Regional differences in vasculotoxic effects of cyclosporin in rats

1995 ◽  
Vol 73 (11) ◽  
pp. 1661-1668 ◽  
Author(s):  
Marleen Verbeke ◽  
Leo de Ridder ◽  
Johan Van de Voorde ◽  
Norbert Lameire
Keyword(s):  
Thoracic Aorta ◽  
Abdominal Aorta ◽  
Regional Differences ◽  
Treatment Schedule ◽  
Study Protocols ◽  
Relaxation Responses ◽  
Thoracic And Abdominal ◽  
And Control

Studies on cyclosporin-induced vasculotoxicity often yielded discrepant results, possibly as a result of differences in study protocols. The aim of the present study was to analyse cyclosporin-induced vasculotoxicity in arteries of different size and origin. Therefore, rats were treated with cyclosporin, 20 mg∙kg−1∙day−1, by gastric gavage for 10 days. In our previous studies, this treatment schedule induced renal functional impairment in vivo and an impaired relaxation response of thoracic aortic rings in vitro. Relaxation of various arteries (thoracic and abdominal aorta and carotid, renal, and interlobar arteries) from cyclosporin-treated and control rats in response to endothelium-dependent and -independent vasodilators was analysed. The thoracic aorta showed diminished endothelium-dependent and -independent relaxations; in the abdominal aorta no impairment was observed. Moreover, the dysfunction of the thoracic aorta seemed to be homogeneous along its length and showed an abrupt termination at the level of the diaphragm. In all other segments studied, no impairment of the relaxation responses was found. A similar pattern of vascular damage was found in rats treated with a very toxic cyclosporin treatment (50 mg∙kg−1∙day−1 s.c. × 7 days). The results indicate regional differences in cyclosporin-induced vasculotoxicity. The thoracic aorta, and in view of the fall of the renal blood flow, most likely also the renal resistance vessels, could be more susceptible than other vessels to cyclosporin-induced vascular dysfunction.Key words: cyclosporin, rat, arteries, vasorelaxation.

Consumption of oxygen by thoracic and abdominal aorta of the rat

1963 ◽  
Vol 205 (6) ◽  
pp. 1200-1202 ◽  
Author(s):  
Robert E. Priest
Keyword(s):  
Nitrogen Content ◽  
Thoracic Aorta ◽  
Abdominal Aorta ◽  
Deoxyribonucleic Acid ◽  
Unit Weight ◽  
Liver And Kidney ◽  
The Difference ◽  
Thoracic And Abdominal ◽  
Low Nitrogen

Consumption of oxygen in vitro by thoracic and abdominal aorta and of liver and kidney of rats was measured by direct Warburg manometry and related to the weight of tissue and to the content of nitrogen and of deoxyribonucleic acid (DNA). On the basis of numbers of cells present, as determined by the content of DNA, thoracic aorta respires at a rate one-fifth that of liver. Thoracic aorta respires more actively than abdominal aorta but also contains more nitrogen and more DNA per unit weight than abdominal aorta. The difference in consumption of oxygen between these two segments of aorta can be explained largely, although not entirely, on the basis of numbers of cells present. Because of the lesser content of nitrogen and DNA in abdominal aorta, it must contain larger amounts of some substance which contributes to weight and has a low nitrogen content.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

Agitation Techniques to Enhance Drainage of Retained Hemothorax

2020 ◽  
pp. 155335062097800
Author(s):  
Ian A. Makey ◽  
Nitin A. Das ◽  
Samuel Jacob ◽  
Magdy M. El-Sayed Ahmed ◽  
Colleen M. Makey ◽  
...  
Keyword(s):  
Trauma Surgery ◽  
Control Group ◽  
In Vivo Experiments ◽  
Vibration Technique ◽  
Retained Hemothorax ◽  
And Control ◽  
Negative Conclusion ◽  
Benchtop Model

Background. Retained hemothorax (RH) is a common problem in cardiothoracic and trauma surgery. We aimed to determine the optimum agitation technique to enhance thrombus dissolution and drainage and to apply the technique to a porcine-retained hemothorax. Methods. Three agitation techniques were tested: flush irrigation, ultrasound, and vibration. We used the techniques in a benchtop model with tissue plasminogen activator (tPA) and pig hemothorax with tPA. We used the most promising technique vibration in a pig hemothorax without tPA. Statistics. We used 2-sample t tests for each comparison and Cohen d tests to calculate effect size (ES). Results. In the benchtop model, mean drainages in the agitation group and control group and the ES were flush irrigation, 42%, 28%, and 2.91 ( P = .10); ultrasound, 35%, 27%, and .76 ( P = .30); and vibration, 28%, 19%, and 1.14 ( P = .04). In the pig hemothorax with tPA, mean drainages and the ES of each agitation technique compared with control (58%) were flush irrigation, 80% and 1.14 ( P = .37); ultrasound, 80% and 2.11 ( P = .17); and vibration, 95% and 3.98 ( P = .06). In the pig hemothorax model without tPA, mean drainages of the vibration technique and control group were 50% and 43% (ES = .29; P = .65). Discussion. In vitro studies suggested flush irrigation had the greatest effect, whereas only vibration was significantly different vs the respective controls. In vivo with tPA, vibration showed promising but not statistically significant results. Results of in vivo experiments without tPA were negative. Conclusion. Agitation techniques, in combination with tPA, may enhance drainage of hemothorax.

