Scintillator high-gain avalanche rushing photoconductor active-matrix flat panel imager: zero-spatial frequency x-ray imaging properties of the solid-state SHARP sensor structure.

PURPOSE: The authors are investigating the feasibility of a new type of solid-state x-ray imaging sensor with programmable avalanche gain: scintillator high-gain avalanche rushing photoconductor active matrix flat panel imager (SHARP-AMFPI). The purpose of the present work is to investigate the inherent x-ray detection properties of SHARP and demonstrate its wide dynamic range through programmable gain. METHODS: A distributed resistive layer (DRL) was developed to maintain stable avalanche gain operation in a solid-state HARP. The signal and noise properties of the HARP-DRL for optical photon detection were investigated as a function of avalanche gain both theoretically and experimentally, and the results were compared with HARP tube (with electron beam readout) used in previous investigations of zero spatial frequency performance of SHARP. For this new investigation, a solid-state SHARP x-ray image sensor was formed by direct optical coupling of the HARP-DRL with a structured cesium iodide (CsI) scintillator. The x-ray sensitivity of this sensor was measured as a function of avalanche gain and the results were compared with the sensitivity of HARP-DRL measured optically. The dynamic range of HARP-DRL with variable avalanche gain was investigated for the entire exposure range encountered in radiography∕fluoroscopy (R∕F) applications. RESULTS: The signal from HARP-DRL as a function of electric field showed stable avalanche gain, and the noise associated with the avalanche process agrees well with theory and previous measurements from a HARP tube. This result indicates that when coupled with CsI for x-ray detection, the additional noise associated with avalanche gain in HARP-DRL is negligible. The x-ray sensitivity measurements using the SHARP sensor produced identical avalanche gain dependence on electric field as the optical measurements with HARP-DRL. Adjusting the avalanche multiplication gain in HARP-DRL enabled a very wide dynamic range which encompassed all clinically relevant medical x-ray exposures. CONCLUSIONS: This work demonstrates that the HARP-DRL sensor enables the practical implementation of a SHARP solid-state x-ray sensor capable of quantum noise limited operation throughout the entire range of clinically relevant x-ray exposures. This is an important step toward the realization of a SHARP-AMFPI x-ray flat-panel imager.

A solid-state amorphous selenium avalanche technology for low photon flux imaging applications.

PURPOSE: The feasibility of a practical solid-state technology for low photon flux imaging applications was investigated. The technology is based on an amorphous selenium photoreceptor with a voltage-controlled avalanche multiplication gain. If this photoreceptor can provide sufficient internal gain, it will be useful for an extensive range of diagnostic imaging systems. METHODS: The avalanche photoreceptor under investigation is referred to as HARP-DRL. This is a novel concept in which a high-gain avalanche rushing photoconductor (HARP) is integrated with a distributed resistance layer (DRL) and sandwiched between two electrodes. The avalanche gain and leakage current characteristics of this photoreceptor were measured. RESULTS: HARP-DRL has been found to sustain very high electric field strengths without electrical breakdown. It has shown avalanche multiplication gains as high as 10(4) and a very low leakage current (< or = 20 pA/mm2). CONCLUSIONS: This is the first experimental demonstration of a solid-state amorphous photoreceptor which provides sufficient internal avalanche gain for photon counting and photon starved imaging applications.

Local VEGF administration enhances healing of colonic anastomoses in a rabbit model.

BACKGROUND/AIMS: Many studies report the role of vascular endothelial growth factor (VEGF) in wound healing, but few describe local VEGF administration to the digestive tract. Leakage from colonic anastomoses, including those due to ischemia, represents a major complication causing increased mortality and morbidity. Angiogenesis is crucial to anastomotic healing and restoration of blood supply, and VEGF is a potent angiogenic factor showing improved healing in various models of reconstruction and anastomosis. Here, we examine the effects of local VEGF-A(165) administration on postoperative rabbit colon anastomosis. METHODS: Two colotomies per animal were made in the sinistral colon on opposite sides of the mesentery. Randomly assigned VEGF (10 microg/0.1 ml) or saline (0.1 ml) was injected into the muscularis propria on both sides of each colonic anastomosis before closing the access laparotomy using single-layer sutures. On postoperative days 3, 4 and 7, the bursting pressure of partially healed anastomoses was measured. On postoperative day 4, anastomotic tissues were examined for the following: hydroxyproline; histopathologically for inflammatory infiltrate and tissue organization and immunohistochemically for capillary proliferation and density; vessel density of midzone collaterals around anastomoses by microangiography. RESULTS: Compared to saline, VEGF administration significantly improved bursting pressure (p = 0.014, paired t test) and increased hydroxyproline (p = 0.027, paired t test) on postoperative day 4. Inflammatory cell infiltration and fibroblast proliferation were prominent, and submucosal capillary vascular counts were significantly higher for VEGF. CONCLUSIONS: Administration of VEGF to colonic anastomosis accelerates wound healing and strengthens the anastomosis by increased angiogenesis.

