Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: an in vivo study utilizing Macitentan

Cardiac magnetic resonance (CMR) imaging is used to assess the right ventricle (RV) of pulmonary hypertensive (PH) patients and more recently to track changes in response to therapy. We wished to investigate if repeat CMRs could be used to assess ventricular changes in the Sugen 5416 hypoxic (Su/Hx) rat model of PH treated with the dual endothelin receptor antagonist Macitentan. Male Sprague Dawley Su/Hx rats were dosed for 3 weeks with either vehicle or Macitentan (30 mg/kg) daily, control rats received only vehicle. All rats underwent three CMR scans; before treatment, 2 weeks into treatment, and end of the study. A separate group of Su/Hx and control rats, treated as above, underwent terminal hemodynamic measurements. Using terminal and CMR measurements, Macitentan was found to lower RV systolic pressure pulmonary artery remodeling and increase RV ejection fraction but not change RV hypertrophy (RVH). Repeat CMRs determined that Su/Hx rats treated with Macitentan had significantly reversed RVH via reducing RV mass as well as reducing elevated left ventricular eccentricity index; reductions in RV mass were also observed in Su/Hx vehicle rats exposed to normoxic conditions. We have demonstrated that repeat CMRs can be used to assess the volume and structural changes in the ventricles of the Su/Hx rat model. Using repeat CMRs has allowed us to build a more complete picture of the response of the RV and the left ventricle to treatment. It is unknown if these effects are a consequence of direct action on the RV or secondary to improvements in the lung vasculature

Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion

Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management

Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. validation using [14C]2-deoxyglucose autoradiography

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T2* MRI (T2* OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T2* signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T2* OC to determine metabolic status of T2*-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n=6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147±32 minutes after stroke, T2* signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T2*-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T2* signal increase of 9.22%±3.9% (mean±s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T2* signal change was negligible in ischemic core, 3.2%±0.78% in contralateral regions, and 1.41%±0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue follow

Differences in the evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats

<p><b>Background and Purpose:</b> Stroke-prone spontaneously hypertensive rats (SHRSP) are a highly pertinent stroke model with increased sensitivity to focal ischemia compared with the normotensive reference strain (Wistar-Kyoto rats; WKY). Study aims were to investigate temporal changes in the ischemic penumbra in SHRSP compared with WKY.</p> <p><b>Methods:</b> Permanent middle cerebral artery occlusion was induced with an intraluminal filament. Diffusion- (DWI) and perfusion- (PWI) weighted magnetic resonance imaging was performed from 1 to 6 hours after stroke, with the PWI-DWI mismatch used to define the penumbra and thresholded apparent diffusion coefficient (ADC) maps used to define ischemic damage.</p> <p><b>Results:</b> There was significantly more ischemic damage in SHRSP than in WKY from 1 to 6 hours after stroke. The perfusion deficit remained unchanged in WKY (39.9±6 mm<sup>2</sup> at 1 hour, 39.6±5.3 mm<sup>2</sup> at 6 hours) but surprisingly increased in SHRSP (43.9±9.2 mm<sup>2</sup> at 1 hour, 48.5±7.4 mm<sup>2</sup> at 6 hours; P=0.01). One hour after stroke, SHRSP had a significantly smaller penumbra (3.4±5.8 mm<sup>2</sup>) than did WKY (9.7±3.8, P=0.03). In WKY, 56% of the 1-hour penumbra area was incorporated into the ADC lesion by 6 hours, whereas in SHRSP, the small penumbra remained static owing to the temporal increase in both ADC lesion size and perfusion deficit.</p> <p><b>Conclusions:</b> First, SHRSP have significantly more ischemic damage and a smaller penumbra than do WKY within 1 hour of stroke; second, the penumbra is recruited into the ADC abnormality over time in both strains; and third, the expanding perfusion deficit in SHRSP predicts more tissue at risk of infarction. These results have important implications for management of stroke patients with preexisting hypertension and suggest ischemic damage could progress at a faster rate and over a longer time frame in the presence of hypertension.</p&gt

Potential use of oxygen as a metabolic biosensor in combination with T2*-weighted MRI to define the ischemic penumbra

We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2* signal change during ‘oxygen challenge’ (OC, 5 mins 100% O2). During OC, T2* increase reflects O2 binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning (n=5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2* acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2* signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2* and apparent diffusion coefficient (ADC) map coregistration revealed that the T2* signal increase extended into the ADC lesion (3.4%). In series 2 (n=5), FLASH T2* and ADC maps coregistered with histology revealed a T2* signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra

