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.

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.

[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.

[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.

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.

Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance.

BACKGROUND: Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated. METHODS AND RESULTS: In 15 patients with single-vessel coronary artery disease and 5 patients without significant coronary artery disease, the signal intensity-time curves of the first pass of a gadolinium-DTPA bolus injected through a central vein catheter were evaluated before and after dipyridamole infusion to validate the technique. A linear fit was used to determine the upslope, and a cutoff value for the differentiation between the myocardium supplied by stenotic and nonstenotic coronary arteries was defined. The diagnostic accuracy was then examined prospectively in 34 patients with coronary artery disease and was compared with coronary angiography. A significant difference in myocardial perfusion reserve between ischemic and normal myocardial segments (1.08+/-0.23 and 2.33+/-0.41; P<0.001) was found that resulted in a cutoff value of 1.5 (mean minus 2 SD of normal segments). In the prospective analysis, sensitivity, specificity, and diagnostic accuracy for the detection of coronary artery stenosis (> or =75%) were 90%, 83%, and 87%, respectively. Interobserver and intraobserver variabilities for the linear fit were low (r=0.96 and 0.99). CONCLUSIONS: MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity-time curves.

Different in vivo tolerogenicity of MHC class I peptides.

The efficacy of MHC class I-derived peptides to induce tolerance was tested in a cardiac transplantation model. Two 25-mer peptides from the polymorphic region of the DA class I molecule (RT1.Aa) were synthesized by F-moc chemistry and injected intrathymically or intraperitoneally into LEW (RT1.1) responder animals. Intrathymic treatment of the recipient animals with peptide 1 (residues 56-80) accompanied by intraperitoneal treatment with peptide 4 (residues 96-120) led to indefinite survival of allogeneic DA cardiac allografts (n = 7; > 100 days). The tolerogenicity of both peptides differed according to the site of inoculation, as donor-specific tolerance was only observed after administration of peptide 1 into the thymus and injection of peptide 2 into the abdominal cavity of LEW recipients, but not vice versa. Donor-specific tolerance was confirmed in vivo by grafting of full-thickness skin and in vitro by appropriate proliferation and cytotoxicity assays using donor and third-party rats. Donor-specific tolerance was associated with up-regulation of interleukin-4, transforming growth factor beta, and interleukin-10 gene expression within cardiac allografts, thus suggesting intrathymic clonal deletion and external suppression with expansion of T-helper 2-type lymphocytes as the underlying mechanisms of tolerance induction.

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.

A prospective study of the association of serum neopterin, beta 2-microglobulin, and hepatitis B surface antigenemia with death in infants and children with HIV-1 disease.

A high percentage of HIV-1-infected infants and children in Romania are coinfected with hepatitis B virus. Little information is available on the impact of concurrent hepatitis B infection on the course of HIV-1 infection. We conducted a prospective cohort study over 1 year in a group of 68 HIV-1-infected infants and children to determine whether hepatitis B surface antigenemia, neopterin, and beta 2-microglobulin (B2M) predicted death. Among the 44 hepatitis B surface antigen-positive (HBsAg+) subjects at enrollment, 13 (30%) died during 1 year of follow-up. In comparison, two of 24 (8%) HBsAg-negative subjects died (RR = 7.7; p = 0.05). Higher initial serum concentrations of neopterin and B2M were negatively associated with survival. After stratifying by baseline clinical evidence of HIV-related disease, survival was negatively associated with HBsAg+ status (p = 0.04) in 33 children in stage P-2, adjusting for age, serum neopterin, and serum B2M levels. The results of this study suggest that serum neopterin is a marker for severity of clinical illness and that HBsAg+ status increases the mortality rate among children with clinical evidence of HIV infection.

Co-transplantation of donor-derived hepatocytes induces long-term tolerance to cardiac allografts in a rat model.

