Influence of Dopamine Deficiency in Early Parkinson's Disease on the Slow Stimulation Multifocal-ERG

Purpose: In animal studies intravitreal injection of tetrodotoxin (TTX) results in mfERG waveform changes similar to those observed in glaucoma. As TTX blocks amacrine as well as ganglion cells, there is still a question regarding the underlying cell population responsible for these changes in waveform. In an attempt to assess the contribution of the amacrine cells to these changes, a mfERG was obtained from patients with Parkinson's disease as some amacrine cells are mediated by dopamine, a substance lacking in Parkinson's. Methods: Eight patients with early Parkinson's disease underwent ophthalmologic examination, testing of contrast sensitivity and electrophysiological examination according to ISCEV standard at least 12h following their last medication with Dopamine. A slow stimulation mfERG was obtained with a stimulus base interval of 53.3ms and with a stimulus base interval of 106.6ms. During MF-ERG recordings 103 hexagons stimulated the central 50deg of the retina simultaneously and independently (m-sequence 213, Lmax: 200cd/m2, ~100% contrast). Results: Contrast sensitivity and ISCEV standard electrophysiological testing was unremarkable. When the mfERG was analyzed, only four patients had an adequate signal-to-noise ratio to allow further data analysis - one of whom was diagnosed with a multi system atrophy in retrospect. The first order response component was analyzed at a filter setting of 10-300Hz and at 100-300Hz (OPs) and compared to mfERGs of a control group. On average, in patients, the amplitude of N1P1 was slightly lower in the central and nasal response averages. When the three OPs at a latency of 72-89ms were analyzed in the 53.3ms base interval recording, the most marked difference in amplitude was observed in the superior nasal response average of the first OP. Here a mean amplitude of 1.3nV/deg2 in patients compared to a mean amplitude of 1.9nV/deg2 in the control group (P: 0.08). Discussion: In contrast to our previous findings in NTG, there was a consistent presence of three OPs. Under the stimulus conditions applied, we did not find an influence of dopaminergic amacrine cells on the mfERG in our patients with moderate stages of Parkinsion's. The difficulties in obtaining an adequate signal-to noise ratio due to e.g. muscle artifacts even in Parkinson patients of moderate disease stages render a success of mfERG recording in patients with more advanced stages unlikely. The question of the influence of dopaminergic amacrine cells on the mfERG could possibly be addressed using MPDT in animal researc

Phantom investigation of 3D motion-dependent volume aliasing during CT simulation for radiation therapy planning

PURPOSE: To quantify volumetric and positional aliasing during non-gated fast- and slow-scan acquisition CT in the presence of 3D target motion. METHODS: Single-slice fast, single-slice slow, and multi-slice fast scan helical CTs were acquired of dynamic spherical targets (1 and 3.15 cm in diameter), embedded in an anthropomorphic phantom. 3D target motions typical of clinically observed tumor motion parameters were investigated. Motion excursions included ± 5, ± 10, and ± 15 mm displacements in the S-I direction synchronized with constant displacements of ± 5 and ± 2 mm in the A-P and lateral directions, respectively. For each target, scan technique, and motion excursion, eight different initial motion-to-scan phase relationships were investigated. RESULTS: An anticipated general trend of target volume overestimation was observed. The mean percentage overestimation of the true physical target volume typically increased with target motion amplitude and decreasing target diameter. Slow-scan percentage overestimations were larger, and better approximated the time-averaged motion envelope, as opposed to fast-scans. Motion induced centroid misrepresentation was greater in the S-I direction for fast-scan techniques, and transaxial direction for the slow-scan technique. Overestimation is fairly uniform for slice widths < 5 mm, beyond which there is gross overestimation. CONCLUSION: Non-gated CT imaging of targets describing clinically relevant, 3D motion results in aliased overestimation of the target volume and misrepresentation of centroid location, with little or no correlation between the physical target geometry and the CT-generated target geometry. Slow-scan techniques are a practical method for characterizing time-averaged target position. Fast-scan techniques provide a more reliable, albeit still distorted, target margin

