In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.

Purpose To evaluate diffusion abnormalities of the retina and optic nerve in patients with central retinal artery occlusion (CRAO) using standard stroke diffusion-weighted magnetic resonance imaging (DWI). Methods In this case-control study, DWI scans of patients with nonarteritic CRAO were retrospectively assessed for acute ischemia of the retina and optic nerve. Two neuroradiologists, blinded for patient diagnosis, randomly evaluated DWI of CRAO patients and controls (a collective of stroke and transient ischemic attack [TIA] patients) for restrictions of the retina and optic nerve. We calculated statistical quality criteria and analyzed inter-rater reliability using unweighted Kappa statistics. Results 20 CRAO patients (60,6 ± 17 years) and 20 controls (60,7 ± 17 years) were included in the study. Sensitivity, specificity, positive and negative predictive values for retinal DWI restrictions were 75%/80%/79%/76% (reader 1) and 75%/100%/100%/80% (reader 2), respectively. Unweighted Kappa was κ = 0,70 (95% CI 0,48‑0,92), indicating “substantial” interrater reliability. In comparison, sensitivity, specificity, PPV and NPV (positive and negative predictive values) for restrictions of the optic nerve in CRAO were 55%/70%/65%/61% (reader 1) and 25%/100%/100%/57% (reader 2). Inter-rater reliability was “fair” with unweighted Kappa κ = 0,32 (95% CI 0,09‑0,56). Conclusions Retinal diffusion restrictions were present in a majority of CRAO patients and detectable with reasonable sensitivity, high specificity and substantial inter-rater reliability. Further studies are necessary to study time dependency of retinal diffusion restrictions, improve image quality and investigate the reliability of retinal DWI to discern CRAO from other causes of acute loss of vision.

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors within the renin–angiotensin system, which mediate tissue-protective actions such as anti-inflammation, antifibrosis, and antiapoptosis. In recent years, several programs have been launched in order to develop drugs that act as agonists on the AT2R or MAS to take therapeutic advantage of the protective and regenerative properties of these receptors. This review article will focus on recent data obtained in preclinical animal and in vitro models with new AT2R-agonistic molecules (Compound 21 and β-amino acid substituted angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely – at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able to attenuate hypertension-induced vascular remodeling and reduce arterial stiffening, which in more chronic settings and together with the natriuretic effect may result in modest lowering of BP. We conclude from these preclinical data that AT2R agonists are not suitable for antihypertensive monotherapy, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage.

BACKGROUND AND PURPOSE: Retinal diffusion restrictions were recently identified as a regular finding in acute central retinal artery occlusion. We sought to investigate the influence of technical MR imaging and clinical parameters on the detection rate of retinal diffusion restrictions on standard brain DWI. MATERIALS AND METHODS:In this retrospective cohort study, MR imaging scans of patients with central retinal artery occlusion were assessed by 2 readers for retinal diffusion restrictions on DWI performed within 2 weeks after vision loss. The influence of clinical and technical MR imaging parameters and the time interval between symptom onset and DWI on the presence of retinal diffusion restrictions were evaluated. RESULTS:One hundred twenty-seven patients (mean age, 69.6 [SD 13.9] years; 59 women) and 131 DWI scans were included. Overall, the MR imaging sensitivity of retinal diffusion restrictions in acute central retinal artery occlusion was 62.6%-67.2%. Interrater and intrarater agreement for retinal diffusion restrictions was "substantial" with k inter ¼ 0.70 (95% CI, 0.57-0.83) and k intra ¼ 0.75 (95% CI, 0.63-0.88). Detection of retinal diffusion restrictions did not differ with differences in field strengths (1.5 versus 3T, P ¼ .35) or sequence type (P ¼ .22). Retinal diffusion restrictions were consistently identified within the first week with a peak sensitivity of 79% in DWI performed within 24 hours after symptom onset. Sensitivity of retinal diffusion restrictions declined in the second week (10.0%, P , .001). Absence of retinal diffusion restrictions was more prevalent in patients without fundoscopic retinal edema (60% versus 27.1%, P ¼ .004) and with restitution of visual acuity at discharge (75% versus 28.4%, P ¼ .006).CONCLUSIONS: Retinal diffusion restrictions in acute central retinal artery occlusion can be reliably identified on DWI performed within 24 hours and 1 week after onset of visual impairment. Detectability of retinal diffusion restrictions is dependent on the clinical course of the disease.ABBREVIATIONS: CRAO ¼ central retinal artery occlusion; logMAR ¼ Logarithm of the Minimum Angle of Resolution; RDR ¼ retinal diffusion restrictions; VA ¼ visual acuity S udden and painless monocular visual impairment is the characteristic clinical feature of nonarteritic acute central retinal artery occlusion (CRAO), which is mainly caused by proximal embolism originating from the heart or atherosclerotic lesions of the aortic arch and carotid arteries. 1 Patients with CRAO develop persistent and debilitating central scotoma if the blood supply to

Hydration influences blood volume, blood viscosity, and water content in soft tissues – variables that determine the biophysical properties of biological tissues including their stiffness. In the brain, the relationship between hydration and stiffness is largely unknown despite the increasing importance of stiffness as a quantitative imaging marker. In this study, we investigated cerebral stiffness (CS) in 12 healthy volunteers using ultrasound time-harmonic elastography (THE) in different hydration states: (i) during normal hydration, (ii) after overnight fasting, and (iii) within 1 h of drinking 12 ml of water per kg body weight. In addition, we correlated shear wave speed (SWS) with urine osmolality and hematocrit. SWS at normal hydration was 1.64 ± 0.02 m/s and decreased to 1.57 ± 0.04 m/s (p < 0.001) after overnight fasting. SWS increased again to 1.63 ± 0.01 m/s within 30 min of water drinking, returning to values measured during normal hydration (p = 0.85). Urine osmolality at normal hydration (324 ± 148 mOsm/kg) increased to 784 ± 107 mOsm/kg (p < 0.001) after fasting and returned to normal (288 ± 128 mOsm/kg, p = 0.83) after water drinking. SWS and urine osmolality correlated linearly (r = −0.68, p < 0.001), while SWS and hematocrit did not correlate (p = 0.31). Our results suggest that mild dehydration in the range of diurnal fluctuations is associated with significant softening of brain tissue, possibly due to reduced cerebral perfusion. To ensure consistency of results, it is important that cerebral elastography with a standardized protocol is performed during normal hydration.