scholarly journals Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 884
Author(s):  
Marta Cherubini ◽  
Scott Erickson ◽  
Kristina Haase
Keyword(s):  
Drug Testing ◽  
Cell Types ◽  
In Vitro Models ◽  
Placental Development ◽  
Scientific Challenge ◽  
Induced Pluripotent ◽  
And Function ◽  
And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

scholarly journals Proanthocyanidins against Oxidative Stress: From Molecular Mechanisms to Clinical Applications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Lingyu Yang ◽  
Dehai Xian ◽  
Xia Xiong ◽  
Rui Lai ◽  
Jing Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Cost ◽  
Natural Agents ◽  
Molecular Damage ◽  
And Control

Proanthocyanidins (PCs) are naturally occurring polyphenolic compounds abundant in many vegetables, plant skins (rind/bark), seeds, flowers, fruits, and nuts. Numerousin vitroandin vivostudies have demonstrated myriad effects potentially beneficial to human health, such as antioxidation, anti-inflammation, immunomodulation, DNA repair, and antitumor activity. Accumulation of prooxidants such as reactive oxygen species (ROS) exceeding cellular antioxidant capacity results in oxidative stress (OS), which can damage macromolecules (DNA, lipids, and proteins), organelles (membranes and mitochondria), and whole tissues. OS is implicated in the pathogenesis and exacerbation of many cardiovascular, neurodegenerative, dermatological, and metabolic diseases, both through direct molecular damage and secondary activation of stress-associated signaling pathways. PCs are promising natural agents to safely prevent acute damage and control chronic diseases at relatively low cost. In this review, we summarize the molecules and signaling pathways involved in OS and the corresponding therapeutic mechanisms of PCs.

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

Increased Renal Sensitivity to Aldosterone in the Potassium-Loaded Rat

1976 ◽  
Vol 51 (s3) ◽  
pp. 315s-317s
Author(s):  
W. R. Adam ◽  
J. W. Funder
Keyword(s):  
Sodium Intake ◽  
Control Diet ◽  
High Potassium ◽  
High Sodium ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
High K ◽  
And Control

1. The renal response to aldosterone (urinary sodium and potassium excretion) was determined in adrenalectomized rats previously fed either a high potassium diet or a control diet. High K+ rats showed an enhanced response to aldosterone at all doses tested. 2. This enhanced response to aldosterone required the presence of the adrenal glands during the induction period, could be suppressed by a high sodium intake, but could not be induced by a low sodium diet. 3. No difference between high K+ and control rats could be detected in renal mineralocorticoid receptors, assessed by both in vivo and in vitro binding of tritiated aldosterone. 4. The method of the induction, and the mechanism of the enhanced response, remain to be defined.

Abstract 518: In Vitro and in vivo Disease Modeling Using Patient Derived iPSCs to Characterize the Calcification Phenotype in Arterial Calcification Due to Deficiency of CD73

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Cynthia St. Hilaire ◽  
Hui Jin ◽  
Yuting Huang ◽  
Dan Yang ◽  
Alejandra Negro ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Dermal Fibroblasts ◽  
In Vivo Studies ◽  
Arterial Calcification ◽  
Patient Specific ◽  
And Control

Objective: The objective of this study was to develop a patient-specific induced pluripotent stem cell (iPSC)-based disease model to understand the process by which CD73-deficiency leads to vascular calcification in the disease, Arterial Calcification due to Deficiency of CD73 (ACDC). Approach & Results: ACDC is an autosomal recessive disease resulting from mutations in the gene encoding for CD73, which converts extracellular AMP to adenosine. CD73-deficiency manifests with tortuosity and vascular calcification of the medial layer of lower-extremity arteries, a pathology associated with diabetes and chronic kidney disease. We previously identified that dermal fibroblasts isolated from ACDC patients calcify in vitro, however in vivo studies of the vasculature are limited, as murine models of CD73 deficiency do not recapitulate the human disease phenotype. Thus, we created iPSCs from ACDC patients and control fibroblasts. ACDC and Control iPSCs form teratomas when injected in immune-compromised mice, however ACDC iPSC teratomas exhibit extensive calcifications. Control and ACDC iPSCs were differentiated down the mesenchymal lineage (MSC) and while there was no difference in chondrogenesis and adipogenesis, ACDC iMSCs underwent osteogenesis sooner than control iPSC, have higher activity of tissue-nonspecific alkaline phosphatase (TNAP), and lower levels of extracellular adenosine. During osteogenic simulation, TNAP activity in ACDC cells significantly increased adenosine levels, however, not to levels needed for functional compensatory stimulation of the adenosine receptors. Inhibition of TNAP with levimisole ablates this increase in adenosine. Treatment with an A2b adenosine receptor (AR) agonist drastically reduced TNAP activity in vitro, and calcification in ACDC teratomas, as did treatment with etidronate, which is currently being tested in a clinical trial on ACDC patients. Conclusions: These results illustrate a pro-osteogenic phenotype in CD73-deficient cells whereby TNAP activity attempts to compensate for CD73 deficiency, but subsequently induces calcification that can be reversed by activation of the A2bAR. The iPSC teratoma model may be used to screen other potential therapeutics for calcification disorders.

