High salt diet impairs cerebral blood flow regulation via salt‐induced angiotensin II suppression

ObjectivesThis study sought to determine whether salt‐induced ANG II suppression contributes to impaired CBF autoregulation.MethodsCerebral autoregulation was evaluated with LDF during graded reductions of blood pressure. Autoregulatory responses in rats fed HS (4% NaCl) diet vs LS (0.4% NaCl) diet were analyzed using linear regression analysis, model‐free analysis, and a mechanistic theoretical model of blood flow through cerebral arterioles.ResultsAutoregulation was intact in LS‐fed animals as MAP was reduced via graded hemorrhage to approximately 50 mm Hg. Short‐term (3 days) and chronic (4 weeks) HS diet impaired CBF autoregulation, as evidenced by progressive reductions of laser Doppler flux with arterial pressure reduction. Chronic low dose ANG II infusion (5 mg/kg/min, i.v.) restored CBF autoregulation between the pre‐hemorrhage MAP and 50 mm Hg in rats fed short‐term HS diet. Mechanistic‐based model analysis showed a reduced myogenic response and reduced baseline VSM tone with short‐term HS diet, which was restored by ANG II infusion.ConclusionsShort‐term and chronic HS diet lead to impaired autoregulation in the cerebral circulation, with salt‐induced ANG II suppression as a major factor in the initiation of impaired CBF regulation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/1/micc12518_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/2/micc12518.pd

Differences in Vascular Reactivity Between Men and Women

The purpose of this study was to compare the gender and age-related differences in vascular reactivity in healthy men and women across a wide age range. Fifty-seven men and 61 women between 20 and 89 years of age, free of cardiovascular disease and risk factors, were categorized into younger (20-39 years), middle-aged (40-59 years), and older (60-89 years) age groups. Subjects were characterized on body weight and height, body mass index (BMI), and calf blood flow under resting, postocclusive reactive hyperemic (PORH), and maximal hyperemic conditions in the lower extremity with use of venous occlusion mercury strain-gauge plethysmography. Similar baseline characteristics were observed among age groups, whereas men had greater body weight (p0.05). Furthermore, the percentage change in calf blood flow from rest to PORH was negatively related to body weight (r = -0.30, p0.05) in the calf blood flow measures were observed among the age groups. In a healthy cohort free of cardiovascular disease, increased BMI accounted for poorer vascular reactivity in men compared to women regardless of age.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of the intravitreal (IVT) injection of Triamcinolone Acetonide (TA) as compared to posterior subtenon (SBT) capsule injection for the treatment of cystoid diabetic macular edema.</p> <p>Methods</p> <p>Fourteen patients with type II diabetes mellitus and on insulin treatment, presenting diffuse cystoid macular edema were recruited. Before TA injection all focal lakes were treated by laser photocoagulation. In the same patients one eye was assigned to 4 mg IVT injection of TA and the fellow eye was then treated with 40 mg SBT injection of TA. Before and one, three and six months after treatment we measured visual acuity with ETDRS chart as well as thickness of the macula with optical coherence tomography (OCT) and intraocular pressure (IOP).</p> <p>Results</p> <p>The eyes treated with an IVT injection displayed significant improvement in visual acuity, both after one (0.491 ± 0.070; p < 0.001) and three months (0.500 ± 0.089; p < 0.001) of treatment. Significant improvement was displayed also in eyes treated with an SBT injection, again after one (0.455 ± 0.069; p < 0.001) and three months (0.427 ± 0.065; p < 0.001). The difference between an IVT injection (0.809 ± 0.083) and SBT injection (0.460 ± 0.072) becomes significant six months after the treatment (p < 0.001).</p> <p>Macular thickness of the eyes treated with IVT injection was significantly reduced both after one (222.7 ± 13.4 μm; p < 0.001) and after three months (228.1 ± 10.6 μm; p < 0.001) of treatment. The eyes treated with SBT injection displayed significant improvement after one (220.1 ± 15.1 μm; p < 0.001) and after three months (231.3 ± 10.9 μm; p < 0.001). The difference between the eyes treated with IVT injection (385.2 ± 11.3 μm) and those treated with SBT injection (235.4 ± 8.7 μm) becomes significant six months after the treatment (p < 0.001).</p> <p>Intraocular pressure of the eyes treated with IVT injection significantly increased after one month (17.7 ± 1.1 mm/Hg; p < 0.020), three (18.2 ± 1.2 mm/Hg; p < 0.003) and six month (18.1 ± 1.3 mm/Hg; p < 0.007) when compared to baseline value (16.1 ± 1.402 mm/Hg). In the SBT injection eyes we didn't display a significant increase of intraocular pressure after one (16.4 ± 1.2 mm/Hg; p < 0.450), three (16.3 ± 1.1 mm/Hg; p < 0.630) and six months (16.2 ± 1.1 mm/Hg; p < 0.720) when compared to baseline value (16.2 ± 1.3 mm/Hg).</p> <p>Conclusion</p> <p>The parabulbar subtenon approach can be considered a valid alternative to the intravitreal injection.</p> <p>Trial registration</p> <p>Current Controlled Trials <b>ISRCTN67086909</b></p

Neuroprotective Effect of Inhaled Nitric Oxide on Excitotoxic-Induced Brain Damage in Neonatal Rat

