Search for Electron Antineutrino Appearance in a Long-Baseline Muon Antineutrino Beam.

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions.

[Modern ulcer surgery : Invasive treatment options using the example of therapy-resistant venous leg ulcers]. / Moderne Ulkuschirurgie : Invasive Behandlungsoptionen am Beispiel des therapieresistenten Ulcus cruris venosum.

The socioeconomic significance of chronic venous leg ulcers is considerable due to the high number of patients, the costs of diagnosis and therapy, the deterioration in quality of life, and the loss of working capacity during the disease. This is further increased by a progressive course and an increased tendency to recurrence. Taking these facts into account, surgical treatment options are of particular importance, especially in otherwise therapy-refractory courses. For this purpose, an extensive spectrum of surgical and new, partly not yet finally evaluated, invasive techniques are now available. Venous surgery and endovenous closure techniques are suitable for eliminating primary or secondary varicosis as a causal therapy for venous leg ulcers. Shave therapy is the method of choice in the presence of dermatolipo(fascio)sclerosis. Current long-term results show good results with cure rates of 70-80%. In individual cases, surgical techniques involving fascia cruris (faciotomy, fasciotomy) can also be used. Recurrence ulcers can often be successfully treated by repeated shave therapy, optionally with simultaneous vacuum-assisted dressing techniques or by a fasciotomy. In addition, local invasive techniques such as autologous fat tissue transplantation or autologous platelet-rich plasma can be used to promote wound healing. Thus, both surgically invasive local therapy and advanced surgery of the causes of chronic venous leg ulcers play a key role in the overall therapy concept.

Precision and reproducibility of automated computer-guided Psoriasis Area and Severity Index measurements in comparison with trained physicians.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) represents the gold standard for psoriasis severity assessments but is limited by its subjectivity and low intra- and inter-rater consistency. OBJECTIVES: To investigate the precision and reproducibility of automated, computer-guided PASI measurements (ACPMs) in comparison with three trained physicians. METHODS: This was a comparative observational study assessing ACPMs attained by automated total-body imaging and computerized digital image analysis in a cohort of 120 patients affected by plaque psoriasis of various severities. The level of agreement between ACPMs and physicians' PASI measurements was calculated by the intraclass correlation coefficient (ICC). The reproducibility of ACPMs in comparison with physicians' PASI measurements was investigated by performing two successive 'repeat PASI calculations' in the same patients. RESULTS: The agreement between ACPMs and physicians' PASI calculations in 120 fully evaluable patients was high (ICC 0·86, 95% confidence interval 0·80-0·90, mean absolute difference 2·5 PASI points). Repeat ACPMs to measure the reproducibility showed an excellent ICC of 0·99 (95% confidence interval 0·98-0·99) with a mean absolute difference of 0·5 PASI points. The ACPMs thus outperformed the three physicians for intrarater reliability (mean ICC 0·86). CONCLUSIONS: The results of this first clinical study investigating ACPMs in 120 patients with psoriasis indicate a similar precision and higher reproducibility in comparison with trained physicians. Limitations arise from poorly observable body sites and from patients unable to attain predefined postures during automated image acquisition.

Urethral length and bladder neck behavior: can dynamic magnetic resonance imaging give the same results as introital ultrasound?

