Eberhard Uhl

Retinoic acid prevents experimental Cushing syndrome

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.

The application of rapid prototyping techniques in cranial reconstruction and preoperative planning in neurosurgery.

The value of rapid prototype models of the skull in our craniofacial and neurosurgical practice was analyzed. Individual skull models of 52 patients were produced by means of rapid prototyping techniques and used in various procedures. Patients were divided into three groups as follows: group I (26 patients) requiring corrective cranioplasty 1) after resection of osseous tumors (15 patients) and 2) with congenital and posttraumatic craniofacial deformities (11 patients), group II (10 patients) requiring reconstructive cranioplasty, and group III (16 patients) requiring planning of difficult skull base approaches. The utility of the stereolithographic models was assessed using the Gillespie scoring system. The esthetic and clinical outcomes were assessed by means of the esthetic outcome score and the Glasgow Outcome Score, respectively. Simulation of osteotomies for advancement plasty and craniofacial reassembly in the model before surgery in group I reduced operating time and intraoperative errors. In group II, the usefulness of the models depended directly on the size and configuration of the cranial defect. The planning of approaches to uncommon and complex skull base tumors (group III) was significantly influenced by the stereolithographic models. The esthetic outcome was pleasing. The indications for the manufacture of individual three-dimensional models could be cases of craniofacial dysmorphism that require meticulous preoperative planning and skull base surgery with difficult anatomical and reconstructive problems. The stereolithographic models provide 1) better understanding of the anatomy, 2) presurgical simulation, 3) intraoperative accuracy in localization of lesions, 4) accurate fabrication of implants, and 5) improved education of trainees.

Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging.

OBJECTIVEChanges of major cerebral vessels in patients with subarachnoid hemorrhage (SAH) are well known from routine cerebral angiography. Data on changes in the microcirculation do not exist. This study sought to provide a qualitative and quantitative analysis of the cortical microcirculation after SAH. METHODSBy means of orthogonal polarization spectral imaging, a qualitative and quantitative analysis of cortical microcirculation was performed during aneurysm surgery in 3 patients with an incidental intracerebral aneurysm and 10 patients with SAH. Vessel diameters, red blood cell velocity, and functional capillary density were analyzed before and after the aneurysm was clipped. RESULTSInitial capillary density in patients with an incidental aneurysm was 91.5 ± 36.5 cm−1 (mean ± standard deviation) compared with 30.5 ± 13.8 in patients with SAH (P < 0.05). In patients with SAH, capillary density increased significantly to 53.9 ± 29.1 cm−1 (P < 0.05) during the operation, as did the frequency of venules with a red blood cell velocity greater than 2 mm/s (P < 0.05). No significant change of arteriolar or venular diameters was observed. However, in patients with SAH, mono- and multisegmental microvasospasms in arterioles were observed, with a reduction of vessel diameters up to 75.1%. CONCLUSIONOrthogonal polarization spectral imaging is a suitable method to study cerebral microcirculation during surgery. In patients with SAH, capillary density is significantly decreased and small arteries and arterioles of the cortical surface exhibit vasospasm that cannot be detected by angiography or transcranial Doppler sonography. These changes may contribute to the initial clinical symptoms and may have an influence on the clinical postoperative course.

Transorbital keyhole approach to anterior communicating artery aneurysms.

OBJECTIVEThe transorbital keyhole approach to anterior communicating artery aneurysms was developed as a minimally invasive method for safe control of the anterior communicating artery complex. This approach does not necessitate resection of the gyrus rectus. METHODSThe technique is described in detail. The transorbital keyhole approach provides more ventral access than the supraorbital approaches, and the anterior communicating artery complex can be controlled by splitting the basal aspect of the interhemispheric fissure. RESULTSSince late 1998, the authors have used the transorbital keyhole approach routinely. During the initial experience with 33 patients, the only observed complication specific to this approach was transient diplopia in one patient. At follow-up examinations 2 to 15 months after surgery, the cosmetic results were favorable as compared with those of standard pterional craniotomy. CONCLUSIONWe have designed a small, custom-tailored approach to the anterior communicating artery complex for routine use. The small orbitocranial approach is a step toward the ideal of purely extra-axial safe control of anterior communicating artery aneurysms. The orbitocranial keyhole approach seems to be substantially better than the craniotomy, although it requires additional effort and time.

Hyperbaric oxygen improves wound healing in normal and ischemic skin tissue.