Direct imaging of glymphatic flow using H217O MRI

The recently proposed glymphatic pathway for solute transport and waste clearance from the brain has been the focus of intense debate. By exploiting an isotopically enriched MRI tracer, H217O, we directly imaged glymphatic water transport in the rat brain in vivo for the first time. Our results reveal glymphatic transport that is dramatically faster and more extensive than previously thought and unlikely to be explained by diffusion alone. Moreover, we confirm the critical role of aquaporin-4 channels in glymphatic transport

Quantitative histopathologic assessment of perfusion MRI as a marker of glioblastoma cell infiltration in and beyond the peritumoral edema region

Background: Conventional MRI fails to detect regions of glioblastoma cell infiltration beyond the contrast‐enhanced T1 solid tumor region, with infiltrating tumor cells often migrating along host blood vessels. Purpose: To quantitatively and qualitatively analyze the correlation between perfusion MRI signal and tumor cell density in order to assess whether local perfusion perturbation could provide a useful biomarker of glioblastoma cell infiltration. Study Type: Animal model. Subjects: Mice bearing orthotopic glioblastoma xenografts generated from a patient‐derived glioblastoma cell line. Field Strength/Sequences: 7T perfusion images acquired using a high signal‐to‐noise ratio (SNR) multiple boli arterial spin labeling sequence were compared with conventional MRI (T1/T2 weighted, contrast‐enhanced T1, diffusion‐weighted, and apparent diffusion coefficient). Assessment: Immunohistochemistry sections were stained for human leukocyte antigen (probing human‐derived tumor cells). To achieve quantitative MRI‐tissue comparison, multiple histological slices cut in the MRI plane were stacked to produce tumor cell density maps acting as a “ground truth.” Statistical Tests: Sensitivity, specificity, accuracy, and Dice similarity indices were calculated and a two‐tailed, paired t‐test used for statistical analysis. Results: High comparison test results (Dice 0.62–0.72, Accuracy 0.86–0.88, Sensitivity 0.51–0.7, and Specificity 0.92–0.97) indicate a good segmentation for all imaging modalities and highlight the quality of the MRI tissue assessment protocol. Perfusion imaging exhibits higher sensitivity (0.7) than conventional MRI (0.51–0.61). MRI/histology voxel‐to‐voxel comparison revealed a negative correlation between tumor cell infiltration and perfusion at the tumor margins (P = 0.0004). Data Conclusion: These results demonstrate the ability of perfusion imaging to probe regions of low tumor cell infiltration while confirming the sensitivity limitations of conventional imaging modalities. The quantitative relationship between tumor cell density and perfusion identified in and beyond the edematous T2 hyperintensity region surrounding macroscopic tumor could be used to detect marginal tumor cell infiltration with greater accuracy

Anakinra for recalcitrant pyoderma gangrenosum

Pyoderma gangrenosum (PG) is an autoinflammatory neutrophilic dermatosis characterized by rapidly enlarging, painful ulcers. Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist that blocks the activity of IL-1α and IL-1β by competitively inhibiting IL-1 binding to the IL-1 type I receptor. We present a series of two patients with recalcitrant PG, who had limited therapeutic options due to multiple previous treatment failures and multiple co-morbidities, who obtained 100% healing with anakinra. Compared to conventional first-line therapies for PG, the safety profile of anakinra may be preferable for patients with multiple co-morbidities. Further research is needed to assess the safety and efficacy of anakinra for PG

The Milky Way's Kiloparsec Scale Wind: A Hybrid Cosmic-Ray and Thermally Driven Outflow

We apply a wind model, driven by combined cosmic-ray and thermal-gas pressure, to the Milky Way, and show that the observed Galactic diffuse soft X-ray emission can be better explained by a wind than by previous static gas models. We find that cosmic-ray pressure is essential to driving the observed wind. Having thus defined a "best-fit" model for a Galactic wind, we explore variations in the base parameters and show how the wind's properties vary with changes in gas pressure, cosmic-ray pressure and density. We demonstrate the importance of cosmic rays in launching winds, and the effect cosmic rays have on wind dynamics. In addition, this model adds support to the hypothesis of Breitschwerdt and collaborators that such a wind may help explain the relatively small gradient observed in gamma-ray emission as a function of galactocentric radius.Comment: 14 pages, 11 figures; Accepted to Ap