Photon-counting MCP/Timepix detectors for soft X-ray imaging and spectroscopic applications.

Detectors with microchannel plates (MCPs) provide unique capabilities to detect single photons with high spatial (<10 µm) and timing (<25 ps) resolution. Although this detection technology was originally developed for applications with low event rates, recent progress in readout electronics has enabled their operation at substantially higher rates by simultaneous detection of multiple particles. In this study, the potential use of MCP detectors with Timepix readout for soft X-ray imaging and spectroscopic applications where the position and time of each photon needs to be recorded is investigated. The proof-of-principle experiments conducted at the Advanced Light Source demonstrate the capabilities of MCP/Timepix detectors to operate at relatively high input counting rates, paving the way for the application of these detectors in resonance inelastic X-ray scattering and X-ray photon correlation spectroscopy (XPCS) applications. Local count rate saturation was investigated for the MCP/Timepix detector, which requires optimization of acquisition parameters for a specific scattering pattern. A single photon cluster analysis algorithm was developed to eliminate the charge spreading effects in the detector and increase the spatial resolution to subpixel values. Results of these experiments will guide the ongoing development of future MCP devices optimized for soft X-ray photon-counting applications, which should enable XPCS dynamics measurements down to sub-microsecond timescales.

[High-resolution distortion-product otoacoustic emissions: method and clinical applications]. / Mit hoher Frequenzauflösung gemessene otoakustische Distorsionsprodukte: Methode und klinische Anwendungen.

Unlike pure tone thresholds that assess both peripheral and central sound processing, distortion-product otoacoustic emissions (DPOAEs) selectively mirror the functioning of the cochlear amplifier. High resolution DPOAEs are missing in the toolbox of routine audiometry due to the fact that high resolution DPOAE measurements are more time-consuming when compared to normal clinical DP grams with rough frequency resolution. Measurements of high resolution DPOAEs allow an early assessment of beginning sensory cell damage due to sound overexposure or administration of ototoxic drugs. When using a rough grid, sensory cell damage would be overlooked as in the early state damage only appears at some distinct cochlear sites. A review is given on the method and application of high resolution DPOAEs.

Clinical evaluation and risk stratification in patients with syncope.

Syncope accounts for approximately 1 % of visits to emergency departments. The first diagnostic step is to rule out nonsyncopal conditions as a cause of the transient loss of consciousness. Next, the basic clinical evaluation should identify patients at high risk for potentially life-threatening events. These patients should be admitted and monitored until a diagnosis is made and definitive treatment can be offered. Guided by the basic evaluation findings, specific tests should be performed to prove or rule out the suspected diagnosis. In low-risk patients, this should preferably be done in an outpatient setting. To date, there is no consensus on a structured algorithm for the evaluation of patients with syncope. Therefore, it seems beneficial to formulate an algorithm based on the current guidelines for the management of syncope for use in the clinical setting.

[Severe pain and livid discoloration in the left leg of a 32-year-old patient after intravascular heroin injection]. / Massive Schmerzen und livide Verfärbung des linken Beins nach intravaskulärer Heroininjektion bei einem 32-jährigen Patienten.

Acute leg ischemia after intra-arterial drug injection represents a critical vascular emergency scenario. Due to lack of evidence-based standards therapeutic strategies are oriented to the underlying pathomechanisms. For a sufficient therapy a close clinical monitoring and laboratory analyses as well as treatment with analgesics, anticoagulants, anti-inflammatory and spasmolytic agents are of utmost importance. This article reports on the diagnostic and therapeutic approaches in a 32-year-old patient with acute leg ischemia after intra-arterial administration of heroin and secondary infection with Peptostreptococcus and Peptoniphilus species.

Development of new photon-counting detectors for single-molecule fluorescence microscopy.