Standard fractionation intensity modulated radiation therapy (IMRT) of primary and recurrent glioblastoma multiforme

<p>Abstract</p> <p>Background</p> <p>Intensity-modulated radiation therapy (IMRT) affords unparalleled capacity to deliver conformal radiation doses to tumors in the central nervous system. However, to date, there are few reported outcomes from using IMRT, either alone or as a boost technique, for standard fractionation radiotherapy for glioblastoma multiforme (GBM).</p> <p>Methods</p> <p>Forty-two patients were treated with IMRT alone (72%) or as a boost (28%) after 3-dimensional conformal radiation therapy (3D-CRT). Thirty-three patients with primary disease and 9 patients with recurrent tumors were included. Thirty-four patients (81%) had surgery, with gross tumor resection in 13 patients (36%); 22 patients (53%) received chemo-radiotherapy. The median total radiation dose for all patients was 60 Gy with a range from 30.6 to 74 Gy. Standard fractions of 1.8 Gy/day to 2.0 Gy/day were utilized.</p> <p>Results</p> <p>Median survival was 8.7 months, with 37 patients (88%) deceased at last contact. Nonparametric analysis showed no survival difference in IMRT-boost vs. IMRT-only groups.</p> <p>Conclusion</p> <p>While technically feasible, preliminary results suggest delivering standard radiation doses by IMRT did not improve survival outcomes in this series compared to historical controls. In light of this lack of a survival benefit and the costs associated with use of IMRT, future prospective trials are needed to evaluate non-survival endpoints such as quality of life and functional preservation. Short of such evidence, the use of IMRT for treatment of GBM needs to be carefully rationalized.</p

Introduction of a guideline for measurements of greenhouse gas fluxes from soils using non-steady-state chambers

Method Soils represent a major global source and sink of greenhouse gases (GHGs). Many studies of GHG fluxes between soil, plant and atmosphere rely on chamber measurements. Different chamber techniques have been developed over the last decades, each characterised by different requirements and limitations. In this manuscript, we focus on the non-steady-state technique which is widely used for manual measurements but also in automatic systems. Although the measurement method appears very simple, experience gained over the years shows that there are many details which have to be taken into account to obtain reliable measurement results. Aim This manuscript aims to share lessons learnt and pass on experiences in order to assist the reader with possible questions or unexpected challenges, ranging from the planning of the design of studies and chambers to the practical handling of the chambers and the quality assurance of the gas and data analysis. This concise introduction refers to a more extensive Best Practice Guideline initiated by the Working Group Soil Gases (AG Bodengase) of the German Soil Science Society (Deutsche Bodenkundliche Gesellschaft). The intention was to collect and aggregate the expertise of different working groups in the research field. As a compendium, this Best Practice Guideline is intended to help both beginners and experts to meet the practical and theoretical challenges of measuring soil gas fluxes with non-steady-state chamber systems and to improve the quality of the individual flux measurements and thus entire GHG studies by reducing sources of uncertainty and error

Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5Gy*cm(2) (0.3-3181) and FT 18 min (0.3-184). The calculated ED was 6.4 mSv (0.1-636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm(2), FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusion: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure

Chemo- and Thermosensory Responsiveness of Grueneberg Ganglion Neurons Relies on Cyclic Guanosine Monophosphate Signaling Elements

Neurons of the Grueneberg ganglion (GG) in the anterior nasal region of mouse pups respond to cool temperatures and to a small set of odorants. While the thermosensory reactivity appears to be mediated by elements of a cyclic guanosine monophosphate (cGMP) cascade, the molecular mechanisms underlying the odor-induced responses are unclear. Since odor-responsive GG cells are endowed with elements of a cGMP pathway, specifically the transmembrane guanylyl cyclase subtype GC-G and the cyclic nucleotide-gated ion channel CNGA3, the possibility was explored whether these cGMP signaling elements may also be involved in chemosensory GG responses. Experiments with transgenic mice deficient for GC-G or CNGA3 revealed that GG responsiveness to given odorants was significantly diminished in these knockout animals. These findings suggest that a cGMP cascade may be important for both olfactory and thermosensory signaling in the GG. However, in contrast to the thermosensory reactivity, which did not decline over time, the chemosensory response underwent adaptation upon extended stimulation, suggesting that the two transduction processes only partially overlap. Copyright (C) 2011 S. Karger AG, Base