Protein synthesis is required for rapid degradation of tubulin mRNA and other deflagellation-induced RNAs in Chlamydomonas reinhardi

1986 ◽  
Vol 6 (1) ◽  
pp. 54-61
Author(s):  
E J Baker ◽  
L R Keller ◽  
J A Schloss ◽  
J L Rosenbaum
Keyword(s):  
Protein Synthesis ◽  
Transcriptional Control ◽  
Protein S ◽  
Protein Synthesis Inhibitors ◽  
Control Factors ◽  
Flagellar Proteins ◽  
The Stability ◽  
And Control

After flagellar detachment in Chlamydomonas reinhardi, there is a rapid synthesis and accumulation of mRNAs for tubulin and other flagellar proteins. Maximum levels of these mRNAs (flagellar RNAs) are reached within 1 h after deflagellation, after which they are rapidly degraded to their predeflagellation levels. The degradation of alpha- and beta-tubulin RNAs was shown to be due to the shortening of their half-lives after accumulation (Baker et al., J. Cell Biol. 99:2074-2081, 1984). Deflagellation in the presence of protein synthesis inhibitors results in the accumulation of tubulin and other flagellar mRNAs by kinetics similar to those of controls. However, unlike controls, in which the accumulated mRNAs are rapidly degraded, these mRNAs are stabilized in cycloheximide. The stabilization by cycloheximide is specific for the flagellar mRNAs accumulated after deflagellation, since there is no change in the levels of flagellar mRNAs in nondeflagellated (uninduced) cells in the presence of cycloheximide. The kinetics of flagellar mRNA synthesis after deflagellation are shown to be the same in cycloheximide-treated and control cells by in vivo labeling and in vitro nuclear runoff experiments. These results show that protein synthesis is not required for the induced synthesis of flagellar mRNAs, and that all necessary transcriptional control factors are present in the cell before deflagellation, but that protein synthesis is required for the accelerated degradation of the accumulated flagellar mRNAs. Since cycloheximide prevents the induced synthesis and accumulation of flagellar proteins, it is possible that the product(s) of protein synthesis required for the accelerated decay of these mRNAs is a flagellar protein(s). The possibility that one or more flagellar proteins autoregulate the stability of the flagellar mRNAs is discussed.

scholarly journals In Vivo Quantification of Regional Circumferential Green Strain in the Thoracic and Abdominal Aorta by Two-Dimensional Spiral Cine DENSE MRI

2019 ◽  
Vol 141 (6) ◽  
Author(s):  
John S. Wilson ◽  
Xiaodong Zhong ◽  
Jackson Hair ◽  
W. Robert Taylor ◽  
John N. Oshinski
Keyword(s):  
Abdominal Aorta ◽  
Aortic Wall ◽  
Patient Specific ◽  
Peak Strain ◽  
Ssfp Cine ◽  
Green Strain ◽  
The Mean ◽  
Thoracic And Abdominal ◽  
Cine Dense

Regional tissue mechanics play a fundamental role in the patient-specific function and remodeling of the cardiovascular system. Nevertheless, regional in vivo assessments of aortic kinematics remain lacking due to the challenge of imaging the thin aortic wall. Herein, we present a novel application of displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) to quantify the regional displacement and circumferential Green strain of the thoracic and abdominal aorta. Two-dimensional (2D) spiral cine DENSE and steady-state free procession (SSFP) cine images were acquired at 3T at either the infrarenal abdominal aorta (IAA), descending thoracic aorta (DTA), or distal aortic arch (DAA) in a pilot study of six healthy volunteers (22–59 y.o., 4 females). DENSE data were processed with multiple custom noise reduction techniques including time-smoothing, displacement vector smoothing, sectorized spatial smoothing, and reference point averaging to calculate circumferential Green strain across 16 equispaced sectors around the aorta. Each volunteer was scanned twice to evaluate interstudy repeatability. Circumferential Green strain was heterogeneously distributed in all volunteers and locations. The mean spatial heterogeneity index (standard deviation of all sector values divided by the mean strain) was 0.37 in the IAA, 0.28 in the DTA, and 0.59 in the DAA. Mean (homogenized) peak strain by DENSE for each cross section was consistent with the homogenized linearized strain estimated from SSFP cine. The mean difference in peak strain across all sectors following repeat imaging was −0.1±2.3%, with a mean absolute difference of 1.7%. Aortic cine DENSE MRI is a viable noninvasive technique for quantifying heterogeneous regional aortic wall strain and has significant potential to improve patient-specific clinical assessments of numerous aortopathies, as well as to provide the lacking spatiotemporal data required to refine patient-specific computational models of aortic growth and remodeling.

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