Two optical configurations are commonly used in single-molecule fluorescence microscopy: point-like excitation and detection to study freely diffusing molecules, and wide field illumination and detection to study surface immobilized or slowly diffusing molecules. Both approaches have common features, but also differ in significant aspects. In particular, they use different detectors, which share some requirements but also have major technical differences. Currently, two types of detectors best fulfil the needs of each approach: single-photon-counting avalanche diodes (SPADs) for point-like detection, and electron-multiplying charge-coupled devices (EMCCDs) for wide field detection. However, there is room for improvements in both cases. The first configuration suffers from low throughput owing to the analysis of data from a single location. The second, on the other hand, is limited to relatively low frame rates and loses the benefit of single-photon-counting approaches. During the past few years, new developments in point-like and wide field detectors have started addressing some of these issues. Here, we describe our recent progresses towards increasing the throughput of single-molecule fluorescence spectroscopy in solution using parallel arrays of SPADs. We also discuss our development of large area photon-counting cameras achieving subnanosecond resolution for fluorescence lifetime imaging applications at the single-molecule level.

Phasor imaging with a widefield photon-counting detector.

Fluorescence lifetime can be used as a contrast mechanism to distinguish fluorophores for localization or tracking, for studying molecular interactions, binding, assembly, and aggregation, or for observing conformational changes via Förster resonance energy transfer (FRET) between donor and acceptor molecules. Fluorescence lifetime imaging microscopy (FLIM) is thus a powerful technique but its widespread use has been hampered by demanding hardware and software requirements. FLIM data is often analyzed in terms of multicomponent fluorescence lifetime decays, which requires large signals for a good signal-to-noise ratio. This confines the approach to very low frame rates and limits the number of frames which can be acquired before bleaching the sample. Recently, a computationally efficient and intuitive graphical representation, the phasor approach, has been proposed as an alternative method for FLIM data analysis at the ensemble and single-molecule level. In this article, we illustrate the advantages of combining phasor analysis with a widefield time-resolved single photon-counting detector (the H33D detector) for FLIM applications. In particular we show that phasor analysis allows real-time subsecond identification of species by their lifetimes and rapid representation of their spatial distribution, thanks to the parallel acquisition of FLIM information over a wide field of view by the H33D detector. We also discuss possible improvements of the H33D detector's performance made possible by the simplicity of phasor analysis and its relaxed timing accuracy requirements compared to standard time-correlated single-photon counting (TCSPC) methods.

Microchannel Plate Imaging Photon Counters for Ultraviolet through NIR Detection with High Time Resolution.

Cross strip and cross delay line readout microchannel plate detectors in 18 mm, 25 mm and 40 mm active area formats including open face (UV/particle) and sealed tube (optical) configurations have been constructed. These have been tested with a field programmable gate array based electronics for single event encoding. Using small pore MCPs (6 µm) operated in a pair, we achieve gains of >1 × 106 which is sufficient to provide spatial resolution of ~17 µm FHWM with the 18 mm and 40 mm cross strip readouts. New cross strip electronics can process high output event rates (> 4 MHz) with high spatial resolution, and self triggered event timing accuracy of ~1.5 ns for sealed tube XS optical sensors. A peak quantum efficiency of between 13% and 19% at 500 nm has been achieved with SuperGenII photocathodes with response from 400 nm to 900 nm for both cross strip and cross delay line sealed tubes. Local area counting rates of up to 40 kHz (100µm spot) have been attained with XS sealed tubes, along with image linearity and stability to better than 50 µm. 25mm cross delay line tubes achieve ~50 µm resolution and > 2 MHz output event rates.

New photon-counting detectors for single-molecule fluorescence spectroscopy and imaging.

Solution-based single-molecule fluorescence spectroscopy is a powerful new experimental approach with applications in all fields of natural sciences. Two typical geometries can be used for these experiments: point-like and widefield excitation and detection. In point-like geometries, the basic concept is to excite and collect light from a very small volume (typically femtoliter) and work in a concentration regime resulting in rare burst-like events corresponding to the transit of a single-molecule. Those events are accumulated over time to achieve proper statistical accuracy. Therefore the advantage of extreme sensitivity is somewhat counterbalanced by a very long acquisition time. One way to speed up data acquisition is parallelization. Here we will discuss a general approach to address this issue, using a multispot excitation and detection geometry that can accommodate different types of novel highly-parallel detector arrays. We will illustrate the potential of this approach with fluorescence correlation spectroscopy (FCS) and single-molecule fluorescence measurements. In widefield geometries, the same issues of background reduction and single-molecule concentration apply, but the duration of the experiment is fixed by the time scale of the process studied and the survival time of the fluorescent probe. Temporal resolution on the other hand, is limited by signal-to-noise and/or detector resolution, which calls for new detector concepts. We will briefly present our recent results in this domain.