PURPOSE: To compare dynamic magnetic resonance imaging (dMRI) and introital ultrasound results with regard to urethral length measurements and the evaluation of bladder neck changes. METHODS: Retrospective analyses of urethral length measurements and detection of bladder neck changes (rotated/vertical bladder neck descent, urethral funneling) were conducted in women-scheduled for surgical treatment with alloplastic material-who had undergone introital ultrasound and dMRI presurgery and 3 months postsurgery. Measurement differences between both imaging modalities were evaluated by assessing the confidence interval for the difference in means between the datasets using bootstrap analysis. RESULTS: Based on data from 40 patients (320 image series), the urethra could be clearly measured on every pre- and postsurgical dMRI dataset but not on preoperative ultrasound images in nine women during Valsalva maneuver due to a large cystocele. The estimation of the mean difference distribution based on 500,000 bootstrap resamples indicated that the urethral length was measured shorter by dMRI pre- and postsurgery at rest and postsurgery during Valsalva maneuver (median 1.6-3.1 mm) but longer by dMRI (median 0.2 mm) during Valsalva maneuver presurgery. Rotated/vertical bladder neck descent and urethral funneling diagnoses showed concordance of 67-74% in the direct comparison of patients; the estimation of the concordance indicated poorer outcomes with 50-72%. CONCLUSIONS: Metric information on urethral length from dMRI is comparable to that from introital ultrasound. dMRI is more advantageous in cases with an extended organ prolapse. At present, dMRI does not give the same diagnosis on bladder neck changes as introital ultrasound does.

Intra- and interobserver variability of image-based PASI assessments in 120 patients suffering from plaque-type psoriasis.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) is the standard for psoriasis severity assessment. However, PASI measurement is complex and subjective, frequently leading to a high intra- and interobserver variability. To date, the precise extent of variability in PASI measurements and its underlying causes remain unknown. OBJECTIVE: To determine the inter- and intrarater variability of image-based PASI measurements by calculating Intra-Class-Correlation-Coefficients (ICCs) and to investigate the impact of the different PASI components and specific anatomic regions on the extent of variability. METHODS: First, the methodology of 'image-based' vs. commonly used 'live' PASI measurements was validated in a pilot study. Next, in an observational cohort study, PASI scores of 120 patients affected by plaque psoriasis were prospectively evaluated by three formally trained physicians by means of total body images (TBI). Each observer independently performed two rounds of image-based PASI calculations in all patients at two different time points. RESULTS: Overall, 720 image-based PASI scores were calculated with a mean PASI of 8.8 (range 0.7-34.8). An interrater variability with an ICC of 0.895 and mean absolute difference (MAD) of 3.3 PASI points were observed. Intrarater variability showed a mean ICC of 0.877 and a MAD of 2.2 points. When considering specific PASI components, the highest agreement was found for the assessment of the involved body surface area (BSA), while the lowest ICCs were calculated for severity scoring of 'scaling' and 'induration'. As BSA scores serve as a multiplier in the calculation of PASI, minor inaccuracies were capable of inducing a large share of variability. CONCLUSION: The overall inter- and intrarater reliability of image-based PASI measurements in this study was good. However, physicians were formally trained and experienced, which frequently is not the case in a real-life clinical setting. Therefore, new strategies for higher standardization and objectivity of PASI calculations are needed.

[Modern imaging of renal tumors - application in diagnostics and therapy. Characterization, operation planning and therapy monitoring of renal lesions]. / Moderne Bildgebung von Nierentumoren - Anwendung in Diagnostik und Therapie: Charakterisierung, Operationsplanung und Therapiemonitoring von Nierenläsionen.

This article elucidates the various tools used for the diagnostics and characterization of renal lesions. The advantages and limitations of ultrasound, contrast-enhanced ultrasound (CEUS), computed tomography (CT) and magnetic resonance imaging (MRI) are presented and discussed. In addition, modern imaging features of CT and MRI, such as iodine quantification in CT as well as diffusion-weighted and perfusion imaging in MRI are presented. Lastly, recent developments in standardized reporting of renal tumors regarding the intraoperative surgical risk are presented.

Measurements of neutrino oscillation parameters from the T2K experiment using 3.6×1021 protons on target.

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC.

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties.

Prospects for beyond the Standard Model physics searches at the Deep Underground Neutrino Experiment: DUNE Collaboration.

