Translation of an esophagus histopathological FT-IR imaging model to a fast quantum cascade laser modality.

The technical progress in fast quantum cascade laser (QCL) microscopy offers a platform where chemical imaging becomes feasible for clinical diagnostics. QCL systems allow the integration of previously developed FT-IR-based pathology recognition models in a faster workflow. The translation of such models requires a systematic approach, focusing only on the spectral frequencies that carry crucial information for discrimination of pathologic features. In this study, we optimize an FT-IR-based histopathological method for esophageal cancer detection to work with a QCL system. We explore whether the classifier's performance is affected by paraffin presence from tissue blocks compared to removing it chemically. Working with paraffin-embedded samples reduces preprocessing time in the lab and allows samples to be archived after analysis. Moreover, we test, whether the creation of a QCL model requires a preestablished FTIR model or can be optimized using solely QCL measurements.

Deactivation vs. asynchronous pacing - prospective evaluation of a protocol for rhythm management in patients with magnetic resonance conditional pacemakers undergoing adenosine stress cardiovascular magnetic resonance imaging.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) imaging with adenosine stress is an important diagnostic tool in patients with known or suspected coronary artery disease (CAD). However, the method is not yet established for CAD patients with pacemakers (PM) in clinical practice. A possible reason is that no recommendations exist for PM setting (paused pacing or asynchronous mode) during adenosine stress. We elaborated a protocol for rhythm management in clinical routine for PM patients that considers heart rate changes under adenosine using a test infusion of adenosine in selected patients. METHODS: 47 consecutive patients (mean age 72.3 ± 10,0 years) with MR conditional PM and known or suspected CAD who underwent CMR in clinical routine were studied in this prospective observational study. PM indications were sinus node dysfunction (SND, n = 19; 40,4%), atrioventricular (AV) block (n = 26; 55.3%) and bradyarrhythmia in permanent atrial fibrillation (AF, n = 2; 4.3%). In patients with SND, normal AV-conduction and resting HR >45 bpm at the time of CMR and in AF the PM was deactivated for the scan. In intermittent AV-block a test infusion of adenosine was given prior to the scan. All patients with permanent higher degree sinuatrial or AV-block or deterioration of AV-conduction in the adenosine test were paced asynchronously during CMR, in patients with preserved AV-conduction under adenosine the pacemaker was deactivated. CMR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. RESULTS: The adenosine test was able to differentiate between mandatory PM stimulation during CMR and safe deactivation of the device. In patients with permanent sinuatrial or AV-block (n = 11; 23.4%) or deterioration of AV conduction in the adenosine test (n = 5, 10.6%) asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm, no competitive stimulation was seen during the scan. 10 of 15 (66,7%) patients with intermittent AV-block showed preserved AV-conduction under adenosine. As in SND and AF deactivation of the PM showed to be safe during CMR, no bradycardia was observed. CONCLUSION: Our protocol for rhythm management during adenosine stress CMR showed to be feasible and safe and may be recommended for pacemaker patients undergoing routine CMR.

Cardiovascular magnetic resonance in patients with magnetic resonance conditional pacemaker systems at 1.5 T: influence of pacemaker related artifacts on image quality including first pass perfusion, aortic and mitral valve assessment, flow measurement, short tau inversion recovery and T1-weighted imaging.

There are only limited data on the impact of device-related artifacts on image quality in cardiovascular magnetic resonance imaging (CMR) in patients with pacemakers (PM). Adenosine stress perfusion, T1-weighted imaging and flow measurement as well as valve characterization have not been evaluated previously concerning artifact burden. We aimed to assess image quality in all routinely used CMR sequences. We analyzed 2623 myocardial segments in CMR scans of 61 patients with MR conditional PM (mean age 72.1 ± 11.5 years), 23 (37.7%) with right sided, 38 (62.3%) with left-sided devices. There were no relevant artifacts in patients with right-sided devices irrespective of the imaging sequence. In left-sided implants no PM-induced artifacts were found in first pass perfusion sequence, flow analysis and T1 weighted imaging. Only few patients with left-sided devices showed significant PM-artifacts in aortic (3/38, 7.9%)/mitral (n = 2/38, 5.3%) valve imaging and STIR (n = 3/35, 8.6%). In STIR only 14/805 (1.7%) segments were involved. In left-sided PM SSFP cine sequences had more artifact burden than LGE with 377/1505 (25.0%) vs. 162/1505 (10.8%) myocardial segments involved by relevant artifacts respectively (p < 0.001). Apart from cine and LGE imaging in anterior myocardial segments with left-sided implants presence of MRI conditional pacemakers does not affect CMR image quality in multimodal CMR examinations to a significant extent. Our data supports evidence that reduced image quality does not need to be a major concern in PM patients undergoing CMR.

Feasibility and safety of adenosine cardiovascular magnetic resonance in patients with MR conditional pacemaker systems at 1.5 Tesla.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) with adenosine stress is a valuable diagnostic tool in coronary artery disease (CAD). However, despite the development of MR conditional pacemakers CMR is not yet established in clinical routine for pacemaker patients with known or suspected CAD. A possible reason is that adenosine stress perfusion for ischemia detection in CMR has not been studied in patients with cardiac conduction disease requiring pacemaker therapy. Other than under resting conditions it is unclear whether MR safe pacing modes (paused pacing or asynchronous mode) can be applied safely because the effect of adenosine on heart rate is not precisely known in this entity of patients. We investigate for the first time feasibility and safety of adenosine stress CMR in pacemaker patients in clinical routine and evaluate a pacing protocol that considers heart rate changes under adenosine. METHODS: We retrospectively analyzed CMR scans of 24 consecutive patients with MR conditional pacemakers (mean age 72.1 ± 11.0 years) who underwent CMR in clinical routine for the evaluation of known or suspected CAD. MR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. RESULTS: Pacemaker indications were sinus node dysfunction (n = 18) and second or third degree AV block (n = 6). Under a pacing protocol intended to avoid competitive pacing on the one hand and bradycardia due to AV block on the other no arrhythmia occurred. Pacemaker stimulation was paused to prevent competitive pacing in sinus node dysfunction with resting heart rate >45 bpm. Sympatho-excitatory effect of adenosine led to a significant acceleration of heart rate by 12.3 ± 8.3 bpm (p < 0.001), no bradycardia occurred. On the contrary in AV block heart rate remained constant; asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm. CONCLUSION: Adenosine stress CMR appears to be feasible and safe in patients with MR conditional pacemakers. Heart rate response to adenosine has to be considered for the choice of pacing modes during CMR.

Nitric oxide decreases the enzymatic activity of insulin degrading enzyme in APP/PS1 mice.

Nitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer's disease, we investigated the activity of two amyloid ß degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice. These data suggest that NOS2 upregulation impairs amyloid ß degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid ß clearance.

Nitration of tyrosine 10 critically enhances amyloid ß aggregation and plaque formation.

Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid ß (Aß) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aß). Nitration of Aß accelerated its aggregation and was detected in the core of Aß plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-Aß, overall Aß deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-Aß into the brain of young APP/PS1 mice induced ß-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.

PPARgamma and RXRgamma ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models.

Glioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti-invasive mechanisms of 6-OH-11-O-hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma activator, in three different glioblastoma cell lines. A dose-dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro-apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator-activated receptor and retinoid X receptor against glioblastoma.