACKGROUND AND OBJECTIVES: Individually manufactured microTargeting™ platforms (MT) provide a novel generation of stereotactic systems based on preoperatively implanted bone markers and screws. The feasibility and reliability of these frames were evaluated for bilateral deep brain stimulation (DBS) in patients with idiopathic Parkinson's disease (IPD). Surgical and clinical results were compared to conventional Zamorano Dujovny frames (ZD) in this prospective study. MATERIALS AND METHODS: Twenty-six IPD patients undergoing surgery for DBS were divided into 2 groups. In group I, electrode implantation was accomplished using conventional ZD. Group II underwent electrode implantation using MT. Microrecording and macrostimulation were performed and surgery time was measured. The clinical outcome was determined using the Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and L-dopa-equivalent doses for a 12-month follow-up postoperatively. RESULTS: Clinical evaluation confirmed comparable outcomes for both targeting procedures and electrode positioning. Surgical time was lower in group II than in group I. Significant improvements were determined for both groups in UPDRS III and L-dopa-equivalent dose. CONCLUSIONS: Both systems allow for reliable and safe neurosurgical procedures, yielding comparable clinical results. MT improved handling and automatic adjustment of frame coordinates. Surgery time was reduced markedly compared to conventional frames.