C-arm-based mobile computed tomography: a comparison with established imaging on the basis of simulated treatments of talus neck fractures in a cadaveric study.

OBJECTIVE: To analyse the image quality and diagnostic effectiveness of a new C-arm-based 3D imaging method (C-arm-CT) for intraoperative evaluation of screw osteosyntheses adjacent to a peripheral joint. MATERIALS AND METHODS: Insertion of screws into four cadaveric specimens simulated the surgical treatment of talus neck fractures. Ten orthopedic surgeons and 10 radiologists evaluated X-ray, C-arm fluoroscopy, C-arm-CT and CT images. RESULTS: The best image quality was obtained with X-rays (p < 0.001), followed by C-arm fluoroscopy (2D) and CT, with the C-arm-CT (3D) being rated lowest (p < 0.001). The most correct diagnoses were obtained with CT and C-arm-CT (with no statistical difference between them), while C-arm-fluoroscopy was inferior (p < 0.001) and X-rays were the worst (p < 0.05). CONCLUSIONS: Even if the image quality of C-arm-CT is definitely inferior to that of CT, screw misplacements can be reliably detected using C-arm-CT. As compared to the current standard procedures (intraoperative fluoroscopy and postoperative radiography), C-arm-CT performed better. C-arm-CT is ideally suited to the intraoperative diagnosis of high-contrast inquiries like bone fragments and OS material, especially at the extremities. Coupling of the new 3D imaging to existing navigation systems is possible. C-arm-CT will support the further development and implementation of open and minimally invasive surgical procedures.     

Pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) in cynomolgus monkeys after single oral and intravenous doses

The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.o. or i.v. bolus and 1 mg/kg p.o. were administered to the animals, the concentrations of FTY720, and the numbers of lymphocytes, CD20+CD2-B cells, and CD2+CD20-T cells in blood were measured over 23 days. A linear three-compartment model characterized the time course of FTY720 concentrations with a terminal half-life of about 31 h, clearance of about 0.53 l/h/kg, and bioavailability of about 38%. The dynamic responses were not area under the curve (or dose) proportional for either males or females. An indirect response model with a distribution pool captured the cell trafficking data for all doses for each cell type, where initial blood counts (R(0)) were about 7650, 2100, and 5250 cells/microl; maximum fractional inhibition (I(max)) about 0.88, 0.85, and 0.91; influx (k(in)) about 6014, 1312, and 5662 cells/microl/h; efflux (k(out)) about 0.798, 0.555, and 1.08 h(-1); intercompartmental k(cp) about 0.134, 0.192, and 0.082 h(-1); and intercompartmental k(pc) rate constants about 3.9 x 10(-4), and 0.016 and 8.9 x 10(-6) h(-1) for lymphocytes, B cells, and T cells, respectively. The inhibition concentration IC(50) was about 0.48 microg/l for all cells, which was remarkably low. The apparent distribution volumes of peripheral pool (V(p)) were markedly larger than blood volume (V(b)) for all cells. The I(max) for cell trafficking was achieved at doses smaller than that producing graft protection, indicating stronger central than peripheral effects of this drug. The profound cell trafficking effects of FTY720 can be readily captured and interpreted with an extended indirect response model.     

Cardiac troponins and creatine kinase content of striated muscle in common laboratory animals

Animal models are important for the investigation of human heart pathology, novel treatments, and medical or surgical interventions for disease. Serum markers of myocardial damage may also be important tools within this field of research. In order to assess the cardiac specificity of widely utilised serum markers, we measured the cardiac troponins and creatine kinase (CK) isoenzymes in cardiac and skeletal muscle samples taken from dog, monkey, pig and rat. These samples were also analysed by immunoblotting for cardiac troponin I (cTnI) and cardiac troponin T (cTnT). The content of cTnI and cTnT in skeletal muscle was below 0.6% of that found in heart for all animal species studied. This low immunoreactivity in skeletal muscle was confirmed by immunoblot analysis. The content of CK was higher in skeletal muscle than in heart muscle for all species. The CK-MB/total CK ratio was lower in skeletal muscle than in cardiac muscle for all species. The differences in CK-MB content of skeletal muscle and heart muscle were much less pronounced than the tissue differences in the amounts of the cardiac troponins. The cardiac troponins are potentially useful serum markers of myocardial damage, with high specificity for myocardial muscle in these common laboratory animals. Creatine kinase-MB is much less cardiac-specific.     

