[Advanced MRI techniques of the fetal brain]. / Zukunftsweisende MRT-Techniken des fetalen Gehirns.

CLINICAL/METHODICAL ISSUE: Evaluation of the normal and pathological fetal brain. STANDARD RADIOLOGICAL METHODS: Magnetic resonance imaging (MRI). METHODICAL INNOVATIONS: Advanced MRI of the fetal brain. PERFORMANCE: Diffusion tensor imaging (DTI) is used in clinical practice, all other methods are used at a research level. ACHIEVEMENTS: Serving as standard methods in the future. PRACTICAL RECOMMENDATIONS: Combined structural and functional data for all gestational ages will allow more specific insight into the developmental processes of the fetal brain. This gain of information will help provide a common understanding of complex spatial and temporal procedures of early morphological features and their impact on cognitive and sensory abilities.

Manual accuracy in comparison with a miniature master slave device--preclinical evaluation for ear surgery.

Manual accuracy in microsurgery is reduced by tremor and limited access. A surgical approach through the middle ear also puts delicate structures at risk, while the surgeon is often working at an unergonomic position. At this point a micromanipulator could have a positive influence. A system was developed to measure "working accuracy", time and precision during manipulation in the middle ear. 10 ENT-surgeons simulated a perforation of the stapedial footplate on a modified 3D print of a human skull in a mock OR. Each trial was repeated more than 200 times aiming manually and using a micro-manipulator. Data of over 4000 measurements was tested and graphically processed. Work strain was evaluated with a questionnaire. Accuracy for manual and micromanipulator perforation revealed a small difference. Learning curves showed a stronger decrease both in deviation and time when the micromanipulator was used. Also a lower work strain was apparent. The micromanipulator has the potential as an aiding device in ear surgery.

The HD-Panoramic Visualization System: a new visualization system for ENT surgery.

This work examines the application possibilities of a new visualization system, the Panoramic Visualization System (HD-PVS), in ENT surgery. The Panoramic Visualization System (PVS) is a novel optical system that is neither an endoscope nor a microscope. It has a focal length of 200 mm, a wide field of view and is used together with an HD camera and an HD monitor (HD-PVS). The analysis of the visualization quality took place in laboratory conditions using 4 close-to-surgery scenarios with altogether 40 data points. Further, the system was used on patients in 45 procedures (tympanoplasty, parotidectomy, neck dissection, septumplasty, transfacial approaches). The results were analyzed following the ICCAS workflow-scheme and with standardized questionnaires. In the analysis of the visualization quality, the PVS exhibited the best total evaluation in the lab test in two out of four scenarios. In one of four scenarios, the PVS as well as the microscope achieved the maximum attainable score. In one out of four scenarios, the endoscope attained a better result than the PVS. The microscope was never superior to the HD-PVS in terms of image quality. In four out of five clinical applications, the PVS was evaluated as operational with slight modifications. Most development is needed in middle ear surgery applications. The remaining procedures already benefit in the system configuration examined here, and they were regularly accomplished with support of the PVS. The present study offers a good basis for introducing the PVS to ENT surgery. The advantages over the existing gold standard include lower initial costs for the optical system than for an operating microscope since the HD-video system is often already in place, smaller space requirements than a microscope, equal or at times better visualization quality than the microscope, the possibility of videoendoscopic representation of surgeries in which this was impossible before, and better ergonomic conditions.

[Modified procedure for patient registration for navigation control instruments in ENT surgery]. / Ein modifiziertes Verfahren zur bissschienenbasierten Patientenregistrierung für die HNO-Navigation.