The influence of hyperbaric oxygen on reepithelialization and on microvascular perfusion of wounds in normal and ischemic skin tissue was investigated by using a standardized model, in ears of hairless mice. Animals were treated within 2 hours of wound creation and then twice daily with 100% oxygen at 2 atmospheres of absolute pressure. Ischemia was induced by ligating two of the three major vessels of the ear 2.5 days before wound creation. Wound surface area was measured every third day after wound creation. In addition, microvascular blood flow before and during the wound healing process was measured by scanning the ear with a new laser Doppler perfusion imager. In normal tissue (n = 13), hyperbaric oxygen therapy significantly accelerated wound healing by 2 days (p < 0.01) as compared with controls (n = 16). In ischemic tissue (n = 16), treatment with hyperbaric oxygen reduced time for reepithelialization in control animals (n = 16) from 14.3 to 9.9 days (p < 0.001). Laser Doppler data showed no difference in tissue blood flow between treated and untreated animals. In comparison with normal tissue, wound healing in ischemic tissue was characterized by a reduced and less intense hyperemic response. These data suggest that hyperbaric oxygen therapy improves reepithelialization in normal and ischemic skin tissue. The beneficial effect is not associated with changes in microvascular perfusion and therefore is probably due to high arteriolar oxygen content and oxygen diffusion.

Expression and localization of endothelin-1 and endothelin receptors in human meningiomas. Evidence for a role in tumoral growth.

In addition to its well-known homoeostatic actions in the cardiovascular system, ET-1 has been shown to constitute a potent growth regulatory peptide in various tissues. We have studied the expression of ET-1 and its receptors (ET-Ar and ET-Br) in human meningiomas (n = 35) as well as their involvement in cellular growth. By PCR of reverse-transcribed RNA we detected ET-1 mRNA in 91% (32 of 35), ET-Ar mRNA in 82% (29 of 35), and ET-Br mRNA in 42% (15 of 35) of human meningiomas examined. The localization of ET-1 mRNA, ET-Ar mRNA, and ET-1 peptide in tumoral cells was observed by in situ hybridization and immunohistochemistry, whereas ET-Br mRNA was expressed at low level only in cells belonging to blood vessels. In addition, we found that ET-1 stimulated [3H] thymidine incorporation in primary cell cultures of 20 meningiomas and that this effect could be blocked by BQ-123, a specific antagonist for ET-Ar. In contrast, RES-701-3, an antagonist of ET-Br, did not block the proliferative effect of ET-1. In conclusion, our data provide evidence that ET-1 constitutes an important growth factor for meningiomas acting via ET-Ar. We can hypothesize that ET-1, acting in concert with other growth factors and cytokines, is involved in the meningioma tumorigenesis.

Vascular Endothelial Growth Factor Production and Regulation in Rodent and Human Pituitary Tumor Cells in vitro

Angiogenesis, the formation of a new blood supply, is an essential step in tumorigenesis. Although vascular endothelial growth factor (VEGF) is known to be a very potent angiogenic factor in most solid tumors, little is known about its production and regulation in pituitary adenomas. We have investigated basal and stimulated VEGF production by rodent pituitary tumor cells (mouse corticotrope AtT20, rat lactosomatotrope GH3, mouse gonadotrope αT3-1 and mouse folliculostellate TtT/GF cells), and by hormone-inactive (27), corticotrope (9), lactotrope (3) and somatotrope (21) human pituitary adenoma cell cultures. All 4 pituitary cell lines secreted VEGF, which in the case of AtT20, GH3 and TtT/GF cells was inhibited by approximately 50% by dexamethasone. TtT/GF cells were the most responsive to the different stimuli used since basal values were augmented by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), interleukin-6 (IL-6), transforming growth factor-α (TGF-α), IGF-I and the somatostatin analogue ocreotide. However, in GH3, AtT20 and αT3-1 cells, basal VEGF levels where not enhanced with any of the stimuli tested. The majority of the human adenomas tested (92%) basally secreted measurable VEGF which was inhibited by dexamethasone in most cases (84%). VEGF levels were increased in hormone inactive adenomas, somatotrope tumors and prolactinomas by TGF-α, PACAP-38, and 17β-estradiol, respectively. In conclusion, pituitary tumor cells are capable of producing VEGF which may be involved in tumoral angiogenesis. Our results concerning the suppression of VEGF by dexamethasone suggest that glucocorticoids may have anti-angiogenic properties and therefore therapeutic relevance for the treatment of pituitary adenomas.

The hairless mouse ear for in vivo studies of skin microcirculation

The homozygous (hr/hr) hairless mouse ear was introduced in 1980 by Eriksson and coworkers as a model for in vivo studies of the skin microcirculation. Herein we expand on this work, presenting results of in vivo microvascular parameter measurements and morphologic studies in the intact ear. The in vivo measurements include microvascular diameter, RBC velocity, capillary density, and the frequency and amplitude of arteriolar vasomotion. In connection with the in vivo studies, a detailed anatomic description of the overall and vascular anatomy is given. Additionally, the preparation techniques for carrying out these in vivo and morphologic studies in the mouse ear are presented in detail.