X-ray phase imaging of biological soft tissue using a direct-sensing x-ray HARP tube camera.

A HDTV camera having a direct-sensing x-ray high-gain avalanche rushing amorphous photoconductor (HARP) tube was used, for the first time, to acquire x-ray phase maps. The tube can achieve a high sensitivity as a result of the avalanche multiplication process in the HARP target. A beryllium plate, rather than a glass plate, was used as the face plate of the tube to minimize the loss of x-rays due to absorption, and a 15 microm thick HARP target was directly formed on it. In the experiment, the x-ray phase shifts produced by a rat liver were measured using synchrotron x-rays (lambda = 0.0766 nm) and a triple Laue-case (LLL) x-ray interferometer. Interference patterns produced by the sample were observed with the direct-sensing x-ray HARP tube camera. A voltage of 1300 V was applied to the HARP target to give an output signal gain of two. The camera was operated in 1125 scanning-line mode, and real-time images were stored on a workstation at a rate of 30 images/s with an image format of 960 (H) x 1100 (V) pixels. A phase-map image of the sample was successfully obtained using the fringe scanning method and phase unwrapping. The observed phase shifts ranged from 50 degrees to 200 degrees . Trees of blood vessels in the rat liver were clearly depicted without using a contrast agent. The spatial resolution of the x-ray camera was estimated to be better than 35 microm in the vertical direction and 100 microm in the horizontal direction.

X-ray imaging with amorphous selenium: pulse height measurements of avalanche gain fluctuations.

Avalanche multiplication in amorphous selenium (a-Se) can provide a large, adjustable gain for active matrix flat panel imagers (AMFPI), enabling quantum noise limited x-ray imaging during both radiography and fluoroscopy. In the case of direct conversion AMFPI, the multiplication factor for each x ray is a function of its depth of interaction, and the resulting variations in gain can reduce the detective quantum efficiency (DQE) of the system. An experimental method was developed to measure gain fluctuations by analyzing images of individual x rays that were obtained using a video camera with an a-Se target operated in avalanche mode. Pulse height spectra (PHS) of the charge produced per x ray were recorded for monoenergetic 30.9, 49.4, and 73.8 keV x-ray sources. The rapid initial decay and long tail of each PHS can be explained by a model in which positive charge dominates the initiation of avalanche. The Swank information factor quantifies the effect of gain fluctuation on DQE and was calculated from the PHS. The information factor was found to be 0.5 for a 25 microm a-Se layer with a maximum gain of approximately 300. Changing the energy of the incident x ray influenced the range of the primary photoelectron and noticeably affected the tail of the experimental PHS, but did not significantly change the avalanche Swank factor.

Angiogenic effect of thymidine phosphorylase on macrophages in glioblastoma multiforme.

OBJECT: Thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF) are known angiogenic factors; however, there are few reports in which the relationship between these two factors is addressed. The authors compared expression patterns of TP and VEGF and investigated their role in the angiogenesis of glioblastoma multiforme (GBM). METHODS: Surgical specimens from 41 cases of GBM were immunohistochemically stained for TP, VEGF, CD68 (a macrophage marker), and CD31 (an endothelial cell marker). Both TP labeling indices and VEGF immunoreactivity displayed significant correlations with vascular density. Although VEGF was diffusely distributed in the tumor, TP was strongly expressed around blood vessels and in vascular proliferation. Double labeling for TP and CD68 in 10 cases indicated that cells that reacted strongly positive for TP were almost always macrophages, and only small numbers of CD68-negative cells weakly expressed TP. The TP messenger (m)RNA expression was investigated using reverse transcription-polymerase chain reaction in six GBMs. All six specimens expressed TP mRNA. In addition, TP mRNA was detected in two of three groups of cultured GBM cells derived from surgical specimens. Macrophages, the production of which was induced from two volunteers' peripheral blood monocytes by applying macrophage colony-stimulating factor, also expressed TP mRNA. The glioma cell lines U251MG and U87MG, which barely express TP mRNA under normal conditions, expressed TP mRNA in response to interferon-beta stimulation or while in an anoxic condition. CONCLUSIONS: Although it is feasible that GBM cells can express TP depending on their growing conditions, the majority of TP-expressing cells present in GBMs appear to be infiltrating macrophages. Coexistence of VEGF and TP may indicate a synergistic upregulation for angiogenesis because VEGF exerts a chemotactic activity on macrophages that express TP.