BACKGROUND: Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates. However, little information is known about its impact on the developing brain submitted to excitotoxic challenge. METHODOLOGY/PRINCIPAL FINDINGS: We investigated here the effect of iNO in a neonatal model of excitotoxic brain lesions. Rat pups and their dams were placed in a chamber containing 20 ppm NO during the first week of life. At postnatal day (P)5, rat pups were submitted to intracranial injection of glutamate agonists. At P10, rat pups exposed to iNO exhibited a significant decrease of lesion size in both the white matter and cortical plate compared to controls. Microglia activation and astrogliosis were found significantly decreased in NO-exposed animals. This neuroprotective effect was associated with a significant decrease of several glutamate receptor subunits expression at P5. iNO was associated with an early (P1) downregulation of pCREB/pAkt expression and induced an increase in pAkt protein concentration in response to excitotoxic challenge (P7). CONCLUSION: This study is the first describe and investigate the neuroprotective effect of iNO in neonatal excitotoxic-induced brain damage. This effect may be mediated through CREB pathway and subsequent modulation of glutamate receptor subunits expression

In vivo fluorescence imaging of the transport of charged chlorine6 conjugates in a rat orthotopic prostate tumour

Polymeric drug conjugates are used in cancer therapy and, varying their molecular size and charge, will affect their in vivo transport and extravasation in tumours. Partitioning between tumour vasculature and tumour tissue will be of particular significance in the case of photosensitizer conjugates used in photodynamic therapy, where this partitioning can lead to different therapeutic effects. Poly-l-lysine chlorine6 conjugates (derived from polymers of averageMr 5000 and 25 000) were prepared both in a cationic state and by poly-succinylation in an anionic state. A fluorescence scanning laser microscope was used to follow the pharmacokinetics of these conjugates in vivo in an orthotopic rat prostate cancer model obtained with MatLyLu cells. Fluorescence was excited with the 454–528 nm group of lines of an argon laser and a 570 nm long pass filter used to isolate the emission. Results showed that the conjugates initially bound to the walls of the vasculature, before extravasating into the tissue, and eventually increasing in fluorescence. The anionic conjugates produced tissue fluorescence faster than the cationic ones, and surprisingly, the largerMr conjugates produced tissue fluorescence faster than the smaller ones with the same charge. These results are consistent with differences in aggregation state between conjugates. © 1999 Cancer Research Campaig

Advancing brain barriers RNA sequencing: guidelines from experimental design to publication

Background: RNA sequencing (RNA-Seq) in its varied forms has become an indispensable tool for analyzing differential gene expression and thus characterization of specific tissues. Aiming to understand the brain barriers genetic signature, RNA seq has also been introduced in brain barriers research. This has led to availability of both, bulk and single-cell RNA-Seq datasets over the last few years. If appropriately performed, the RNA-Seq studies provide powerful datasets that allow for significant deepening of knowledge on the molecular mechanisms that establish the brain barriers. However, RNA-Seq studies comprise complex workflows that require to consider many options and variables before, during and after the proper sequencing process.Main body: In the current manuscript, we build on the interdisciplinary experience of the European PhD Training Network BtRAIN (https://www.btrain-2020.eu/) where bioinformaticians and brain barriers researchers collaborated to analyze and establish RNA-Seq datasets on vertebrate brain barriers. The obstacles BtRAIN has identified in this process have been integrated into the present manuscript. It provides guidelines along the entire workflow of brain barriers RNA-Seq studies starting from the overall experimental design to interpretation of results. Focusing on the vertebrate endothelial blood–brain barrier (BBB) and epithelial blood-cerebrospinal-fluid barrier (BCSFB) of the choroid plexus, we provide a step-by-step description of the workflow, highlighting the decisions to be made at each step of the workflow and explaining the strengths and weaknesses of individual choices made. Finally, we propose recommendations for accurate data interpretation and on the information to be included into a publication to ensure appropriate accessibility of the data and reproducibility of the observations by the scientific community.Conclusion: Next generation transcriptomic profiling of the brain barriers provides a novel resource for understanding the development, function and pathology of these barrier cells, which is essential for understanding CNS homeostasis and disease. Continuous advancement and sophistication of RNA-Seq will require interdisciplinary approaches between brain barrier researchers and bioinformaticians as successfully performed in BtRAIN. The present guidelines are built on the BtRAIN interdisciplinary experience and aim to facilitate collaboration of brain barriers researchers with bioinformaticians to advance RNA-Seq study design in the brain barriers community

Aging-Induced Collateral Dysfunction: Impaired Responsiveness of Collaterals and Susceptibility to Apoptosis via Dysfunctional eNOS signaling

Despite positive animal studies, clinical angiogenesis trials have been disappointing, possibly due to risk factors present in humans but usually unexplored in animals. We recently demonstrated aging causes impaired collateral remodeling and collateral dropout; here, we investigate potential mechanisms responsible for these findings. Four-, 10-, and 18-month-C57BL/6J mice were subjected to femoral artery ligation; flow was measured using laser Doppler perfusion imaging. Endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS were measured in calf muscle. Apoptosis was assessed in endothelial (EC) and smooth muscle (SMC) cells isolated from young and old mice. Angiogenesis was measured using a Matrigel plug assay. Lethally irradiated young and old mice received bone marrow cells (BMC) from either young or old donors and were subjected to femoral artery ligation (FAL). BMC mobilization and homing were assessed. Flow recovery was impaired and less eNOS and phosphorylated eNOS was present in older vs. young mice (pp=0.015, respectively). ECs and SMCs from older mice were more sensitive to an apoptotic stimulus, but were rescued by NO-enhancing drugs. In older mice, angiogenesis (Matrigel plug assay) was impaired, as was mobilization and homing of BM progenitor cells following FAL. Although both mobilization and homing improved when older mice received BMC transplantation from young donors, flow recovery failed to improve. Aging impairs BMC mobilization and homing, collateral responsiveness to angiogenic stimuli, and increases EC and SMC susceptibility to apoptosis via dysfunctional eNOS signaling. The latter could contribute to impaired remodeling and collateral dropout. These finding identify potential obstacles to therapeutic interventions in elderly patients