Intraoperative Computed Tomography With Integrated Navigation System in Spinal Stabilizations

Study Design. A prospective interventional case-series study plus a retrospective analysis of historical patients for comparison of data. Objective. To evaluate workflow, feasibility, and clinical outcome of navigated stabilization procedures with data acquisition by intraoperative computed tomography. Summary of Background Data. Routine fluoroscopy to assess pedicle screw placement is not consistently reliable. Our hypothesis was that image-guided spinal navigation using an intraoperative CT-scanner can improve the safety and precision of spinal stabilization surgery. Methods. CT data of 94 patients (thoracolumbar [n = 66], C1/2 [n = 12], cervicothoracic instability [n = 16]) were acquired after positioning the patient in the final surgical position. A sliding gantry 40-slice CT was used for image acquisition. Data were imported to a frameless infrared-based neuronavigation workstation. Intraoperative CT was obtained to assess the accuracy of instrumentation and, if necessary, the extent of decompression. All patients were clinically evaluated by Odom-criteria after surgery and after 3 months. Results. Computed accuracy of the navigation system reached <2 mm (0.95 ± 0.3 mm) in all cases. Additional time necessary for the preoperative image acquisition including data transfer was 14 ± 5 minutes. The duration of interrupting the surgical process for iCT until resumption of surgery was 9 ± 2.5 minutes. Control-iCT revealed incorrect screw position ≥2 mm without persistent neurologic or vascular damage in 20/414 screws (4.8%) leading to immediate correction of 10 screws (2.4%). Control-iCT changed the course of surgery in 8 cases (8.5% of all patients). The overall revision rate was 8.5% (4 wound revisions, 2 CSF fistulas, and 2 epidural hematomas). There was no reoperation due to implant malposition. According to Odom-criteria all patients experienced a clinical improvement. A retrospective analysis of 182 patients with navigated thoracolumbar transpedicular stabilizations in the preiCT era revealed an overall revision rate of 10.4% with 4.4% of patients requiring screw revision. Conclusion. Intraoperative CT in combination with neuronavigation provides high accuracy of screw placement and thus safety for patients undergoing spinal stabilization. Reoperations due to implant malpositions could be completely avoided. The system can be installed into a pre-existing operating environment without need for special surgical instruments. The procedure is rapid and easy to perform without restricted access to the patient and—by replacing pre- and postoperative imaging—is not associated with an additional exposure to radiation. Multidisciplinary use increases utilization of the system and thus improves cost-efficiency relation.

Intraoperative computed tomography with integrated navigation system in a multidisciplinary operating suite.

OBJECTIVE We report our preliminary experience in a prospective series of patients with regard to feasibility, work flow, and image quality using a multislice computed tomographic (CT) scanner combined with a frameless neuronavigation system (NNS). METHODS A sliding gantry 40-slice CT scanner was installed in a preexisting operating room. The scanner was connected to a frameless infrared-based NNS. Image data was transferred directly from the scanner into the navigation system. This allowed updating of the NNS during surgery by automated image registration based on the position of the gantry. Intraoperative CT angiography was possible. The patient was positioned on a radiolucent operating table that fits within the bore of the gantry. During image acquisition, the gantry moved over the patient. This table allowed all positions and movements like any normal operating table without compromising the positioning of the patient. For cranial surgery, a carbon-made radiolucent head clamp was fixed to the table. RESULTS Experience with the first 230 patients confirms the feasibility of intraoperative CT scanning (136 patients with intracranial pathology, 94 patients with spinal lesions). After a specific work flow, interruption of surgery for intraoperative scanning can be limited to 10 to 15 minutes in cranial surgery and to 9 minutes in spinal surgery. Intraoperative imaging changed the course of surgery in 16 of the 230 cases either because control CT scans showed suboptimal screw position (17 of 307 screws, with 9 in 7 patients requiring correction) or that tumor resection was insufficient (9 cases). Intraoperative CT angiography has been performed in 7 cases so far with good image quality to determine residual flow in an aneurysm. Image quality was excellent in spinal and cranial base surgery. CONCLUSION The system can be installed in a preexisting operating environment without the need for special surgical instruments. It increases the safety of the patient and the surgeon without necessitating a change in the existing surgical protocol and work flow. Imaging and updating of the NNS can be performed at any time during surgery with very limited time and modification of the surgical setup. Multidisciplinary use increases utilization of the system and thus improves the cost-efficiency relationship.