Biological role of thymidine phosphorylase in human astrocytic tumors.

Thymidine phosphorylase (TP) has strong angiogenic activity and is overexpressed in a wide variety of malignant tumors. To elucidate the role of TP in human astrocytic tumors, we immunohistochemically investigated the expression of TP in 62 astrocytic tumors (12 astrocytomas, 12 anaplastic astrocytomas and 38 glioblastomas). Fifty-five astrocytic tumors (88.7%) were immunopositive for TP. The level of TP-expression was significantly correlated with the malignancy grade of astrocytic tumors; most of malignant gliomas highly expressed TP, while a small number of cells were positive in low grade astrocytomas (p < 0.001). Using double-immunostaining, we clarified that TP-expression was predominantly detectable in macrophages. There was no significant correlation between MIB-1 labeling index and TP-expression. However, TP-expression and the microvessel density were well correlated. These suggest that TP, mainly produced by the infiltrated macrophages, may play an important role in the progression of astrocytic tumors via neovascularization. Inhibitor of TP may represent a therapeutic modality for treating malignant gliomas.

Visualization, quantification and therapeutic evaluation of angiogenic vessels in cancer by synchrotron microangiography.

The usefulness of a synchrotron microangiography system for depicting, quantitating and therapeutically evaluating angiogenic vessels in cancer is illustrated. In 20 mice transplanted with murine colon cancer, sequential changes in the angiogenic vessels were determined by using synchrotron microangiography, using changes in tumor volume for reference. This system allowed the depiction and quantification of angiogenic vessels in the period from one to four weeks after transplantation. The effects of antiangiogenic therapy were evaluated by using a neutralizing antibody against vascular endothelial growth factor. The neutralizing antibody partially suppressed angiogenesis and tumor growth. Synchrotron microangiography is shown to be useful for the depiction, quantification and evaluation of angiogenic vessels in cancer.

Application of a newly developed, highly sensitive camera and a 3-dimensional high-definition television system in experimental ophthalmic surgeries.

OBJECTIVE: To apply a new television system, which displays highly sensitive, high-quality 3-dimensional (3-D) images, in performing experimental ophthalmic surgeries. METHODS: By combining a high-gain avalanche rushing-amorphous photoconductor (HARP) camera, recently developed in Japan, which has 600 times greater sensitivity than conventional television cameras, and a single-camera, 3-D high-definition television system, which displays high-quality 3-D images, we performed cataract/intraocular lens surgeries and pars plana vitrectomies under various illumination intensities in pig cadaver eyes. RESULTS: Cataract/intraocular lens surgeries were performed using 7.3% the intensity of ordinary surgical microscopic illumination; vitrectomies were performed using 30.2% the intensity of an ordinary endoillumination probe with the HARP camera and by observing the stereoscopic display of the single-camera 3-D high-definition television system. Images identical to those observed by the surgeon were displayed on the stereoscopic display monitor. CONCLUSION: The system not only allowed surgeries to be performed under lower intensities of operating light but also provided real-time, highly sensitive 3-D images identical to those observed by the surgeon; thus, the device may be effectively used for education, team surgery, and telesurgery. CLINICAL RELEVANCE: The new television system for ocular surgeries to be performed under lower intensities of operating light as well as providing real-time, highly sensitive 3-D images identical to those observed by the surgeon may be effectively used for education and telesurgery.

Branching patterns of intramural coronary vessels determined by microangiography using synchrotron radiation.

The intramural coronary artery (IMCA) with a diameter of 50-500 micrometers is critical for blood supply to the inner layers of heart muscle. We introduced digital measurement to microangiography using monochromatic synchrotron radiation and quantified branching patterns of the IMCA, the epicardial coronary artery (EPCA), and the distal ileal artery (DIA). The pre- and postbranching diameters were measured (95-1,275 micrometers) in seven dogs. A typical arterial segment divided into two nearly equivalent branches, and a regression line of daughter-to-mother diameter plots was almost identical among the EPCA (y = 0.838x - 16.7 in micrometers), IMCA (y = 0.737x - 2.18), and DIA (y = 0.755x + 8.63). However, a considerable difference was present at a segment where a proximal IMCA branched off from an EPCA (y = 0.182x + 90.2). Moreover, a proximal IMCA diameter had no relationship to the branching order from an EPCA. The precision of this method was confirmed by the good correlation of diameter measurements between two independent observers (r = 0.999, y = 1.02x - 1.07). In conclusion, using digital microangiography we demonstrated that the self-similar branching pattern of coronary arteries was discrete at the connection between the IMCA and EPCA.

Synchrotron microangiography reveals configurational changes and to-and-fro flow in intramyocardial vessels.