PROBLEM: Surgical navigation and navigation-controlled instruments demand a robust and precise patient registration process. For navigation in the skull, a bite-splint-based registration method has been widely applied, which had to be manufactured by dental technicians. The additional cost and time could be avoided by directly using the manufactured imprint, which is prepared by the ENT surgeon in one step. MATERIAL AND METHODS: This study examined the re-positioning accuracy for three silicon materials in a laboratory study with a 3D measuring device (Faro-arm) after several re-positioning cycles (simulating erosion) in comparison to the gold standard. RESULTS: The mean deviation after two cycles was lower for all three materials compared to the gold standard. Only C-Silikon Optosil was better then the gold standard after all cycles and with a deviation of 0.17 mm it well below that of the conventional bite-splint (0.28 mm). The additional cost benefits of 10 euro per imprint compared to the bite-splint with >100 euro favor this material for clinical application. CONCLUSIONS: As a consequence of this investigation Optosil was successfully used in 6 patients during the period from 01.09.2007 to 30.11.2007. The bite-splint was manufactured completely in the ENT department and could be used during the planning CT and surgery. The resulting accuracy corresponded to the experiences gained in previous surgery with a maximum deviation of 0.87 mm. The favorable ergonomic characteristics for patient and surgeon could be confirmed. As a result of this study this clinic now exclusively uses the procedure described in this article for bite-splint-based registration.

[A new visualization device for ENT surgery : the panoramic visualization system (HD-PVS)]. / Ein neues Visualisierungssystem für die HNO-Chirurgie : Das HD-Panoramic-visualisation-System.

BACKGROUND: This work examines the application possibilities of the panoramic visualization system (HD-PVS) in ENT surgery. The HD-PVS is a new optical system that is neither an endoscope nor a microscope. It has a focal length of 200 mm and a wide field of view. PATIENT AND METHODS: The analysis of the visualization quality took place under laboratory conditions at 4 close-to-surgery scenarios with a total of 40 result values. Furthermore, the system was used for 45 operative procedures on patients (tympanoplasty, parotidectomy, neck dissection, septumplasty, transfacial approaches). The results were analyzed following the ICCAS workflow-scheme and with standardized questionnaires. RESULTS: The analysis of the visualization quality of the PVS exhibited the best total evaluation in 2 out of 4 scenarios, in 1 scenario HD-PVS attained the maximum score possible, as did the microscope and the endoscope was better than HD-PVS in 1 scenario. The microscope was never evaluated as being better than HD-PVS. Apart from its use in middle ear surgery, the HD-PVS can be considered operational in 4 out of 5 clinical applications with only slight modifications. CONSEQUENCES: The advantages of HD-PVS over gold standards such as the surgical microscope are lower initial costs for the optical system with frequently already existing HD-video system, smaller space requirements, equal or sometimes better visualization quality, possibility of videoendoscopic representation of surgery and better ergonomic conditions.

[Evaluation of a daily used navigation system for FESS]. / Untersuchungen zur Effizienz eines Navigationssystems für die HNO-Chirurgie: Auswertungen von 300 Patienten.

PROBLEM: The aim of this study is to proof the clinical efficiency by using a modern navigation system for Functional Endoscopic Sinus Surgery (FESS). MATERIAL AND METHODS: An optical navigation system was used in clinical routine of 300 patients. Two groups with 150 patients each were examined. Group A was treated with navigation assistance (Karl Storz Navigation Panel Unit NPU), Group B was treated without navigation by conventional FESS. Examination period was limited to 12 months. Median follow-up is 22 and 26 weeks. Perioperative, intraoperative and postoperative parameters were recorded by workflow-analysis, clinical and radiological findings and standardized questionnary. RESULTS: Application of the navigation system needs 1.1 min additional perioperative time in average. Intraoperative time reduction by the navigation system was about 10 min per case (Group A 32.6 (SD 11.2) min, Gruppe B 42.7 (SD 9.5) min). Specific information by the navigation system was evaluated in all surgical areas as usefull and additional to a-priori-knowledge. Postoperatively patients from group A (10/89) show lower rate of re-polyposis then in group B (24/71). Fenestration of the sphenoid sinus were sufficient by CT-evaluation in 100% (group A) and 23% (group B). CONCLUSIONS: The advantages of the examined navigation system in comparison to the gold standard of FESS are proven. Navigation assistance led to an reduced intraoperative time consumption, increased postoperative results and lowered the workload of the surgeons.