High Speed Multichannel Charge Sensitive Data Acquisition System with Self-Triggered Event Timing.

A number of modern experiments require simultaneous measurement of charges on multiple channels at > MHz event rates with an accuracy of 100-1000 e(-) rms. One widely used data processing scheme relies on application of specific integrated circuits enabling multichannel analog peak detection asserted by an external trigger followed by a serial/sparsified readout. Although this configuration minimizes the back end electronics, its counting rate capability is limited by the speed of the serial readout. Recent advances in analog to digital converters and FPGA devices enable fully parallel high speed multichannel data processing with digital peak detection enhanced by finite impulse response filtering. Not only can accurate charge values be obtained at high event rates, but the timing of the event on each channel can also be determined with high accuracy.We present the concept and first experimental tests of fully parallel 128-channel charge sensitive data processing electronics capable of measuring charges with accuracy of ~1000 e- rms. Our system does not require an external trigger and, in addition to charge values, it provides the event timing with an accuracy of ~1 ns FWHM. One of the possible applications of this system is high resolution position sensitive event counting detectors with microchannel plates combined with cross strip readout. Implementation of fast data acquisition electronics increases the counting rates of those detectors to multi-MHz level, preserving their unique capability of virtually noiseless detection of both position (with accuracy of ~10 µm FWHM) and timing (~1 ns FWHM) of individual particles, including photons, electrons, ions, neutrals, and neutrons.

Catheter-based cryoablation of atrial fibrillation: state of the art.

Catheter-based ablation has been adopted as second-line therapy for both paroxysmal and persistent atrial fibrillation (AF) and is currently investigated as a primary approach. Reported success rates of catheter-based radiofrequency (RF) ablation vary between 65% and 85% depending on the technique used, patient selection and experience of the center. However, catheter ablation of AF is not without risk. In a worldwide survey major complications were reported in up to 6% of the procedures. Also, in high volume centers a complication rate of 5% is reported, which declined after excluding the learning curve during the first 100 procedures to 4.3%. These complications and the observation that AF-ablation using RF-energy is a demanding procedure in terms of operator competency and dexterity limiting the world-wide availability of this therapy lead to an extensive search for alternative energy and delivery sources. In four studies from Europe the new cryoballoon approach is effective and safe and appears to have a similar success rate than RF-ablation at least in paroxysmal AF and normally sized left atria. Changes in catheter design and additional equipment will probably improve this technique. Further clinical studies should focus on a head-to-head comparison between cryoablation and RF-ablation in AF. The favou-rable risk profile of cryoenergy might pave the way for cryoballoon ablation as a first-line treatment option in patients with paroxysmal AF.

Clinical validation of an automated vessel-segmentation software of the extracranial-carotid arteries based on 3D-MRA: a prospective study.

OBJECTIVES: To determine the accuracy of automated vessel-segmentation software for vessel-diameter measurements based on three-dimensional contrast-enhanced magnetic resonance angiography (3D-MRA). METHOD: In 10 patients with high-grade carotid stenosis, automated measurements of both carotid arteries were obtained with 3D-MRA by two independent investigators and compared with manual measurements obtained by digital subtraction angiography (DSA) and 2D maximum-intensity projection (2D-MIP) based on MRA and duplex ultrasonography (US). In 42 patients undergoing carotid endarterectomy (CEA), intraoperative measurements (IOP) were compared with postoperative 3D-MRA and US. RESULTS: Mean interoperator variability was 8% for measurements by DSA and 11% by 2D-MIP, but there was no interoperator variability with the automated 3D-MRA analysis. Good correlations were found between DSA (standard of reference), manual 2D-MIP (rP=0.6) and automated 3D-MRA (rP=0.8). Excellent correlations were found between IOP, 3D-MRA (rP=0.93) and US (rP=0.83). CONCLUSION: Automated 3D-MRA-based vessel segmentation and quantification result in accurate measurements of extracerebral-vessel dimensions.