The Deep Underground Neutrino Experiment (DUNE) will be a powerful tool for a variety of physics topics. The high-intensity proton beams provide a large neutrino flux, sampled by a near detector system consisting of a combination of capable precision detectors, and by the massive far detector system located deep underground. This configuration sets up DUNE as a machine for discovery, as it enables opportunities not only to perform precision neutrino measurements that may uncover deviations from the present three-flavor mixing paradigm, but also to discover new particles and unveil new interactions and symmetries beyond those predicted in the Standard Model (SM). Of the many potential beyond the Standard Model (BSM) topics DUNE will probe, this paper presents a selection of studies quantifying DUNE's sensitivities to sterile neutrino mixing, heavy neutral leptons, non-standard interactions, CPT symmetry violation, Lorentz invariance violation, neutrino trident production, dark matter from both beam induced and cosmogenic sources, baryon number violation, and other new physics topics that complement those at high-energy colliders and significantly extend the present reach.

Pelvic organ prolapse: does the postoperative course of mesh-repair surgery differ in elderly women when compared with younger patients?

Pelvic organ prolapse (POP) is a common disease in elderly women. Among a wide range of possibilities in POP surgery, the use of partially absorbable meshes appears to be very promising. The problem concerning POP therapy in elderly patients has not yet been not sufficiently investigated. We enrolled 64 patients with POP stages 3 and 4. All patients underwent mesh-repair surgery and afterwards were stratified into two age groups. Data obtained from anamnesis, pelvic organ prolapse quantification (POP-Q) scale, dynamic MRI and prolapse quality of life (P-QoL) questionnaire were analysed and compared between both age groups. A total of 64 patients completed the study protocol. Outcome of the surgery was promising and comparable between both age groups. One recurrence of prolapse and one mesh erosion was reported. P-QoL showed a good overall satisfaction. Our data show that the surgical correction of POP with use of polypropylene mesh in elderly women appears to be a successful method with an acceptable morbidity, adverse events rate and high satisfaction of the patients.

Multidetector CT evaluation of the course of nonresectable pancreatic carcinomas with neoadjuvant therapy.

OBJECTIVE: A prospective study to determine the value of multidetector CT (MD-CT) in assessing the course of nonresectable pancreatic carcinoma during therapy. MATERIAL AND METHODS: 26 patients with nonresectable pancreatic carcinoma underwent MD-CT before and after therapy. The examinations were evaluated with regard to tumor size and vascular invasion using an invasion score (IS) by 2 radiologists independently (kappa analysis). Diagnosis was confirmed surgically, by biopsy or clinical course. RESULTS: Sensitivity for the assessment of irresectability was 100%. Following therapy, 54% of all the tumors were smaller (14/26), 42% had increased in volume (11/26), and one tumor remained stable (1/26). The IS (veins) during follow-up changed in 26 patients (portal vein: 5 higher (mean score 10.4/16.2), 4 lower (mean score 17.5/11.5); superior mesenteric vein: 12 higher (11/14.4), 5 lower (16.2/14.6); p = 0.026). The IS (arteries) changed in 13 patients (celiac trunk: 3 higher (3.3/10); hepatic artery: 4 higher (5.7/10.2), 3 lower (11.6/10.3); superior mesenteric artery: 2 higher (4.5/9.5), 1 lower (12/11)). The kappa values were calculated between 0.56 and 0.87. CONCLUSION: MD-CT is suitable for evaluating tumor spread during therapy for nonresectable pancreatic carcinoma. The IS is useful for assessing the degree of change in vessel invasion.

Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging.

Commercial microscopy systems make use of tandem scanning i.e. either slow or fast scanning. We constructed, for the first time, an advanced control system capable of delivering a dynamic line scanning speed ranging from 2.7 kHz to 27 kHz and achieve variable frame rates from 5 Hz to 50 Hz (512 × 512). The dynamic scanning ability is digitally controlled by a new customized open-source software named PScan1.0. This permits manipulation of scanning rates either to gain higher fluorescence signal at slow frame rate without increasing laser power or increase frame rates to capture high speed events. By adjusting imaging speed from 40 Hz to 160 Hz, we capture a range of calcium waves and transient peaks from soma and dendrite of single fluorescence neuron (CAL-520AM). Motion artifacts arising from respiratory and cardiac motion in small animal imaging reduce quality of real-time images of single cells in-vivo. An image registration algorithm, integrated with PScan1.0, was shown to perform both real time and post-processed motion correction. The improvement is verified by quantification of blood flow rates. This work describes all the steps necessary to develop a high performance and flexible polygon-mirror based multiphoton microscope system for in-vivo biological imaging.