First clinical evaluation of the navigated controlled drill at the lateral skull base.

Surgery on the lateral skull base puts delicate structures at risk. To support the surgeon in identifying and protecting the risk structures the principle of Navigated Control (NC) can be used for preventing iatrogenic injuries. In this paper the application of Navigated Control for surgery on the lateral skull base was investigated for the first time in clinical use. There was no risk structure damage with NC. Navigated Control in lateral skull base surgery seems to have a great potential for safe risk structure protection, a morbidity reduction and in a relief of strain for the surgeon.

Surgery on the lateral skull base with the navigated controlled drill employed for a mastoidectomy (pre clinical evaluation).

Patients who are treated with a mastoidectomy usually suffer from an inflammation of the petrosal bone. The intervention is a time consuming landmark based surgery and usually performed with a powered drill. Delicate risk structures must be respected. Navigated Control (NC) describes the control for a power driven instrument which is controlled by a surgeon and additionally controlled according to the position of the instrument relatively to a deliberated position known from a preoperatively segmented work space which excludes risk structures. The force of a drill can be regulated by the principle of NC. Following results were received: 1. Risk structure segmentation is feasible 2. The drill and a phantom can be registered. 3. With NC the resection is faster, more accurate and with no risk structures damage. 4. The phantom is suitable.

Clonogenic growth in vitro: an independent biologic prognostic factor in ovarian carcinoma.

A retrospective analysis was performed to investigate the prognostic value of growth in a human tumor clonogenic assay system for 84 ovarian cancer patients. A significant difference in survival probability (determined by the method of Kaplan-Meier) was found by univariate analysis between patients with ovarian carcinoma whose tumors manifested clonogenic growth (defined as growth of greater than or equal to five colonies per plate) and patients whose tumors did not grow. Clonogenic growth in vitro was associated with worse prognosis (P = .007, log-rank test). A number of generally accepted prognostic factors, International Federation of Gynecology and Obstetrics (FIGO) stage (P = .003), residual tumor mass (P less than .001), and grade (P = .011), were also of prognostic importance in our patient population. Multivariate analysis, based on the Cox regression model, identified clonogenic growth as a significant independent prognostic parameter in ovarian carcinoma (P = .031), in addition to the conventional risk factors. Estimation of survival of individual patients was best accomplished by combining the factors of residual tumor mass (P less than .05), age (P less than .01), and clonogenic growth (P less than .05) (in sequence of decreasing potential of risk).

Intermittent administration of betalactam-antibiotics for treatment of severe infection in hemodialysis patients.

Infections are a leading cause of morbidity and mortality in hemodialysis patients. Still, due to altered pharmacokinetics and potential toxic sideeffects, safe and efficient antibiotic therapy in dialysis patients remains a major challenge. We reviewed our experience with intermittent administration of betalactam antibiotics for treatment of severe infections in hemodialysis patients. A total of 81 episodes of infection in 45 patients was assessed. All patients were treated with betalactam antibiotics (cefepime in 11 episodes, cefpirom in 33 episodes, piperacillin in 9 episodes, amoxicillin in 18 episodes, ceftazidime in 10 episodes, respectively). All antibiotics were given post hemodialysis 3x per week. Treatment was considered efficient in case of a significant decrease in CRP in addition to clinical response. Overall treatment success rate was 85% (69 episodes of infection). The decrease of CRP was 52% (6.9 +/- 5.8 to 3.3 +/- 4.9 mg/dl; p = 0.00003). The mean duration of treatment was 19 +/- 13 days. Treatment was generally well tolerated. We conclude, that severe infections in hemodialysis patients can be treated safely and efficiently with an empiric therapy with betalactam antibiotics. Intermittent administration, potentially allowing ambulatory treatment, is possible.

The hepatic interleukin-6 receptor. Down-regulation of the interleukin-6 binding subunit (gp80) by its ligand.