BACKGROUND: Liver allografts transplanted between MHC-disparate mice, rats, and swine are spontaneously accepted in most strain combinations without requirement for immunosuppression. The underlying mechanism has, however, remained elusive. Here, we demonstrate that co-transplantation of donor-derived hepatocytes protect Lewis (RT1.A1) cardiac allografts from acute and chronic rejection in DA (RT1.Aa) recipients indefinitely. METHODS: Livers of donor Lewis rats were harvested and the hepatocytes separated from hepatic leukocytes by collagenase digestion and gradient separation. DA recipient animals were transplanted Lewis cardiac allografts and simultaneously intraportally infused either Lewis-derived hepatocytes or hepatic leukocytes. Recipient animals were either not further treated or received a single dose of 15 mg/kg cyclosporine. RESULTS: Donor hepatocytes alone significantly protected syngeneic cardiac allografts from rejection, whereas hepatic leukocytes failed to influence graft survival. In combination with cyclosporine, recipient cardiac allografts were indefinitely protected from rejection. Graft-infiltrating cells in tolerant animals presented as clusters of CD4+ T cells and stained mostly positive for interleukin-4, whereas graft-infiltrating cells in rejected allografts were predominantly positive for interferon-gamma. Adoptive transfer of splenocytes derived from tolerant animals protected Lewis cardiac allografts from rejection in DA recipients without immunosuppression. In contrast, hepatic leukocytes protected only 50% of the allografts from rejection. CONCLUSION: We propose that donor hepatocytes induce permanent engraftment of syngeneic allografts by establishing a Th2 type alloresponse that is transferable to new graft recipients. The results of this study demonstrate that liver parenchymal cells significantly mediate spontaneously liver-induced tolerance.

Childhood asthma and lung function in mid-adult life.

The longitudinal lung function data in 286 subjects from a 28 year follow-up of childhood asthma is reported. Airway obstruction in mid-adult life was present mainly in those with moderately severe asthma. Subjects who had been wheeze free for at least 3 years, even if asthma had been persistent in childhood, had normal lung function and no increased bronchial reactivity. Only two subjects, both with persistent asthma from childhood, failed to show an improvement in FEV1 of greater than 10% following inhalation of a beta-adrenergic agonist. Subjects with relatively mild asthma who had not taken inhaled steroids did not appear to be disadvantaged with respect to lung function.

Assessment of diffuse coronary artery disease by quantitative analysis of coronary morphology based upon 3-D reconstruction from biplane angiograms.

Quantitative evaluations on coronary vessel systems are of increasing importance in cardiovascular diagnosis, therapy planning, and surgical verification. Whereas local evaluations, such as stenosis analysis, are already available with sufficient accuracy, global evaluations of vessel segments or vessel subsystems are not yet common. Especially for the diagnosis of diffuse coronary artery diseases, the authors combined a 3D reconstruction system operating on biplane angiograms with a length/volume calculation. The 3D reconstruction results in a 3D model of the coronary vessel system, consisting of the vessel skeleton and a discrete number of contours. To obtain an utmost accurate model, the authors focussed on exact geometry determination. Several algorithms for calculating missing geometric parameters and correcting remaining geometry errors were implemented and verified. The length/volume evaluation can be performed either on single vessel segments, on a set of segments, or on subtrees. A volume model based on generalized elliptical conic sections is created for the selected segments. Volumes and lengths (measured along the vessel course) of those elements are summed up. In this way, the morphological parameters of a vessel subsystem can be set in relation to the parameters of the proximal segment supplying it. These relations allow objective assessments of diffuse coronary artery diseases.

Evaluation of segmentation algorithms for generation of patient models in radiofrequency hyperthermia.

Time-efficient and easy-to-use segmentation algorithms (contour generation) are a precondition for various applications in radiation oncology, especially for planning purposes in hyperthermia. We have developed the three following algorithms for contour generation and implemented them in an editor of the HyperPlan hyperthermia planning system. Firstly, a manual contour input with numerous correction and editing options. Secondly, a volume growing algorithm with adjustable threshold range and minimal region size. Thirdly, a watershed transformation in two and three dimensions. In addition, the region input function of the Helax commercial radiation therapy planning system was available for comparison. All four approaches were applied under routine conditions to two-dimensional computed tomographic slices of the superior thoracic aperture, mid-chest, upper abdomen, mid-abdomen, pelvis and thigh; they were also applied to a 3D CT sequence of 72 slices using the three-dimensional extension of the algorithms. Time to generate the contours and their quality with respect to a reference model were determined. Manual input for a complete patient model required approximately 5 to 6 h for 72 CT slices (4.5 min/slice). If slight irregularities at object boundaries are accepted, this time can be reduced to 3.5 min/slice using the volume growing algorithm. However, generating a tetrahedron mesh from such a contour sequence for hyperthermia planning (the basis for finite-element algorithms) requires a significant amount of postediting. With the watershed algorithm extended to three dimensions, processing time can be further reduced to 3 min/slice while achieving satisfactory contour quality. Therefore, this method is currently regarded as offering some potential for efficient automated model generation in hyperthermia. In summary, the 3D volume growing algorithm and watershed transformation are both suitable for segmentation of even low-contrast objects. However, they are not always superior to user-friendly manual programs for contour generation. When the volume growing algorithm is used, the contours have to be postprocessed with suitable filters. The watershed transformation has a large potential if appropriately developed to 3D sequences and 3D interaction features. After all, the practicality and feasibility of every segmentation method critically depend on various details of the user software as pointed out in this article.