Outcome study of substance impaired physicians and physician assistants under contract with North Carolina Physicians Health Program for the period 1995-2000.

The objective of this 6-year retroactive chart review is to compare outcome between chemically dependent physicians and physician assistants under contract with the North Carolina Physicians Health Program (NCPHP). Of 233 physicians 91% had a good outcome, compared to only 59% of 34 physician assistants in this sample (significant by Chi Square method, 99.99% confidence). Fifteen percent of physicians and 37 percent of physician assistants were female with basically the same outcome. Alcohol, followed by opioids, was the predominant substance used by both groups. Most subjects in both groups were between the ages of 30 and 55 with best outcome between the ages of 25-29 and the worst in those over 55. With paucity of data on physician assistants in the literature, the present study may be one of the first to single out this group and compare their recovery rates with those of physicians while receiving similar NCPHP services.

Multiresolution fuzzy clustering of functional MRI data.

Recent developments in the analysis of functional MRI data reveal a shift from hypothesis-driven statistical tests to unsupervised strategies. One of the most promising approaches is the fuzzy clustering algorithm (FCA), whose potential to detect activation patterns has already been demonstrated. But the FCA suffers from three drawbacks: first the computational complexity, second the higher sensitivity to noise and third the dependence on the random initialization. With the multiresolution approach presented here, these weak points are significantly improved, as is demonstrated in our tests with simulated and real functional MRI data.

Apparent diffusion coefficient mapping of infarcted tissue and the ischaemic penumbra in acute stroke.

MRI assessment of diffusion changes in acute cerebral ischaemia necessitates analysis of the apparent diffusion coefficient (ADC). We used the concept of relative weighted mean ADC (rwmADC) to obtain an accurate estimate of the extent of infarcted tissue. We studied ten patient with of acute ischaemic stroke, using diffusion- and perfusion- weighted MRI. The rwmADC was used to calculate a corrected ADC-lesion volume (DLVR), which was compared with the diffusion-lesion volume (DLV), initial perfusion lesion volumes and the follow-up infarct volume on T2-weighted images. We looked at correlations between the MRI and clinical findings. DLVR was closest to the final infarct size and had the best clinicoradiological correlation (r=0.77). Weighting the mean ADC within the ischaemic and normal parenchyma can give a more correct estimate of the volume of infarcted brain parenchyma, thus improving the definition of the penumbra.

Diffusion and perfusion MRI for the localisation of epileptogenic foci in drug-resistant epilepsy.

Drug-resistant epilepsy is an important clinical challenge, both diagnostically and therapeutically. More and more surgical options are being considered, but precise presurgical assessment is necessary. We prospectively studied eight patients with drug-resistant epilepsy, who underwent clinical examination, single photon emission computed tomography (SPECT) and interictal MRI, including diffusion- and perfusion-weighted echoplanar sequences. Lesions suspected on SPECT of being epileptogenic showed mild hypoperfusion, while the diffusion-weighted MRI (DWI) revealed increased apparent diffusion coefficients relative to the other side. However, these abnormalities were not visible on the corresponding maps. We showed that DWI and perfusion-weighted MRI could be used confirm the characteristics and site of an epileptogenic area in patients with drug-resistant epilepsy.

Optical properties and quantum efficiency of thin-film alkali halides in the far ultraviolet.

