Rationale:The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone.Objective: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels. Methods and Results:Catestatin induced migration, proliferation, and antiapoptosis in endothelial cells and exerted capillary tube formation in vitro in a Matrigel assay, and such effects were mediated via G protein, mitogen-activated protein kinase, and Akt. Catestatin-induced endothelial cell functions are further mediated by basic fibroblast growth factor, as shown by blockade of effects by a neutralizing fibroblast growth factor antibody. Furthermore, catestatin released basic fibroblast growth factor from endothelial cells and stimulated fibroblast growth factor signaling. In addition to its function on endothelial cells, catestatin also exerted effects on endothelial progenitor cells and vascular smooth muscle cells. In vivo, catestatin induced angiogenesis in the mouse cornea neovascularization assay and increased blood perfusion and number of capillaries in the hindlimb ischemia model. In addition to angiogenesis, catestatin increased density of arterioles/arteries and incorporation of endothelial progenitor cells in the hindlimb ischemia model, indicating induction of arteriogenesis and postnatal vasculogenesis. Conclusion:We conclude that catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. (Circ Res. 2010;107:1326-1335.) Key Words: angiogenesis Ⅲ blood vessels Ⅲ endothelium Ⅲ endothelial progenitor cells C hromogranin (Cg)A, the index member of the chromogranin/secretogranin protein family, is the major soluble protein of catecholamine storage vesicles of sympathetic nerve terminals and the adrenal medulla. 1,2 CgA is a proprotein giving rise to biological active peptides like the dysglycemic hormone pancreastatin, 3 the vasodilator vasostatin, 4 and catestatin 5 (CST) ), which inhibits catecholamine release by acting as a nicotinic cholinergic antagonist, resulting in a negative-feedback mechanism. Although plasma CgA is high in human essential (hereditary) hypertension, the plasma concentration of CST is lower in both established cases and in normotensive subjects with a family history of the disease, 6 suggesting a mechanism whereby diminished CST might increase the risk for later development of hypertension. Consistent with the human findings, high blood pressure has been reported in mice after targeted ablation of the Chga gene (Chga knockout), and such high blood pressure can be "rescued" either by replacement with CST or introduction of the human ortholog in the Chga knockout background. 7 Angiogenesis, the growth of new vessels from the preexisting vasculature, is an important process in many physiological conditions including embryonic development and wound healing. However, defects in the regula- Original received February 25, 2010; revision received September 27, 2010;...

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Key Words: angiogenesis Ⅲ endothelium Ⅲ gene therapy Ⅲ hypoxia Ⅲ peripheral vascular disease C ardiovascular diseases represent the leading cause of death worldwide. 1 In the case of peripheral arterial disease, a substantial number of patients who develop critical limb ischemia are not eligible for surgical or interventional revascularization and, despite optimal medical therapy, have reduced quality of life and life expectancy. 2,3 This group of patients would require new therapeutic methods to increase collateral blood flow to areas of decreased tissue perfusion distal to arterial occlusion.Angiogenesis, the growth of new blood vessels from the preexisting vasculature, plays an important role in wound healing, tumor growth, diabetic retinopathy, tissue ischemia, and inflammatory diseases. 4 Cytokines mediating this process include vascular endothelial growth factor (VEGF) 5 and basic fibroblast growth factor (b-FGF). 6 For stability of newly formed vessels, recruitment of pericytes and smooth muscle cells (SMCs) is important; such recruitment is known as arteriogenesis, which is mediated by cytokines such as monocyte chemoattractant protein-1 and platelet-derived growth factor (PDGF)-BB. 7,8 Postnatal vasculogenesis, which is the mobilization and incorporation of bone marrow-derived endothelial progenitor cells (EPCs), also plays an important role in the growth of new vessels. 9 Recently, application of endothelial cytokines as proteins or genes has been of scientific and clinical interest to treat limb or myocardial ischemia, a procedure called therapeutic angiogenesis. 10 -14 We recently demonstrated that the neuropeptide secretoneurin (SN) induces angiogenesis and postnatal vasculogen- MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Construction of the Human SN Expression PlasmidSynthetic oligonucleotides encoding SN and a signal peptide were cloned into the expression vector pAAV-MCS (Stratagene). The plasmid vector is described in the Online Data Supplement. Animals, Mouse Hindlimb Ischemia Model, SN Gene Therapy, and Bone Marrow Transplantation ModelMice at ages between 12 and 18 months were subjected to unilateral hindlimb surgery and injected with plasmid DNA expressing SN or green fluorescent protein (GFP) into thigh and calf muscles immediately after surgery.Bone marrow transplantation was performed as described. 19 After hindlimb ischemia, injection of SN plasmid or saline was performed. Blood Flow Measurement and In Vivo Assessment of Limb Function and Ischemic DamageBlood flow measurements were performed using a laser-Doppler perfusion imaging (LDPI) analyzer. Blood perfusion is expressed as LDPI index representing the ratio of left (ie, operated, ischemic leg) versus right (ie, unoperated, not-ischemic leg) limb blood flow. Movement score and analysis of necrosis are described in the Online Data Supplement. Immunofluorescence and Fluorescence-Activated Cell Sorting AnalysisECs were stained for CD31, and arteries/arteriole...

