Werner W. Roeck

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7−CD45RA− effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (TCM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Quantitative fluorescence tomography using a combined tri-modality FT/DOT/XCT system

In this work, a first-of-its-kind fully integrated tri-modality system that combines fluorescence, diffuse optical and x-ray tomography (FT/DOT/XCT) into the same setting is presented. The purpose of this system is to perform quantitative fluorescence tomography using multi-modality imaging approach. XCT anatomical information is used as structural priori while optical background heterogeneity information obtained by DOT measurements is used as functional priori. The performance of the hybrid system is evaluated using multi-modality phantoms. In particular, we show that a 2.4 mm diameter fluorescence inclusion located in a heterogeneous medium can be localized accurately with the functional a priori information, although the fluorophore concentration is recovered with 70% error. On the other hand, the fluorophore concentration can be accurately recovered within 8% error only when both DOT optical background functional and XCT structural a priori information are utilized to guide and constrain the FT reconstruction algorithm.

Characterization of the veiling glare PSF in x-ray image intensified fluoroscopy.

A theoretical derivation for the point spread function (PSF) which describes the veiling glare in x-ray image intensifiers (II) is presented. The PSF is dependent on two parameters which can be determined experimentally for a given II. An experimental investigation of the linearity of veiling glare phenomenon is undertaken. The experimental results indicate that veiling glare could be described as a linear process to a high degree of accuracy.

Videodensitometric determination of minimum coronary artery luminal diameter before and after angioplasty

Quantitative measurements of coronary stenoses were made from digital coronary angiograms in 19 patients before and after percutaneous transluminal coronary angioplasty (PTCA). Two methods of measurement were compared. Mean stenosis before PTCA was 67 +/- 10% by the edge detection method and 67 +/- 12% by videodensitometry (difference not significant). After PTCA, the mean stenosis was 32 +/- 14% by edge detection and 30 +/- 13% by videodensitometry (difference not significant). In addition, a new method was developed to rapidly calculate the absolute minimum luminal area and diameter by videodensitometry. The minimum luminal diameter before PTCA was 1.0 +/- 0.5 mm and after PTCA increased to 2.4 +/- 0.5 mm (p less than 0.001). The validity of the videodensitometric method was analyzed in a series of Lucite phantom studies, which suggested that when there is an irregular angiographic appearance, the densitometric method may be more accurate than standard edge detection methods. Digital acquisition of coronary angiograms provides a means for rapid application of quantitative analysis during coronary interventional procedures.

Development of an MR-compatible SPECT system (MRSPECT) for simultaneous data acquisition

In medical imaging, single-photon emission computed tomography (SPECT) can provide specific functional information while magnetic resonance imaging (MRI) can provide high spatial resolution anatomical information as well as complementary functional information. In this study, we developed a miniaturized dual-modality SPECT/MRI (MRSPECT) system and demonstrated the feasibility of simultaneous SPECT and MRI data acquisition, with the possibility of whole-body MRSPECT systems through suitable scaling of components. For our MRSPECT system, a cadmium-zinc-telluride (CZT) nuclear radiation detector was interfaced with a specialized radiofrequency (RF) coil and placed within a whole-body 4 T MRI system. Various phantom experiments characterized the interaction between the SPECT and MRI hardware components. The metallic components of the SPECT hardware altered the B(0) field and generated a non-uniform reduction in the signal-to-noise ratio (SNR) of the MR images. The presence of a magnetic field generated a position shift and resolution loss in the nuclear projection data. Various techniques were proposed to compensate for these adverse effects. Overall, our results demonstrate that accurate, simultaneous SPECT and MRI data acquisition is feasible, justifying the further development of MRSPECT for either small-animal imaging or whole-body human systems by using appropriate components.

Detection and quantitation of coronary artery stenoses from digital subtraction angiograms compared with 35-millimeter film cineangiograms

To assess the ability to detect coronary artery narrowings from computer-acquired angiograms, a panel of 4 observers independently identified and measured focal coronary narrowings from digital subtraction angiograms and compared the results to those obtained from standard 35-mm cine film angiograms. Both cine and digital angiograms were obtained sequentially using selective intracoronary artery injection of standard amounts of iodinated contrast media. Digital images were obtained at 8 frames/s with a 512 X 512 X 8-bit pixel matrix. Modifications in the imaging chain for computer acquisition included a slower pulsed radiographic mode, a progressive scan camera, and initial storage of the images on an 80-megabyte digital hard disk. Postprocessing computer algorithms were used to enhance the unsubtracted digital images; these included single-frame, mask-mode subtraction, vessel boundary edge enhancement, and 4-fold pixel magnification. In 19 patient studies, 32 arteries were reduced more than 25% in diameter according to at least 1 of 4 observers on either the digital or cine film angiograms. There was no significant difference in the mean percent diameter narrowing for all the narrowings between the digital angiograms (53 +/- 31%) and the cineangiograms (52 +/- 31%). In addition, a 2-way analysis of variance yielded no significant difference between the amount of variability in the measurements between the cine film and the digital technique. This similar variability persisted when subsets of patients based on the degrees of stenosis were considered (e.g., only narrowings from 50 to 90% diameter reduction).(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of image intensifier veiling glare by mathematical deconvolution techniques