The optical constants of thin films of CsI, KI, and KBr and the quantum efficiency (QE) of planar photocathodes made with these alkali halides in the 53.6-174.4-nm spectral range are presented. The optical constants were obtained from measurements of the reflectance as a function of incidence angle. The effect of film heating and exposure to UV irradiation on the optical properties and on the QE of the three alkali halides was investigated. KBr was found to be the most stable material for both heating and UV irradiation. KI appeared to be close to temperature stable, whereas UV exposure affected its optical constants. CsI optical constants changed after 420 K heating and after UV exposure. The changes in the optical constants were related to the QE changes, and a certain correlation between both variations was determined. However, it was also demonstrated that the QE changes cannot be explained solely by the changes in optical constants.

Reperfusion demonstrated by apparent diffusion coefficient mapping after local intra-arterial thrombolysis for ischaemic stroke.

Diffusion-weighted MRI (DWI) is becoming important for diagnosis and investigation of acute cerebral ischaemia. It has been reported that apparent diffusion coefficient (ADC) maps could be an indicator of reperfusion. Our aim was to use echo-planar technology to investigate this phenomenon. We report 19 patients treated by local intra-arterial thrombolysis for middle cerebral artery stroke within 6 h of the onset of symptoms, in whom we performed follow-up DWI. ADC were found to be higher in the patients with angiographically proven reperfusion.

Association between allergy and asthma from childhood to middle adulthood in an Australian cohort study.

A cohort of 378 asthmatic children was studied from 7 to 35 yr of age at 7-yr intervals. On selection for inclusion in the study sample, the children had a wide range of severity of wheezing. At each 7-yr review, asthma severity, the presence of eczema or hay fever, and skin test reactivity to house dust mite or rye grass were recorded by questionnaire or clinical interview. We report on the course of asthma and these atopic conditions over the study period and discuss associations between the two phenomena. The presence of an atopic condition in childhood was found to increase the odds of more severe asthma in later life (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.17 to 2.36 in the case of eczema; OR = 1. 39, 95% CI: 1.00 to 1.92 for hay fever; and OR = 2.25, 95% CI: 1.49 to 3.39 for skin test reactivity). Additionally, the odds of eczema and hay fever in later life increased with severity of asthma in childhood. The findings of this study provide substantially new quantitative information on the extent of association between asthma and atopic conditions from childhood into middle adulthood.

An alternative approach to deal with geometric uncertainties in computer analysis of two-dimensional electrophoresis gels.

With the growing importance of proteomics in biomedical and pharmaceutical sciences a need has emerged for computing tools that are capable of digitally visualizing and analyzing protein spot patterns within two-dimensional electrophoresis (2-DE) gel. Matching programs need to meet requirements such as interlaboratory comparison and the comparison of samples from different origins. For such research purposes, we have developed the CAROL system that implements new algorithms for spot detection and matching, which enable researchers to take a different approach to protein spot identification and comparison. The present short communication discusses how the system deals with uncertain geometric spot information that arises from streaks and complex spot regions and how this can be amplified for the matching procedure.

Coronary arterial stents: safety and artifacts during MR imaging.

PURPOSE: To investigate the safety and imaging artifacts with different coronary arterial stents and magnetic resonance (MR) imaging sequences. MATERIALS AND METHODS: The heating, artifacts, and ferromagnetism with different stents were studied with a 1.5-T MR tomograph with ultrafast gradients by using turbo spin-echo, turbo gradient-echo, and echo-planar imaging sequences. Nineteen stents, which were 8-25 mm in length and 3.0-4.5 mm in diameter, were evaluated. Stent deviation induced by the magnetic field and during MR imaging, migration, and heating caused by the radio-frequency pulses were examined. The size of imaging artifacts was measured with all the stents under standardized conditions and with six stents after their implantation into the coronary arteries of freshly explanted pig hearts. RESULTS: All except two types of stents showed minimal ferromagnetism. No device migration or heating was induced. Turbo spin-echo images had minimal artifacts; larger artifacts were seen on the turbo gradient-echo and echo-planar images. With ultrafast gradients, the artifacts on the echo-planar images were substantially reduced. CONCLUSION: The studied coronary stents were not influenced by heating or motion during 1.5-T MR imaging. Artifact size differed according to the type and size of the stent and the MR imaging sequence used. Thus, patients with these stents can be safely examined.