In 8 dogs, in situ microangiography using synchrotron radiation visualized penetrating transmural arteries (PTAs) with a diameter of >60 micrometers and allowed quantitation of vessel diameters of >140 micrometers. Myocardial contraction reduced the vascular short-axial diameters to 87 +/- 17% (n = 62, P < 0.001, paired t-test) of the end-diastolic values and increased the longitudinal dimension to 129 +/- 5% (n = 45, P < 0.001). The diameter reduction in the subendocardial PTA segments was significantly more marked than that in the subepicardial PTA segments (60 +/- 12 vs. 88 +/- 12%, n=13, P < 0.001, paired t-test). Intracoronary administration of dobutamine (0.1 micrograms. kg-1. min-1) increased, and in contrast, partial clamping of the coronary artery (ischemia) decreased, the configurational changes. To-and-fro blood flow was clearly observed in PTAs with visual identification of capacitive backflow, resistive forward flow during ischemia on coronary arteriography, and even under baseline conditions in coronary venography. Thus this method advances our understanding of mechanical influences on the coronary circulation.

Use of synchrotron radiation microangiography to assess development of small collateral arteries in a rat model of hindlimb ischemia.

BACKGROUND: Current methods of angiography cannot provide images of arteries measuring < 200 microns in diameter. We have recently developed a new angiography system that uses monochromatic synchrotron radiation and a high-definition video system with a spatial resolution of 30 microns. In the present study, we applied this microangiography system to visualize small arteries in normal and ischemic rat limbs and investigated the development of collateral arteries. METHODS AND RESULTS: Microangiography was performed in the normal and the ischemic limb 4 weeks after the excision of the femoral artery. In the normal limb, up to the fourth branches of the iliac and/or femoral arteries (diameter < 100 microns) were readily identified. Some of these branches were found to perfuse the distal thigh area. In the ischemic limb, an extensive structural remodeling of the vascular network was observed. Numerous small arteries had developed from the branches of the iliac artery to constitute a fine arterial network, the so-called "midzone," which was composed of linear, normal appearing arteries and those with an undulating, unbranched appearance. CONCLUSIONS: The small collateral artery network was angiographically visualized with a resolution limit < 100 microns. The linear collaterals appeared to result from an opening of preexisting vessels. The undulating, unbranched vessels were not observed in the normal limbs and seemed to be vessels that were newly formed after limb ischemia. Synchrotron radiation microangiography appears to be a powerful means of assessing the development of small collateral arteries, which may help to provide a basis for understanding of the collateral circulation.

Small-vessel radiography in situ with monochromatic synchrotron radiation.

PURPOSE: To evaluate the usefulness of a radiographic system with monochromatic synchrotron radiation to depict small vessels and peripheral secretory ducts. MATERIALS AND METHODS: Radiography of various organs was tested in 14 anesthetized dogs and pancreatography was performed in an excised human pancreas by using the following system: monochromatic synchrotron radiation with an energy level just above the k absorption edge of iodine as an x-ray source and a high-definition TV system with a high-light-sensitivity image pick-up tube camera coupled with a fluorescent screen as a detector. RESULTS: This system allowed depiction of small vessels (diameter < 50-100 microns) of the heart (penetrating transmural artery), brain (perforating arteries that arise directly in the circle of Willis), and intestinal organs (vasa recta and their submucosal communications) and of small branches (down to the fifth order) of the pancreatic duct. CONCLUSION: The synchrotron radiation system may be useful for evaluating microcirculatory disorders and early-stage malignant tumors in various human organs.

Prenatal diagnosis of Tay-Sachs disease with heat-labile beta-hexosaminidase B.

Two consecutive pregnancies at risk for Tay-Sachs disease with heat-labile beta-hexosaminidase B were monitored. Differential isozyme detection of beta-hexosaminidase in cell free amniotic fluid by DEAE cellulose column chromatography and cellulose acetate paper electrophoresis showed an affected fetus in the first pregnancy and an unaffected in the second. These results were confirmed in the aborted fetus and in a newborn baby, respectively.

Identification of fatty acid methyl esters in kidneys and livers of two patients with Reye's syndrome.

An unusual lipid, having an Rf value between that of cholesterol ester and of triglyceride on thin-layer chromatography, was clearly demonstrated in lipids from kidneys and livers of two Japenese children with Reye's syndrome. Gas chromatography-mass spectrometry revealed that the unusual lipid from viscera of the patients was a mixture of fatty acid methyl esters. Whether the occurrence of fatty acid methyl ester is the result of an inborn error of metabolism common to both patients, who were the progeny of consanguineous marriages, or whether it is a common biochemical feature in Reye's syndrome remains the subject of future studies.