[Quality control of thoracic X-rays in children in diagnostic centers with and without pediatric-radiologic competence]. / Qualitätskontrolle von Röntgenthoraxaufnahmen bei Kindern in diagnostischen Zentren mit und ohne kinderradiologische Kompetenz.

PURPOSE: Radiation protection in pediatric radiology is very important because of the particular sensitivity of radiosensitive organs in younger patients. Optimized image quality supports radiation protection and should be targeted. In our study we examined the quality of pediatric chest X-rays at diagnostic centers (university hospitals and other large clinics). We then evaluated differences in image quality in departments without pediatric competence (R) and departments with pediatric competence (PR). MATERIALS AND METHODS: Our study was based on 313 conventional chest X-rays from 207 patients (192 p. a./a. p. and 121 lateral, 43 from R, 258 from PR and 12 neither from R nor KR) and 38 digital chest X-rays from 26 patients (25 p. a./a. p. and 13 lateral, 1 from R and 37 from PR). All patients (age 0 - 18 years) are from Nephroblastoma-Study SIOP-93/01-GPOH. We examined all initial chest X-rays, which were sent to us for evaluation upon request between 4/3/2002 and 6/14/2002. The examined parameters were: exposure, centering of the X-rays/patient positioning, collimation and sharpness. The X-rays were evaluated on a scale from 1 (best result) to 5 (worst result), resulting in an overall score of A = optimum, B = minor problems, C = major problems, or D = unusable. The optical density, the center of the image and the relative field size were also measured. Statistical tests (Mann-Whitney-U and log regression) were carried out on the conventional images. The study was performed retrospectively. The exposure, sharpness and optical density of the digital X-rays were not analyzed. RESULTS: In the case of all conventional X-rays, the quality of the centering of the X-rays/patient positioning and collimation was moderate (average scale value: 2.4 and 2.8), and the quality of the exposure and sharpness was good and very good (average scale value: 1.9 and 1.5). The quality of the chest X-rays in departments with additional pediatric radiological expertise was better mainly in the case of younger patients (younger than 5 years) than departments without additional pediatric radiological expertise (average scale value in age group 0 - 1 month: PR = 1.7; average scale value in age group 2 months - 2 years: R = 2.4 and PR = 1.8; average scale value in age group 3 - 5 years: R = 2.5 and PR = 1.8). CONCLUSION: Despite the good overall image quality, the quality of the centering of the X-rays/patient positioning and collimation was insufficient in both examiner groups (R and PR). For this reason, some radiation protection requirements could not be fulfilled. X-rays from PR were higher quality than X-rays from R in this special study group. Day-to-day quality checks are necessary for pediatric chest X-rays in order to achieve a high quality standard.

Further reduction of disqualification rates by additional MRI-targeted biopsy with transperineal saturation biopsy compared with standard 12-core systematic biopsies for the selection of prostate cancer patients for active surveillance.

