Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model.

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE(-/-)), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE(-/-) and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE(-/-) mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE(-/-) mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE(-/-) mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased Akt(S473) phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated Akt(S473) phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE(-/-) mice is a favorable setting for mammary tumor growth and metastasis.

Spectral-domain low coherence interferometry/optical coherence tomography system for fine needle breast biopsy guidance.

A novel technology and instrumentation for fine needle aspiration (FNA) breast biopsy guidance is presented. This technology is based on spectral-domain low coherence interferometry (SD-LCI). The method, apparatus, and preliminary in vitro/in vivo results proving the viability of the method and apparatus are presented in detail. An advanced tissue classification algorithm, preliminarily tested on breast tissue specimens and a mouse model of breast cancer is presented as well. Over 80% sensitivity and specificity in differentiating all tissue types and 93% accuracy in differentiating fatty tissue from fibrous or tumor tissue was obtained with this technology and apparatus. These results suggest that SD-LCI could help for more precise needle placement during the FNA biopsy and therefore could substantially reduce the number of the nondiagnostic aspirates and improve the sensitivity and specificity of the FNA procedures.

Dual-beam Fourier domain optical Doppler tomography of zebrafish.

We have developed a dual-beam Fourier domain optical Doppler tomography (FD-ODT) system to image zebrafish (Danio rerio) larvae. Two beams incident on the zebrafish with a fixed angular separation allow absolute blood flow velocity measurement to be made regardless of vessel orientation in a sagittal plane along which the heart and most of the major vasculature lie. Two spectrometers simultaneously acquire spectra from two interferometers with a typical (maximum) line rate of 18 (28) kHz. The system was calibrated using diluted milk and microspheres and a 0.5-mm thick flow cell. The average deviation from the set velocity from 1.4 to 34.6 mm/s was 4.1%. Three-dimensional structural raster videos were acquired of an entire fish, and through the head, heart, and upper tail of the fish. Coarse features that were resolved include the telencephalon, retina, both heart chambers (atrium and ventricle), branchial arches, and notochord. Other fine structures within these organs were also resolved. Zebrafish are an important tool for high-throughput screening of new pharmacological agents. The ability to generate high-resolution three-dimensional structural videos and accurately measure absolute flow rates in major vessels with FD-ODT provides researchers with additional metrics by which the efficacy of new drugs can be assessed.

Three dimensional tracking for volumetric spectral-domain optical coherence tomography.

We present a three-dimensional (3D) tracker for a clinical ophthalmic spectral domain optical coherence tomography (SD-OCT) system that combines depth-tracking with lateral tracking, providing a stabilized reference frame for 3D data recording and post acquisition analysis. The depth-tracking system is implemented through a real-time dynamic feedback mechanism to compensate for motion artifact in the axial direction. Active monitoring of the retina and adapting the reference arm of the interferometer allowed the whole thickness of the retina to be stabilized to within +/-100 mum. We achieve a relatively constant SNR from image to image by stabilizing the image of the retina with respect to the depth dependent sensitivity of SD-OCT. The depth tracking range of our system is 5.2 mm in air and the depth is adjusted every frame.nhancement in the stability of the images with the depth-tracking algorithm is demonstrated on a healthy volunteer.

Noninvasive ventilation during gastrostomy tube placement in patients with severe duchenne muscular dystrophy: case reports and review of the literature.

Individuals with Duchenne muscular dystrophy may benefit from gastrostomy tube feeding due to progressive dysphagia and malnutrition. However, due to their severely impaired pulmonary function, these individuals are at risk of severe complications when they are sedated or undergo anesthesia for the procedure. We previously described a technique of noninvasive positive pressure ventilation to provide respiratory support during gastrostomy tube placement in such patients, but this technique had risks and limitations. In this case report, we examine two alternative techniques we used to provide respiratory support successfully to patients with severe muscular dystrophy and malnutrition who underwent percutaneous endoscopic gastrostomy tube placement. We then review the literature and discuss the potential benefits, risks, and limitations of the above techniques and of other options for gastrostomy placement in people with severe muscular dystrophy.

Hybrid retinal imager using line-scanning laser ophthalmoscopy and spectral domain optical coherence tomography.

We demonstrate for the first time the integration of two technologies, Spectral Domain Optical Coherence Tomography (SDOCT) and Line-Scanning Laser Ophthalmoscopy (LSLO) into a single compact instrument that shares the same imaging optics and line scan camera for both OCT and LSLO imaging. Co-registered high contrast wide-field en face retinal LSLO and SDOCT images are obtained non-mydriatically with less than 600 microwatts of broadband illumination at 15 frames/sec. The LSLO/SDOCT hybrid instrument could have important applications in clinical ophthalmic diagnostics and emergency medicine.