Cerebral processing of food-related stimuli: effects of fasting and gender

To maintain nutritional homeostasis, external food-related stimuli have to be evaluated in relation to the internal states of hunger or satiety. To examine the neural circuitry responsible for integration of internal and external determinants of human eating behaviour, brain responses to visual and complex gustatory food-related stimuli were measured using functional magnetic resonance imaging in 18 healthy non-smokers (10 women, 8 men). Each individual was studied on two occasions, the order of which was counterbalanced; after eating as usual and after 24 h fasting. Raised plasma free fatty acids and lower insulin and leptin concentrations confirmed that participants fasted as requested. When fasted, participants reported more hunger, nervousness and worse mood and rated the visual (but not gustatory) food-related stimuli as more pleasant. The effect of fasting on hunger was stronger in women than in men. No circuitry was identified as differentially responsive in fasting compared to satiety to both visual and gustatory food-related stimuli. The left insula response to the gustatory stimuli was stronger during fasting. The inferior occipito-temporal response to visual food-related stimuli also tended to be stronger during fasting. The responses in the occipito-temporal cortex to visual and in the insula to gustatory stimuli were stronger in women than in men. There was no interaction between gender and fasting. In conclusion, food reactivity in modality-specific sensory cortical areas is modulated by internal motivational states. The stronger reactivity to external food-related stimuli in women may be explored as a marker of gender-related susceptibility to eating disorders.     

Variant classification in precision oncology

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.     

Computer applications in intravenous anaesthetic admin0tration

The place of computerization in intravenous anaesthesia delivery:1. Although total intravenous anaesthesia may have advantages over inhalational anaesthesia in certain circumstances, it has drawbacks from the point of view of feedback control. The ideal agent is not available, although di-isopropylphenol holds promise. There is an undefinable end-point. Inadequate dosage produces the extremely unpleasant phenomenon of intra-operative awareness.Future developments, it seems, should include the development of suitable intravenous agents and transducers of anaesthetic depth, rather than increasingly complicated control systems.2. It is extremely unlikely that a computer will replace the anaesthetist in the foreseeable future. The anaesthetist is still required for, amongst other things, specifying the desired depth of anaesthesia and varying it during the operation, and for responding to unforeseen crises. It may be hoped that, by liberating the anaesthetist from those tasks which can be automated, more time can be devoted to patient monitoring and other aspects of anaesthetic care, thereby improving patient safety.3. There is an undoubted place for computerized delivery of anaesthesia in teaching (particularly teaching pharmacokinetic principles) and in research (for standardization of anaesthetic depth).     

Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis

The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.     

Parallax-free intra-operative X-ray image stitching

We present a novel method to generate parallax-free panoramic X-ray images during surgery by enabling the mobile C-arm to rotate around its X-ray source center, relative to the patient’s table. Rotating the mobile C-arm around its X-ray source center is impractical and sometimes impossible due to the mechanical design of mobile C-arm systems. In order to ensure that the C-arm motion is a relative pure rotation around its X-ray source center, we propose to move the table to compensate for the translational part of the motion based on C-arm pose estimation. For this we employ a visual marker pattern and a Camera Augmented Mobile C-arm system that is a standard mobile C-arm augmented by a video camera and mirror construction. We are able to produce a parallax-free panoramic X-ray image independent of the geometric configuration of imaged anatomical structures. Our method does not require a fronto-parallel setup or any overlap between the acquired X-ray images. This generated parallax-free panoramic X-ray image preserves the linear perspective projection property. It also presents a negligible difference (below 2 pixels) in the overlapping area between two consecutive individual X-ray images and has a high visual quality. This promises suitability for intra-operative clinical applications in orthopedic and trauma surgery. The experiments on phantoms and ex-vivo bone structure demonstrate both the functionality and accuracy of the method.     

C-arm-based three-dimensional navigation: a preliminary feasibility study.

OBJECTIVE: With the new Siremobil Iso-C3D C-arm, three-dimensional (3D) datasets can be acquired intraoperatively in near-real time. Preliminary studies investigated the advantages of this system for depiction in joint and spinal surgery. Three-dimensional navigation seems feasible using the DICOM dataset of the Siremobil Iso-C3D in navigation devices. An experimental study was designed to investigate the feasibility and accuracy of this new technique. MATERIALS AND METHODS: After implantation of fiducial markers (titanium mini-screws, Leibinger), a Siremobil Iso-C3D C-arm with standard imaging options was used to acquire pre-interventional 3D datasets of the specimens. These isotropic voxel data were transferred via DICOM to a medivision navigation system using the spine module. After registration of the fiducials, a total of 20 pedicle screws were implanted (in 4 artificial-bone vertebral bodies and 6 cadaver vertebrae in situ) with the use of the navigation system in real-time mode. Post-interventionally, Iso-C3D and CT scans were obtained to control for implant position in the cadaver study. RESULTS: Fiducial marker implantation and registration require a special protocol to ensure correct identification and patient orientation in the DICOM dataset. The obtained accuracy was within 2 mm. Post-interventional imaging of the cadaveric vertebrae showed 10 of 12 screws to be correctly placed, with the other two in marginal intraosseous positions. CONCLUSIONS: Three-dimensional navigation with the Siremobil Iso-C3D data set is feasible, the accuracy being comparable to that of CT-based navigation and adequate for clinical interventions. Fiducial marker-based registration allows navigation of different bones in the same dataset without additional 3D scanning. This method is very useful as an additional tool in registration-free Iso-C3D-based navigation, since the navigation system allows the use of only one dynamic reference base (DRB).