BACKGROUND: Active surveillance (AS) is commonly based on standard 10-12-core prostate biopsies, which misclassify ~50% of cases compared with radical prostatectomy. We assessed the value of multiparametric magnetic resonance imaging (mpMRI)-targeted transperineal fusion-biopsies in men under AS. METHODS: In all, 149 low-risk prostate cancer (PC) patients were included in AS between 2010 and 2015. Forty-five patients were initially diagnosed by combined 24-core systematic transperineal saturation biopsy (SB) and MRI/transurethral ultrasound (TRUS)-fusion targeted lesion biopsy (TB). A total of 104 patients first underwent 12-core TRUS-biopsy. All patients were followed-up by combined SB and TB for restratification after 1 and 2 years. All mpMRI examinations were analyzed using PIRADS. AS was performed according to PRIAS-criteria and a NIH-nomogram for AS-disqualification was investigated. AS-disqualification rates for men initially diagnosed by standard or fusion biopsy were compared using Kaplan-Meier estimates and log-rank tests. Differences in detection rates of the SB and TB components were evaluated with a paired-sample analysis. Regression analyses were performed to predict AS-disqualification. RESULTS: A total of, 48.1% of patients diagnosed by 12-core TRUS-biopsy were disqualified from AS based on the MRI/TRUS-fusion biopsy results. In the initial fusion-biopsy cohort, upgrading occurred significantly less frequently during 2-year follow-up (20%, P<0.001). TBs alone were significantly superior compared with SBs alone to detect Gleason-score-upgrading. NPV for Gleason-upgrading was 93.5% for PIRADS⩽2. PSA level, PSA density, NIH-nomogram, initial PIRADS score (P<0.001 each) and PIRADS-progression on consecutive MRI (P=0.007) were significant predictors of AS-disqualification. CONCLUSIONS: Standard TRUS-biopsies lead to significant underestimation of PC under AS. MRI/TRUS-fusion biopsies, and especially the TB component allow more reliable risk classification, leading to a significantly decreased chance of subsequent AS-disqualification. Cancer detection with mpMRI alone is not yet sensitive enough to omit SB on follow-up after initial 12-core TRUS-biopsy. After MRI/TRUS-fusion biopsy confirmed AS, it may be appropriate to biopsy only those men with suspected progression on MRI.

Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

[Selective RPE laser treatment with a scanned cw laser beam in rabbits]. / Selektive Behandlung des RPE unter Verwendung eines gescannten CW-Laserstrahls im Kaninchenmodell.

BACKGROUND: Selective RPE laser therapy with sparing of the neurosensory layer is possible by applying repetitive microsecond laser pulses. Macular diseases such as diabetic maculopathy, soft confluent drusen due to age-related macular degeneration or central serous chorioretinopathy were shown to be treated successfully-without concurrent laser scotoma-by this technique. It was the goal of this study to show, if selectivity could also be achieved using a conventional green cw-laser by scanning the beam across the retina during irradiation. MATERIAL AND METHODS: A cw-laser beam at 532 nm was coupled to a slitlamp via a single mode optical fiber. The spot (18 microm) was scanned across the retina of Dutch-belted rabbits through a contact lens using a two-dimensional acusto-optical deflector. The scan-field was 300 microm x 300 microm in size and consisted of six separate scan lines. The scanning speed was adjusted so as to produce 5 micros exposure at each absorber in the center of the scan line. The entire scan pattern was applied 100 times at each site at a frame rate of 100 Hz. Dose response curve was measured by variation of the laser power. ED(50)-thresholds for RPE damage were calculated by fluorescein angiographic leakage in irradiated areas after exposure to different laser intensities. The extent of selectivity was examined by light microscopy. RESULTS: Clinically the selective laser-induced RPE defect was demonstrated by fluorescein angiographic leakage and concurrent absence of ophthalmoscopic visibility. The angiographic ED(50)-damage threshold was 161 mJ/cm(2) (66 mW). Ophthalmoscopic visibility was not noticed even with the maximum available radiant exposure of 438 mJ/cm(2) (180 mW). Thus the safety range between angiographic and ophthalmoscopic thresholds had a factor of at least 2.7. First histological examinations revealed selective RPE destruction with intact photoreceptors for irradiation at laser power levels 2 times above angiographic threshold. CONCLUSION: Selective RPE targeting is feasible with a conventional green cw-laser when scanning the focused laser beam across the fundus with a speed such that every point in exposed RPE is irradiated for duration of 5 micros.