Interleukin-6 (IL6) exerts its action via a cell surface receptor composed of an 80 kDa IL6-binding protein (gp80) and a 130 kDa polypeptide involved in signal transduction (gp130). We studied the role of gp80 in binding, internalization and down-regulation of the hepatic IL6-receptor (IL6R) by its ligand in human hepatoma cells (HepG2). Comparison of transfected HepG2 cells overexpressing gp80 with parental cells indicate that gp80 is responsible for low affinity binding (Kd = 500 pM) of IL6. Furthermore, gp80 is rate-limiting in internalization and degradation of IL6. Internalization resulted in a rapid down-regulation (t1/2 approximately 15-30 min) of IL6-binding sites at the cell surface. More than 80% of the internalized [125I]rhIL6 was degraded. The reappearance of IL6-binding sites at the cell surface required greater than 8 h and was sensitive to cycloheximide, suggesting that gp80 is not recycled after internalization. The down-regulation of the hepatic IL6R by its ligand might play an important role as a protection against overstimulation.

A complex of the soluble interleukin-6 receptor and interleukin-6 is internalized via the signal transducer gp130.

In human body fluids a soluble form of the interleukin-6 receptor (sIL-6R) has been found which together with interleukin-6 (IL-6) acts agonistically on cells expressing the signal transducer gp130. The means by which the sIL-6R is removed from the circulation is unknown. Here, we show that a complex of 125I-labelled recombinant sIL-6R and IL-6 is internalized by MDCK cells stably transfected with gp130 and by human hepatoma cells HepG2 that endogenously express the IL-6R and gp130. We further show that most of the internalized sIL-6R is degraded within lysosomes. Our studies suggest that cells expressing gp130 are capable of endocytosing an IL-6/sIL-6R complex, thereby removing both from the circulation.

Differential shedding of the two subunits of the interleukin-6 receptor.

cDNAs coding for the two receptor subunits of the interleukin-6 receptor have been stably expressed in Madine Darby canine kidney (MDCK) cells. The fate of the IL-6 binding protein (IL-6R) and of the signal transducing protein gp130 was studied independently. Both proteins were proteolytically cleaved from cells metabolically labeled with [35S]methionine/cysteine leading to the release of soluble receptor proteins of 55 kDa and 100 kDa, respectively. In contrast to the shedding of the IL-6R gp130 was inefficiently released from the cells and the process was not significantly stimulated by the phorbolester PMA. In addition we show that the soluble forms of the IL-6R and gp130 released by transfected cells can form a ternary complex with interleukin-6 indicating that such complexes also may occur in vivo.

Separation of clonogenic and differentiated cell phenotypes of ovarian cancer cells (HOC-7) by discontinuous density gradient centrifugation.

We isolated clonogenic cells from differentiated HOC-7 ovarian cancer cells. Both cell subsets were characterised in respect to morphology, growth behaviour, DNA content and expression of tumour-associated antigens and nuclear oncogenes. Ten cell fractions (Fr) were separated by centrifugation in a discontinuous density gradient (Fr 1 less than 1.037 g/ml to Fr 10 greater than 1.069 g/ml, steps 0.004 g/ml). Large adenoid cells containing vacuoles filled with neutral polysaccharides were concentrated in Fr 1-4. These cells were non-clonogenic in soft agar. The growth on solid substrate was highest in Fr 6 and 7, intermediate in Fr 2-5 and Fr 8-10 and lowest in Fr 1. The mean cloning efficiencies of the fractions in soft agar were highest in Fr 6 (8.1%) and lowest in Fr 2 and 3 (0.1%). Diploid and near tetraploid cell subsets were found with similar frequency in all fractions. Immunocytochemistry revealed 4-7% Ki-67 positive cells in Fr 1-6 and 12-20% in Fr 7-10. In Fr 3-10 greater than or equal to 79% of the cells expressed CA 125. Positivity for c-myc, c-myb and c-fos (greater than or equal to 74%) was not correlated with clonogenicity. In conclusion, differentiated cells (Fr 1-4) were separated from cells with higher growth rates (Fr 5-10). Clonogenic cells were enriched in Fr 6. These data indicate that discontinuous density gradient fractionation represents a useful method for separation of cells with different degrees of differentiation, growth potential and clonogenicity.

