The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice. Using near-infrared fluorescence imaging, we showed that tracers quickly exited the subarachnoid space by transport through the lymphatic system to the systemic circulation in awake mice, significantly limiting their spread to the paravascular spaces of the brain. Magnetic resonance imaging and fluorescence microscopy through the skull under anesthetized conditions indicated that tracers remained confined to paravascular spaces on the surface of the brain. Immediately after death, a substantial influx of tracers occurred along paravascular spaces extending into the brain parenchyma. We conclude that under normal conditions a rapid CSF turnover through lymphatics precludes significant bulk flow into the brain.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1916-x) contains supplementary material, which is available to authorized users.

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In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.

The combination of the two complementary imaging modalities (19) F magnetic resonance imaging (MRI) and fluorescence imaging (FLI) possesses high potential for biological and medical applications. Herein we report the first design, synthesis, dual detection validation, and cytotoxic testing of four promising BODIPY dyes for dual (19) F MRI-fluorescence detection. Using straightforward Steglich reactions, small fluorinated alcohols were easily covalently tethered to a BODIPY dye in high yields, leaving its fluorescence properties unaffected. The synthesized compounds were analyzed with various techniques to demonstrate their potential utility in dual imaging. As expected, the chemically and magnetically equivalent trifluoromethyl groups of the agents exhibited a single NMR signal. The determined longitudinal relaxation times T1 and the transverse relaxation times T2 , both in the lower second range, enabled the imaging of four compounds in vitro. The most auspicious dual (19) F MRI-fluorescence agent was also successfully imaged in a mouse post-mortem within a 9.4 T small-animal tomograph. Toxicological assays with human cells (primary HUVEC and HepG2 cell line) also indicated the possibility for animal testing.

Although exercise mediates beneficial effects in patients after myocardial infarction (MI), the underlying mechanisms as well as the question of whether an early start of exercise after MI is safe or even beneficial are incompletely resolved. The present study analyzed the effects of exercise before and reinitiated early after MI on cardiac remodeling and function. Male C57BL/6N mice were housed sedentary or with the opportunity to voluntarily exercise for 6 wk before MI induction (ligation of the left anterior descending coronary artery) or sham operation. After a 5-day exercise-free phase after MI, mice were allowed to reexercise for another 4 wk. Exercise before MI induced adaptive hypertrophy with moderate increases in heart weight, cardiomyocyte diameter, and left ventricular (LV) end-diastolic volume, but without fibrosis. In sedentary mice, MI induced eccentric LV hypertrophy with massive fibrosis but maintained systolic LV function. While in exercised mice gross LV end-diastolic volumes and systolic function did not differ from sedentary mice after MI, LV collagen content and thinning of the infarcted area were reduced. This was associated with ameliorated activation of inflammation, mediated by TNF-␣, IL-1␤, and IL-6, as well as reduced activation of matrix metalloproteinase 9. In contrast, no differences in the activation patterns of various MAPKs or adenosine receptor expressions were observed 5 wk after MI in sedentary or exercised mice. In conclusion, continuous exercise training before and with an early reonset after MI ameliorates adverse LV remodeling by attenuating inflammation, fibrosis, and scar thinning. Therefore, an early reonset of exercise after MI can be encouraged. exercise; remodeling; scar thinning; magnetic resonance imaging; fibrosis; myocardial infarction NEW & NOTEWORTHY Our data provide new insights into the exercise-mediated cardioprotection by implying that an early reinitiation of exercise after myocardial infarction attenuates left ventricular fibrosis and scar thinning, presumably by attenuating the coordinated proinflammatory response involving TNF-␣, IL-6, and IL-1␤. These findings could translate into clinical benefits in patients.CORONARY ARTERY DISEASE is the single most frequent cause of death worldwide. In Europe, every sixth man and every seventh woman will die of myocardial infarction (MI) (71). Those patients who survive MI frequently develop systolic heart failure due to the infarct-induced loss of functional myocardium per se and remodeling of the remainder of the left ventricular (LV) myocardium, which is frequently associated with thinning of the LV wall in the area of MI and its border zone, LV dilation, and systolic dysfunction. These parameters of myocardial remodeling are important prognostic markers for the long-term outcome of these patients. For instance, regional wall thinning is associated with postinfarction ventricular arrhythmia (36) and adverse outcome in patients undergoing coronary artery bypass surgery (87).Scar formation occurs secondary to isc...

Decompressive craniectomy has been widely used in patients with head trauma. The randomized clinical trial on an early decompression (DECRA) demonstrated that craniectomy did not improve the neurological outcome, in contrast to previous animal experiments. The goal of our study was to analyze the effect of decompressive craniectomy in a murine model of head injury. Male mice were assigned into the following groups: sham, decompressive craniectomy, closed head injury (CHI), and CHI followed by craniectomy. At 24 h post-trauma, animals underwent the Neurological Severity Score test (NSS) and Beam Balance Score test (BBS). At the same time point, magnetic resonance imaging was performed, and volume of edema and contusion was assessed, followed by histopathological analysis. According to NSS, animals undergoing both trauma and craniectomy presented the most severe neurological impairment. Also, balancing time was reduced in this group compared with sham animals. Both edema and contusion volume were increased in the trauma and craniectomy group compared with sham animals. Histopathological analysis showed that all animals that underwent trauma presented substantial neuronal loss. In animals treated with craniectomy after trauma, a massive increase of edema with hemorrhagic transformation of contusion was documented. Decompressive craniectomy applied after closed head injury in mice leads to additional structural and functional impairment. The surgical decompression via craniectomy promotes brain edema formation and contusional blossoming in our model. This additive effect of combined mechanical and surgical trauma may explain the results of the DECRA trial and should be explored further in experiments.

Secondary lymphedema is a common complication of cancer treatment characterized by chronic limb swelling with interstitial inflammation. The rodent hindlimb is a widely used model for the evaluation of novel lymphedema treatments. However, the assessment of limb volume in small animals is challenging. Recently, high-resolution three-dimensional (3D) imaging modalities have been introduced for rodent limb volumetry. In the present study we evaluated the validity of microcomputed tomography (μCT), magnetic resonance imaging (MRI) and ultrasound in comparison to conventional measuring techniques. For this purpose, acute lymphedema was induced in the mouse hindlimb by a modified popliteal lymphadenectomy. The 4-week course of this type of lymphedema was first assessed in 6 animals. In additional 12 animals, limb volumes were analyzed by μCT, 9.4 T MRI and 30 MHz ultrasound as well as by planimetry, circumferential length and paw thickness measurements. Interobserver correlation was high for all modalities, in particular for μCT analysis (r = 0.975, p < 0.001). Importantly, caliper-measured paw thickness correlated well with μCT (r = 0.861), MRI (r = 0.821) and ultrasound (r = 0.800). Because the assessment of paw thickness represents a time- and cost-effective approach, it may be ideally suited for the quantification of rodent hindlimb lymphedema.