Improved detection of anterior fibromuscular stroma and transition zone prostate cancer using biparametric and multiparametric MRI with MRI-targeted biopsy and MRI-US fusion guidance.

BACKGROUND: The objective of this study was to analyze the potential of prostate magnetic resonance imaging (MRI) and MRI/transrectal ultrasound-fusion biopsies to detect and to characterize significant prostate cancer (sPC) in the anterior fibromuscular stroma (AFMS) and in the transition zone (TZ) of the prostate and to assess the accuracy of multiparametric MRI (mpMRI) and biparametric MRI (bpMRI) (T2w and diffusion-weighted imaging (DWI)). METHODS: Seven hundred and fifty-five consecutive patients underwent prebiopsy 3 T mpMRI and transperineal biopsy between October 2012 and September 2014. MRI images were analyzed using PIRADS (Prostate Imaging-Reporting and Data System). All patients had systematic biopsies (SBs, median n=24) as reference test and targeted biopsies (TBs) with rigid software registration in case of MRI-suspicious lesions. Detection rates of SBs and TBs were assessed for all PC and sPC patients defined by Gleason score (GS)⩾3+4 and GS⩾4+3. For PC, which were not concordantly detected by TBs and SBs, prostatectomy specimens were assessed. We further compared bpMRI with mpMRI. RESULTS: One hundred and ninety-one patients harbored 194 lesions in AFMS and TZ on mpMRI. Patient-based analysis detected no difference in the detection of all PC for SBs vs TBs in the overall cohort, but in the repeat-biopsy population TBs performed significantly better compared with SBs (P=0.004 for GS⩾3+4 and P=0.022 for GS⩾4+3, respectively). Nine GS⩾4+3 sPCs were overlooked by SBs, whereas TBs missed two sPC in men undergoing primary biopsy. The combination of SBs and TBs provided optimal local staging. Non-inferiority analysis showed no relevant difference of bpMRI to mpMRI in sPC detection. CONCLUSIONS: MRI-targeted biopsies detected significantly more anteriorly located sPC compared with SBs in the repeat-biopsy setting. The more cost-efficient bpMRI was statistically not inferior to mpMRI in sPC detection in TZ/AFMS.

Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.

Synthesis of [11C]dapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey.

[11C]Dapoxetine.HCl, S-(+)-N,N-dimethyl-a-[2-(naphthalenyloxy)ethyl] benzenemethanamine hydrochloride, a potent serotonin re-uptake inhibitor was prepared from its mono-methyl precursor, S-(+)-N-methyl-a-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride. Biodistribution was determined in rats at 5, 30 and 60 min after injection and preliminary PET studies were performed in a Rhesus monkey. 11CH3I was bubbled into a solution of S-(+)-N-methyl-alpha-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride (3.0 mg in DMSO) and the mixture was heated at 110 degrees C for 8 min. [11C]Dapoxetine.HCl was purified by HPLC on a C18 cartridge eluted with MeOH:phosphate buffer, pH 7,2 (75:25) with a 10% yield (end of synthesis). The time required for the synthesis was 40 min, from the end of bombardment. Radiochemical purity of the final product was > 99% and specific activity was routinely > 400 mCi/mumol [EOS]. In the biodistribution studies the highest concentration (%ID/g +/- SEM) of dapoxetine.HCl was detected in lung: 4.56 +/- 0.27 (5 min), 1.28 +/- 0.18 (30 min) and 0.67 +/- 0.04 (60 min). Brain accumulation was 0.76 +/- 0.02 (5 min), 0.46 +/- 0.04 (30 min) and 0.27 +/- 0.01 (60 min). Preliminary PET studies demonstrated significant displaceable binding in the cerebral cortex and subcortical grey matter. These results demonstrate that [11C]dapoxetine.HCl can be prepared in high purity and may be useful for the in vivo evaluation of serotonin re-uptake mechanisms.