Analysis of factors influencing clonogenic growth in vitro of cells from ovarian carcinoma patients.

Clonogenic growth (defined as the formation of greater than or equal to 5 colonies per 5 x 10(5) viable nucleated cells per plate) of ovarian cancer specimens assessed in our clonogenic assay system was significantly associated with the proportion of tumor cells in the suspensions plated (N = 87; P = 0.0006), although there was no quantitative relationship with the corresponding plating efficiencies. An inverse correlation was observed between monocytes/macrophages/mesothelial cells (M) proportion and clonogenic growth (P = 0.013). These associations were most evident when only effusions were considered. Univariate analyses identified tumor cell content, M proportion and, to a lesser degree, granulocyte content as the only factors out of 12 examined to be correlated with colony formation. Multivariate analysis using a logistic regression model identified the proportion of tumor cells as the only significant factor predicting clonogenic growth in vitro (P = 0.0006). The overall accuracy of prediction for growth or non-growth was 63.2%.

Tyrosine kinase signaling pathways control the expression of retinoic acid receptor-alpha in SK-BR-3 breast cancer cells.

Breast carcinomas are frequently characterized by hyperactivated c-erbB receptor tyrosine kinase signaling. Combination of anti-proliferative retinoids with growth-inhibitory c-erbB-specific agents might induce therapeutic benefit. We demonstrate close interactions between the c-erbB and the retinoic acid receptor system in SK-BR-3 breast cancer cells. Epidermal growth factor and heregulin-beta1 activate c-erbB receptors and dose- and time-dependently up-regulate retinoic acid receptor-alpha (RAR-alpha) mRNA. Similar effects have been found for the growth-inhibitory c-erbB-2 receptor tyrosine kinase-activating antibody 4D5 and the tyrosine phosphatase inhibitor orthovanadate. In contrast, the tyrosine kinase-inhibitor herbimycin A reduces tyrosine-specific protein phosphorylation and down-regulates RAR-alpha. Our data demonstrate that the expression of RAR-alpha, which represents a key mediator of the anti-proliferative effects of retinoids in breast cancer cells, is regulated by modulators of tyrosine kinase signaling. The levels of RAR-beta and -gamma mRNAs, however, are not affected by such agents.

A preceding exchange with polyglucose versus glucose solution modifies peritoneal equilibration test results.

The peritoneal equilibration test (PET) is an important tool for evaluating peritoneal membrane characteristics. The polyglucose icodextrin induces ultrafiltration caused by colloid osmosis through the small pores of the peritoneal membrane and therefore is especially effective during long dwell times. The main indications for polyglucose solutions are daytime dwells in patients on automated peritoneal dialysis and nighttime exchanges in continuous ambulatory peritoneal dialysis (CAPD) patients. In CAPD patients, PET is started immediately after the icodextrin exchange. Therefore, we performed two PETs in each of 15 CAPD patients. PET post-1.36% glucose was performed immediately after a preceding exchange with 2 L of 1.36% glucose dialysate solution (dwell time, 10 hours). PET postpolyglucose was started immediately after a preceding exchange with 2 L of 7.5% icodextrin solution (dwell time, 10 hours). The dialysate to plasma (D/P) ratio of creatinine, phosphate, and sodium during PET postpolyglucose was significantly greater than during PET post-1.36% glucose at 1, 2, 3, and 4 hours of dwell time. The quotient of dialysate glucose at 1, 2, and 4 hours of dwell time to dialysate glucose at 0 dwell time was significantly lower in PET postpolyglucose compared with PET post-1.36% glucose. In the case of creatinine, phosphate, and glucose, PET postpolyglucose curves tended to be steeper than those of PET post-1.36% glucose during the first hour of dwell time, whereas both curves were parallel between 1 and 4 hours of dwell time. The course of D/P ratio curves of urea nitrogen, protein, and albumin was nearly identical between PET postpolyglucose and PET post-1.36% glucose. In a subgroup of 5 patients, D/P ratios of creatinine and phosphate were also greater in PET postpolyglucose compared with PET performed after a long dwell with 2.27% glucose solution. Before a scheduled PET, CAPD patients using icodextrin solution during the nighttime should perform their nighttime exchange with conventional glucose solution.