Transcatheter interventions for the treatment of peripheral atherosclerotic lesions: part II.

Transcatheter endovascular procedures are increasingly used to treat symptomatic peripheral atherosclerosis. This second part of a two-part review assesses the existing supportive evidence for the application of recently introduced transcatheter treatments for lesions that cause cerebrovascular ischemia and stroke. Studies were identified via MEDLINE (January 1993 through April 1999) and reference lists of identified articles. When multicenter prospective randomized trials or other high-quality studies were unavailable, studies with at least 50 patients per treated group and a minimum follow-up duration of 6 months were included. For each application, the authors assessed the quality of evidence (efficacy, safety, and, where available, cost-effectiveness) and made recommendations with appropriate caveats. Although recommendations based on proven efficacy and cost-effectiveness cannot be made in general, the use of transcatheter therapies can be supported in specific circumstances based on expected reduction in procedure-related morbidity and/or mortality. It is hoped that the identification of deficiencies in the literature will inform and inspire critically needed research in this area.

Current status of carotid bifurcation angioplasty and stenting based on a consensus of opinion leaders.

OBJECTIVE: Carotid bifurcation angioplasty and stenting (CBAS) has generated controversy and widely divergent opinions about its current therapeutic role. To resolve differences and establish a unified view of CBAS' present role, a consensus conference of 17 experts, world opinion leaders from five countries, was held on November 21, 1999. METHODS: These 17 participants had previously answered 18 key questions on current CBAS issues. At the conference these 18 questions and participants' answers were discussed and in some cases modified to determine points of agreement (consensus), near consensus, (prevailing opinion), or divided opinion (disagreement). RESULTS: Conference discussion added two modified questions, placing a total of 20 key questions before the participants, representing four specialties (interventional radiology, seven; vascular surgery, six; interventional cardiology, three; neurosurgery, one). It is interesting that consensus was reached on the answers to 11 (55%) of 20 of the questions, and near consensus was reached on answers to 6 (30%) of 20 of the questions. Only with the answers to three (15%) of the questions was there persisting controversy. Moreover, both these differences and areas of agreement crossed specialty lines. Consensus Conclusions: CBAS should not currently undergo widespread practice, which should await results of randomized trials. CBAS is currently appropriate treatment for patients at high risk in experienced centers. CBAS is not generally appropriate for patients at low risk. Neurorescue skills should be available if CBAS is performed. When cerebral protection devices are available, they should be used for CBAS. Adequate stents and technology for performing CBAS currently exist. There were divergent opinions regarding the proportions of patients presently acceptable for CBAS treatment (<5% to 100%, mean 44%) and best treated by CBAS (<3% to 100%, mean 34%). These and other consensus conclusions will help physicians in all specialties deal with CBAS in a rational way rather than by being guided by unsubstantiated claims.

Initial in vivo results of a hybrid retinal photocoagulation system.

We describe initial in vivo experimental results of a new hybrid digital and analog design for retinal tracking and laser beam control. An overview of the design is given. The results show in vivo tracking rates which exceed the equivalent of 38 degrees/s in the eye. A robotically assisted lesion pattern is created for laser surgery to treat conditions such as diabetic retinopathy and retinal breaks.

Pulsatile tinnitus cured by angioplasty and stenting of petrous carotid artery stenosis.

Pulsatile tinnitus may result from turbulent flow within the ipsilateral internal carotid artery. Surgical endarterectomy and carotid artery ligation have been used to treat atherosclerotic stenosis with or without associated pulsatile tinnitus. To our knowledge, this is the first reported case of pulsatile tinnitus, attributable to internal carotid artery stenosis, successfully treated by angioplasty and stenting.

Hybrid retinal photocoagulation system using analog tracking.

We describe initial in vivo experimental results of a new hybrid digital and analog design for retinal tracking and laser beam control. An overview of the design is given. The results show in vivo tracking rates which exceed the equivalent of 38 degrees per second in the eye, with automated lesion pattern creation. Robotically-assisted laser surgery to treat conditions such as diabetic retinopathy and retinal breaks may soon be realized under clinical conditions with requisite safety using standard video hardware and inexpensive optical components based on this design.

Three-dimensional reconstruction of arteriovenous malformations from multiple stereotactic angiograms.