X-ray images acquired with an image intensifier detector system suffer from veiling glare, a low-frequency degradation described by a point spread function (PSF). The PSF has two experimentally determined parameters unique to a given image intensifier. This information is utilized to deconvolve the degradation from digitally acquired images. Results demonstrate a significant increase in contrast ratio of high-contrast objects after deconvolution and image restoration.

Digital angiography in assessment of ventricular function and wall motion during pacing in patients with coronary artery disease

Using digital subtraction angiography, left ventriculograms were obtained with 10 ml of iodinated contrast material in 21 patients both at rest and during atrial pacing. In 15 patients with significant coronary artery lesions (CAD) (greater than 50% diameter narrowing in at least 1 major artery), ejection fraction decreased during atrial pacing from a mean of 62 +/- 14% to 51 +/- 15% (p less than 0.001). In 14 (93%) of 15 patients, ejection fraction decreased or was unchanged during pacing. In 6 patients with chest pain but normal coronary arteries, ejection fraction increased from a mean of 66 +/- 9% at rest to 72 +/- 6% during atrial pacing (p less than 0.01). Ejection fraction increased by greater than or equal to 5% during pacing in 5 of 6 patients with normal coronary arteries. Patients with CAD also had an abnormal response in end-systolic volume during atrial pacing (50 +/- 31 ml at rest versus 47 +/- 24 ml during pacing) compared with patients with normal coronary arteries (46 +/- 16 ml at rest versus 26 +/- 9 ml during pacing; p less than 0.01). The digital ventriculograms demonstrated new or increased wall motion abnormalities during atrial pacing in 4 of 5 patients with CAD who had wall motion abnormalities at rest and in 8 of 10 patients with CAD who had normal wall motion at rest. Moreover, these wall motion abnormalities occurred in myocardial wall segments that were supplied by coronary arteries with significant lesions. Thus, because digital subtraction angiography allows multiple left ventriculograms to be obtained during routine cardiac catheterization, intervention studies such as atrial pacing can be used to obtain a functional assessment of the severity of coronary arterial lesions.

Quantitative fluorescence tomography using a trimodality system: in vivo validation.

A fully integrated trimodality fluorescence, diffuse optical, and x-ray computed tomography (FT/DOT/XCT) system for small animal imaging is reported in this work. The main purpose of this system is to obtain quantitatively accurate fluorescence concentration images using a multimodality approach. XCT offers anatomical information, while DOT provides the necessary background optical property map to improve FT image accuracy. The quantitative accuracy of this trimodality system is demonstrated in vivo. In particular, we show that a 2-mm-diam fluorescence inclusion located 8 mm deep in a nude mouse can only be localized when functional a priori information from DOT is available. However, the error in the recovered fluorophore concentration is nearly 87%. On the other hand, the fluorophore concentration can be accurately recovered within 2% error when both DOT functional and XCT structural a priori information are utilized together to guide and constrain the FT reconstruction algorithm.

QUANTIFICATION OF CORONARY ARTERIAL CALCIUM BY DUAL ENERGY DIGITAL SUBTRACTION FLUOROSCOPY

Clinical studies of the heart with fluoroscopy have shown that fluoroscopic visualization of calcium in the coronary arteries is strongly associated with coronary artery disease. However, fluoroscopic detection is limited by its low sensitivity, which is partly due to the interfering background tissue structures and image quantum noise. Moreover, quantification of the absolute amount of calcium in an arterial segment has not been possible. A real-time dual-energy subtraction technique has been investigated as a possible solution to the above problem. In this energy subtraction technique, the kVp and filtration are switched at 30 Hz. In order to assess the potential utility of this videodensitometric technique to quantitate coronary artery calcium, arterial phantoms and excised segments of diseased human arteries were imaged. The low- and high-energy images were corrected for scatter and veiling glare before subtraction. Calcium measurements were made using the tissue-suppressed energy-subtracted images. The estimated calcium phosphate and ashed weights of the calcified arterial segments (N = 20) were highly correlated (slope = 1.04, Intercept = -0.33 mg, r = 0.92).