Aimof this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma.Patients and methodsA total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17). Ninety-one patients received various systemic treatments prior to irradiation. Following an initial screening visit post-RT, two additional visits after 12 and 25 weeks were conducted including radiographic examination. In addition, general anamnesis and the co-medication were recorded. The endpoint was reached as soon as a pneumonitis was developed or at maximum of six months post-treatment.ResultsA pneumonitis incidence of 13% was determined. Of 91 patients with prior systemic therapy, 11 patients developed pneumonitis. Smoking history and chronic obstructive pulmonary disease (COPD) appeared to be positive predictors, whereas past pneumonia clearly promoted pneumonitis. Further pneumonitis-promoting predictors are represented by the applied field extensions (2 field radiotherapy [2FRT] < 3 field radiotherapy [3FRT] < 4 field radiotherapy [4FRT]) and the type of combined initial systemic therapies. As a consequence, all of the three patients in the study cohort treated with 4FRT and initial chemotherapy combined with anti-hormone and antibody protocols developed pneumonitis. A combination of the hormone antagonists tamoxifen and goserelin might enhance the risk for pneumonitis. Remarkably, none of the 11 patients co-medicated with statins suffered from pneumonitis.ConclusionsThe rapidly increasing use of novel systemic therapy schedules combined with radiotherapy (RT) needs more prospective studies with larger cohorts. Our results indicate that contribution to pneumonitis occurrence of various (neo)adjuvant therapy approaches followed by RT is of minor relevance, whereas mean total lung doses of >10 Gy escalate the risk of lung tissue complications. The validity of potential inhibitors of therapy-induced pneumonitis as observed for statin co-medication should further be investigated in future trials.

BackgroundThe present study investigates the intrafractional accuracy of a frameless thermoplastic mask used for head immobilization during stereotactic radiotherapy. Non-invasive masks cannot completely prohibit head movements. Previous studies attempted to estimate the magnitude of intrafractional inaccuracy by means of pre- and postfractional measurements only. However, this might not be sufficient to accurately map also intrafractional head movements.Materials and methodsIntrafractional deviation of mask-fixed head positions was measured in five patients during a total of 94 fractions by means of close-meshed repeated ExacTrac measurements (every 1.4 min) conducted during the entire treatment session. A median of six (range: 4 to 11) measurements were recorded per fraction, delivering a dataset of 453 measurements.ResultsRandom errors (SD) for the x, y and z axes were 0.27 mm, 0.29 mm and 0.29 mm, respectively. Median 3D deviation was 0.29 mm. Of all 3D intrafractional motions, 5.5 and 0.4% exceeded 1 mm and 2 mm, respectively. A moderate correlation between treatment duration and mean 3D displacement was determined (rs = 0.45). Mean 3D deviation increased from 0.21 mm (SD = 0.26 mm) in the first 2 min to a maximum of 0.53 mm (SD = 0.31 mm) after 10 min of treatment time.ConclusionPre- and post-treatment measurement is not sufficient to adequately determine the range of intrafractional head motion. Thermoplastic masks provide both reliable interfractional and intrafractional immobilization for image-guided stereotactic hypofractionated radiotherapy. Greater positioning accuracy may be obtained by reducing treatment duration (< 6 min) and applying intrafractional correction.Trial registrationClinicaltrials.gov, NCT03896555, Registered 01 April 2019 - retrospectively registered.

The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

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The aetiology of neuronal death in neurodegenerative diseases, including Huntington's disease, is still unknown. There could be a complex interplay among altered energy metabolism, excitotoxicity and oxidative stress. Our aim was to examine the effects of intrastriatal injection of a selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, and a non-specific potent nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester, in order to study the possible involvement of glutathione, an important antioxidant, in quinolinic acid-induced striatal toxicity in the rat. Unilateral administration of quinolinic acid to rat striatum in a single dose of 150 nmol/L was used as a model of Huntington's disease. The other group of animals were pretreated with 7nitroindazole and Nw-nitro-L-arginine methyl ester, respectively. Control groups were treated with saline solution and olive oil, respectively. Content of total glutathione, was increased in the ipsi-and contralateral striatum, forebrain cortex, basal forebrain and hippocampus in the groups treated with nitric oxid synthase inhibitors and quinolinic acid compared to the quinolinic acid-treated animals. These results support the hypothesis that oxygen free radicals contribute to excitotoxic neuronal injury, and also that nitric oxide synthase inhibitors could be potential neuroprotective agents in Huntington's disease.