Will fire danger be reduced by using Solar Radiation Management to limit global warming to 1.5°C compared to 2.0°C

This is the author accepted manuscript. The final version is available from American Geophysical Union (AGU) via the DOI in this record.The commitment to limit warming to 1.5°C as set out in the Paris Agreement is widely regarded as ambitious and challenging. It has been proposed that reaching this target may require a number of actions, which could include some form of carbon removal or Solar Radiation Management in addition to strong emission reductions. Here we assess one theoretical solution using Solar Radiation Management to limit global mean warming to 1.5°C above pre‐industrial temperatures, and use the McArthur fire danger index to evaluate the change in fire danger. The results show that globally fire danger is reduced in most areas when temperatures are limited to 1.5°C compared to 2.0°C. The number of days where fire danger is ‘high’ or above is reduced by up to 30 days per year on average, although there are regional variations. In certain regions, fire danger is increased, experiencing 31 more days above ‘high’ fire danger.This work was supported by the European Commission‟s 7th Framework Programme (EU/FP7) under Grant Agreement 603864 (HELIX), and the Joint UK BEIS/Defra Met Office Hadley Centre Climate Programme (GA01101)

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs

Surgical outcomes after neoadjuvant ablative dose radiation among patients with borderline resectable and locally advanced pancreas cancer from the multi-institutional phase 2 Stereotactic MR-Guided Adaptive Radiation Therapy (SMART) trial

Background: Acute grade 3+ toxicity was rare in the multi-institutional phase 2 stereotactic MR-guided on-table adaptive radiation therapy (SMART) trial (NCT03621644) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). Surgery may be considered after ablative SMART although the feasibility and safety of this is not well understood. Postoperative outcomes of the subset of patients in the SMART trial are examined here. Methods: Trial eligibility included BRPC or LAPC without metastases after a minimum of 3 months of induction chemotherapy. All patients received SMART prescribed to 50 Gy in 5 fractions using an integrated 0.35T MR-radiation therapy device equipped with cutting edge soft tissue tracking, automatic beam gating, and on-table adaptive replanning. Surgery was permitted after SMART, often after multi-disciplinary review. Perioperative details and postoperative outcomes, including morbidity, mortality, and overall survival (OS), were analyzed. Results: 136 patients across 13 sites were enrolled between 2019-2022. 44 patients (32.4%) had surgery after SMART (33 BRPC, 11 LAPC). Surgical procedures included pancreaticoduodenectomy (81.8%), distal pancreatectomy with splenectomy (9.1%), total pancreatectomy (6.8%), and distal pancreatectomy with celiac axis resection (2.3%). 52.3% required vascular resection/reconstruction, a majority of which were venous resections (65.2%), with a smaller proportion needing both venous/ arterial (21.7%), or arterial (13%). Surgery was performed after a mean 51.4 ± 52.8 days from SMART. Postoperative hospitalization was 10.5 ± 8.9 days. Nine patients (20.5%) had Clavien-Dindo complications of grade III or higher; 3 deaths resulted from post-pancreatectomy hemorrhage in patients who had portal vein resection. One-year OS in patients who had surgery versus no surgery after SMART was 66% vs. 43%, respectively. Conclusions: These are the first prospectively evaluated surgical outcomes after 5-fraction ablative SMART for BRPC/LAPC. The rate of surgery for BRPC compares favorably to radiated patients on the Alliance A021501 trial. Despite the use of ablative radiation dose and frequent need for vascular resection, the incidence of serious surgical complications was similar to what is reported after non-ablative radiation therapy. However, several deaths occurred after surgery and we therefore we urge caution when considering surgery after ablative radiation therapy. Further analysis of other variables such as the time between SMART and surgery, approaches to vascular resections, and discrete events such as delayed gastric emptying, operative duration, and post-operative pancreatic fistula are needed to better understand the surgical morbidity seen in these patients