Accuracy and precision of angiographic volumetry methods for left and right ventricle.

We imaged and quantified 60 ventricle casts (30 LV, 30 RV) to evaluate the accuracy and reliability of angiographic ventricle volumetry. We analyzed the seven biplane methods most frequently used in clinical routine: Arcilla, Arvidsson, Dodge, Ferlinz, Simpson (LV + RV) and Wynne. The ventricle contours were defined by (1) manual drawing on the computer screen, (2) manual drawing using a graphical tablet and (3) automatic contour detection. A high inter-class variation in volume accuracy between the different methods was observed (S.D. = 12.7 ml). The volume methods for the LV (mean differences MDLV: [-2.2, +8.5] ml, average MDLV = 1.8 ml) are more accurate than for the RV (MDRV: [-11.4, +33.1] ml, average MDRV = 12.1 ml). The intrinsic error is about the same for all approaches and is very high: average S.D. = 20 ml, RMS = 185 ml. Manual contour definition results in a volume over-estimation (average MDman = +32.8 ml, r = 0.731) compared with automatic contour detection (average MDauto = +6.2 ml, r = 0.810). LV hypertrophy results in a volume under-estimation of the LV (MDLV = -7 ml) and an over-estimation of the RV (MDRV = +6 ml). RV hypertrophy leads to the opposite effect. It was shown that ventricle volumetry and the calculation of derived parameters (ejection fraction) is extremely case dependent and can only be an estimate of the actual value.

[Communication and integration of medical documents for the teleconference use. An outcome of the BERMED project]. / Kommunikation und Integration medizinischer Dokumente für Telekonferenz-Anwendungen: Ein Ergebnis aus dem Projekt BERMED.

The collaboration between physicians is supported in the BERMED project by implementing the remote access to distributed patient data and the realisation of computer-based medical conferencing. This requires the integration of the multimedia data in form of a meta-patient record for our medical application systems. These applications are supported by a distributed information management promoting access to different information systems, imaging modalities and digital archival storage systems. The features of image processing are concerned with quantification, segmentation and 3-D-visualisation to obtain additional information. This paper gives an overview of the actual state of the teleconferencing system in radiology.

Association between neopterin and beta-2-microglobulin levels and HIV status in Romanian orphanage children.

Serologic markers of immune activation, neopterin and beta-2-microglobulin (B2M), have been shown to predict progressive human immunodeficiency virus type 1 (HIV-1) disease based on cohort studies in adults. Both parameters appear also to be valuable in distinguishing HIV-1 infants with progressive disease from asymptomatic infants and HIV-1 seronegative infants. In a cross-sectional study we examined the utility of neopterin and B2M testing in 135 infants of an orphanage in Romania, 69 of the infants (51%) were found to be HIV-1 antibody seropositive; 95% of the 135 infants were either hepatitis B virus (HBV) antigen or antibody seropositive. In the HIV-1 seronegative infants B2M was higher in those with HBV antigenaemia. Serum neopterin and B2M concentrations were higher in HIV-1 seropositive than in seronegative infants (p = 7 x 10(-12) and 1 x 10(-6)). Children with CDC stage P2 had only slightly higher neopterin and B2M values as compared to stage P1 (P = 0.04 and 0.08). Our study indicates that measurement of neopterin and B2M is useful to monitor HIV-1 infection, particularly in areas where laboratory facilities are limited. Both parameters continue to be associated with HIV-1 infection even when there is a high background rate of other infections.

[Phenomenologic and functional variability of violence among children]. / Phänomenologische und funktionale Vielfalt von Gewalt unter Kindern.

Examination of ten-year old children's everyday interactions with peers observed in natural settings of a school demonstrates that violence was present in many situations of help, sanctions, and rough-and-tumble play. Thorough analysis reveals diverse functions of violence in children's interactions: affirmation of reciprocity and justice, experience of agency and control, preservation of territories against intruders, clear messages, compensations of lacking capacities, and defense of the self.

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.