Ontogenesis of the GnRH neuron system in the rat. A quantitative immunohistochemical study with special reference to the extra cerebral GnRH-positive cells and the occupation of intracerebral termination fields.

The distribution of GnRH immunopositive cells in the rat was studied from day 13 of fetal life to day 10 of postnatal life with the aid of a GnRH antibody (H-16) generated against the decapeptide p-Glu1-LHRH in the rabbit and following a PAP immunohistochemical staining protocol on 70 um serial Vibratome sections. The first appearance of GnRH cells was observed simultaneously in both intra- and extra-cerebral regions on day 16 of fetal life. At all stages of development, at least 10 times more GnRH cells were found in the brain than in extracerebral areas. The population of GnRH cells was maximum in the nasal mucosa on day 20, and in intracranial, extracerebral regions (along the anterior cerebral artery and the terminal nerve) on day 22 of fetal life: it declined thereafter. The population of GnRH cells in the brain continued to increase until the day of birth and remained unchanged thereafter. Our findings are in accordance with the theory of nasal placodal origin of the GnRH neuronal system, but also suggest that in the rat, shifting of the cells from the nasal placode to the brain is somewhat preceding the onset of GnRH synthesis. Our other field of endeavor was to examine the GnRH axon terminal fields in the course of development. On day 18 of fetal life, the vascular organ of the lamina terminalis, the median eminence and the medial habenular nuclei received their GnRH axon terminals. On day 19 the subfornical organ, mammillary nuclei and the central nucleus of the amygdala, and on day 21 the periaqueductal gray and the interpeduncular nucleus became invaded by GnRH axons. These data serve the better understanding of the onset of the different functional activities of the GnRH system in the rat.

Is absorption of high-dose oral iron sufficient in peritoneal dialysis patients?

OBJECTIVE: Iron supplementation plays a major role in erythropoietin-treated end-stage renal disease patients. For peritoneal dialysis (PD) patients, oral iron substitution is more convenient than intravenous therapy. However, disturbed iron absorption and adverse effects may be limiting factors for oral treatment. Nevertheless, we compared the response to a high-dose and low-dose oral iron absorption test between PD patients and healthy control subjects. PATIENTS AND INTERVENTIONS: In 34 PD patients and 15 healthy control subjects, blood samples were taken at baseline as well as 2, 4, and 8 hours after oral intake of 4 tablets iron sulfate (105 mg elemental iron per tablet). In a subgroup of 6 PD patients and 6 control subjects, the oral iron absorption test was repeated using 1 tablet iron sulfate. RESULTS: There was no significant difference in the increase in serum iron during the test between the two groups. As known for healthy subjects, iron absorption was significantly better in PD patients with absolute iron deficiency compared to those with functional iron deficiency. Iron-repleted PD patients showed the lowest iron absorption, indicating that a high dose of oral iron did not overwhelm the ability of the bowel tract to reject unneeded iron. Increasing the oral iron dose from 1 to 4 tablets was followed by a better response in a small subgroup of PD patients compared to control subjects. Side effects such as nausea and vomiting occurred more frequently during high-dose oral iron in control subjects than in PD patients (20% vs 8.8%). CONCLUSION: High-dose oral iron is well absorbed in iron-depleted PD patients. This kind of oral iron therapy should be considered in some subgroups of PD patients with iron deficiency, particularly in those patients with poor vascularization of arm veins or intolerance to intravenous iron preparations.

Quality of care for psychiatric emergency service patients presenting with substance use problems.

Psychiatric emergency service assessments of 683 patients were observed to better understand the quality of care substance users receive and the effects of clinicians' attitudes toward their patients on such care. Findings run counter to those of previous reports in that substance users, once recognized, are likely to receive better care than other patients.