Stereotactic angiography is the preferred imaging modality in the radiosurgical treatment of arteriovenous malformations (AVM). A major limitation of this technique is the inability to determine the three-dimensional shape and the volume of the AVM. We developed a technique for reconstructing the AVM from multiple stereotactic angiograms. The fiducial marks and the identified target area are digitized for each view. The 2-D target area is then stereotactically backprojected into a 3-D volume. The spatial boundary of the target volume is defined by superimposing the backprojections from each of the views. In feasibility studies with a phantom, this technique accurately reconstructed complex 3-D structures, depicting fine details as small as 1 mm. Clinical studies in two patients indicated that this novel technique is very useful for the 3-D reconstruction of AVM for radiosurgical treatment. The number of views required depends on the complexity of the object. In general, six to eight views appear adequate. The accuracy of the reconstruction can be compromised if the view angles are limited as with the current radiographic frame. A new frame design with practically unlimited view angles is proposed to avoid this potential limitation. However, structures that are always obscured (such as concavity) could not be accurately reconstructed, leading to overestimates of the object size. This "limitation" has a positive side, in that the technique will not underestimate the actual target volume. The ability to delineate both the shape and volume of the lesion should facilitate optimal target coverage while sparing a significant amount of normal tissue.

Medical management in the endovascular treatment of carotid-cavernous aneurysms.

Carotid-cavernous aneurysms account for between 1.9% and 9.0% of intracranial aneurysms. Entirely intercavernous aneurysms are believed to have a relatively benign course, with cranial nerve findings or headache being the usual initial symptomatology; however, subarachnoid hemorrhage or carotid-cavernous fistula formation can result from rupture. Over the past 15 years endovascular parent artery occlusion has essentially replaced surgical carotid occlusion as the treatment of choice. The authors describe a series of 39 consecutive patients at the University of Virginia Health Sciences Center who underwent endovascular treatment of a carotid-cavernous aneurysm. Aggressive invasive hemodynamic monitoring and maintenance of a state of normo- to mild hypervolemia in the asymptomatic patient was used throughout the periprocedural period. Rapid institution of hypervolemic-hypertensive therapy can reverse early neurological deficits related to hypoperfusion in these patients. Only one individual managed with this protocol developed neurological deficits not reversible with hypertensive-hypervolemic therapy. Heparin therapy was administered for 48 hours after occlusion, with patients receiving subsequent aspirin therapy for 6 months to combat distal embolism secondary to thrombosis. Long-term complications were not seen in patients receiving aneurysm trapping; however, two individuals with proximal carotid occlusion developed late optic neuropathy and one had recurrent transient ischemic attacks that ceased with supraclinoidal carotid clipping.

Hybrid eye tracking for computer-aided retinal surgery.

We describe initial results of a new hybrid digital and analog design for tracking the retina and controlling the laser beam. The results demonstrate tracking rates which exceed the equivalent of 50 degrees per second in the eye, with automatic lesion pattern creation and robust loss of lock detection. Robotically-assisted laser surgery to treat conditions such as diabetic retinopathy, macular degeneration, and retinal tears can now be realized under clinical conditions with requisite safety using standard video hardware and inexpensive optical components.

[Reflection measurement during retinal laser coagulation in patients. Development of an automatically controlled dosimeter]. / Reflexionsmessung während Netzhautlaserkoagulationen bei Patienten. Entwicklung einer automatisch gesteuerten Dosiseinrichtung.

PURPOSE: Retinal laser coagulation has limited reproducibility, because every laser exposition is unpredictably affected by pigmentation and media opacities. This can lead to complications. A feedback-controlled dosimeter would make retinal laser treatment a safer, more reproducible and faster procedure. METHOD: A reflectometer was developed that allows monitoring of the reflection of laser light during standard photocoagulation. Hundreds of coagulations in rabbit eyes and about 12,000 coagulations in patients undergoing routine laser treatment were recorded. RESULTS: The results of the first reflectance measurements in humans are presented along with extensive animal studies. A typical reflectance history was found for different lesion intensities. The degree of retinal whitening correlates with reflectance characteristics. These characteristics allow an early prediction of lesion intensity. Motion during laser exposure affects each coagulation in a fashion similar to spot size and exposure time. CONCLUSION: Reflectometry is the currently most effective means of monitoring lesion development. An automatic dosimeter for retinal photocoagulation seems feasible.

A topographical model of mu-opioid and brain somatostatin receptor selective ligands. NMR and molecular dynamics studies.

We have refined the 1H NMR-based conformations of the mu-opioid receptor selective peptides related to somatostatin of general formula Xxx-Yyy1-Cys-Zzz-D-Trp-Lys(Orn)5-Thr-Pen-Thr8- NH2, where Xxx, Yyy, Zzz are 0, D-Phe and Tyr for 1; 0, D-Tic and Tyr for 2; Gly, D-Tic and Tyr for 3; and 0, D-Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275-2283), using a molecular-dynamics approach. We present evidence that the NMR data are compatible with beta II'-, gamma- and gamma'-turns for the central tetrapeptide Tyr-D-Trp-Lys/Orn-Thr. Based on detailed structural and topographical considerations, we suggest that the mu-opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of D-Tic1 and Tyr3 (7.5 A), and that the opioid receptor recognition domain is located in the N-terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a mu-opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.