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  1. Article: Mapping of the functional microcirculation in vital organs using contrast-enhanced in vivo video microscopy.

    Varghese, Hemanth J / MacKenzie, Lisa T / Groom, Alan C / Ellis, Christopher G / Chambers, Ann F / MacDonald, Ian C

    American journal of physiology. Heart and circulatory physiology

    2004  Volume 288, Issue 1, Page(s) H185–93

    Abstract: A functional microcirculation is vital to the survival of mammalian tissues. In vivo video microscopy is often used in animal models to assess microvascular function, providing real-time observation of blood flow in normal and diseased tissues. To extend ...

    Abstract A functional microcirculation is vital to the survival of mammalian tissues. In vivo video microscopy is often used in animal models to assess microvascular function, providing real-time observation of blood flow in normal and diseased tissues. To extend the capabilities of in vivo video microscopy, we have developed a contrast-enhanced system with postprocessing video analysis tools that permit quantitative assessment of microvascular geometry and function in vital organs and tissues. FITC-labeled dextran (250 kDa) was injected intravenously into anesthetized mice to provide intravascular fluorescence contrast with darker red blood cell (RBC) motion. Digitized video images of microcirculation in a variety of internal organs (e.g., lung, liver, ovary, and kidney) were processed using computer-based motion correction to remove background respiratory and cardiac movement. Stabilized videos were analyzed to generate a series of functional images revealing microhemodynamic parameters, such as plasma perfusion, RBC perfusion, and RBC supply rate. Fluorescence contrast revealed characteristic microvascular arrangements within different organs, and images generated from video sequences of liver metastases showed a marked reduction in the proportion of tumor vessels that were functional. Analysis of processed video sequences showed large reductions in vessel volume, length, and branch-point density, with a near doubling in vessel segment length. This study demonstrates that postprocessing of fluorescence contrast video sequences of the microcirculation can provide quantitative images useful for studies in a wide range of model systems.
    MeSH term(s) Animals ; Blood Flow Velocity ; Contrast Media ; Dextrans ; Erythrocytes ; Female ; Fluorescein-5-isothiocyanate/analogs & derivatives ; Image Enhancement ; Image Processing, Computer-Assisted ; Liver Circulation ; Liver Neoplasms/blood supply ; Liver Neoplasms/secondary ; Mice ; Mice, Inbred Strains ; Microcirculation ; Microscopy, Fluorescence ; Microscopy, Video ; Ovary/blood supply ; Pulmonary Circulation ; Renal Circulation
    Chemical Substances Contrast Media ; Dextrans ; fluorescein isothiocyanate dextran ; Fluorescein-5-isothiocyanate (I223NX31W9)
    Language English
    Publishing date 2004-09-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603838-4
    ISSN 1522-1539 ; 0363-6135
    ISSN (online) 1522-1539
    ISSN 0363-6135
    DOI 10.1152/ajpheart.01022.2003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model.

    Varghese, Hemanth J / Mackenzie, Lisa T / Groom, Alan C / Ellis, Christopher G / Ryan, Anderson / MacDonald, Ian C / Chambers, Ann F

    Angiogenesis

    2004  Volume 7, Issue 2, Page(s) 157–164

    Abstract: Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on ... ...

    Abstract Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of approximately 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.
    MeSH term(s) Angiogenesis Inhibitors/administration & dosage ; Angiogenesis Inhibitors/pharmacology ; Animals ; Apoptosis/drug effects ; Blood Vessels/drug effects ; Blood Vessels/pathology ; Cell Line, Transformed ; Disease Models, Animal ; Female ; Liver Neoplasms/blood supply ; Liver Neoplasms/drug therapy ; Liver Neoplasms/secondary ; Mice ; Mice, SCID ; Microscopy, Video ; Neoplasm Metastasis/drug therapy ; Neoplasm Transplantation ; Neovascularization, Pathologic/drug therapy ; Organophosphorus Compounds/administration & dosage ; Organophosphorus Compounds/pharmacology ; Piperidines/administration & dosage ; Piperidines/pharmacology ; Quinazolines/administration & dosage ; Quinazolines/pharmacology
    Chemical Substances Angiogenesis Inhibitors ; N-acetylcochinol-O-phosphate ; Organophosphorus Compounds ; Piperidines ; Quinazolines ; vandetanib (YO460OQ37K)
    Language English
    Publishing date 2004-06-01
    Publishing country Germany
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1484717-6
    ISSN 0969-6970
    ISSN 0969-6970
    DOI 10.1007/s10456-004-1941-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article: Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases.

    Varghese, Hemanth J / Davidson, Melanie T M / MacDonald, Ian C / Wilson, Sylvia M / Nadkarni, Kishore V / Groom, Alan C / Chambers, Ann F

    Cancer research

    2002  Volume 62, Issue 3, Page(s) 887–891

    Abstract: Mutant, activated ras oncogenes are found in many human cancers. Experimental studies have shown that Ras enhances metastatic ability in several cell types. However, the biological mechanisms by which Ras contributes to metastasis remain poorly ... ...

    Abstract Mutant, activated ras oncogenes are found in many human cancers. Experimental studies have shown that Ras enhances metastatic ability in several cell types. However, the biological mechanisms by which Ras contributes to metastasis remain poorly understood. Our goal was to determine which steps in the formation of macroscopic metastases were affected by Ras. Green fluorescent protein-transfected NIH 3T3 and T24 H-ras-transformed (PAP2) fibroblasts were injected via mesenteric vein to target mouse liver. The proportion of cells that survived at each step of the metastatic process (at 60 min to 14 days after injection) were quantified. We found that Ras did not enhance the ability of cells to extravasate from liver sinusoids or to survive as solitary undivided cells in liver tissue. Furthermore, we found that a subset of cells from both cell lines initiated growth to form micrometastases by day 3. Only micrometastases formed by ras-transformed cells, however, persisted to form macroscopic metastases by day 14, whereas most NIH 3T3 micrometastases disappeared. We investigated this difference in maintenance of developing metastases by quantifying apoptosis and proliferation within the micrometastases. PAP2 metastases had a significantly higher proportion of proliferating cells as compared with apoptosing cells, whereas NIH 3T3 metastases had low proliferation and high apoptosis levels. Whereas the ability of Ras to induce vascular endothelial growth factor has suggested one way that Ras might affect metastatic ability (through induction of angiogenesis), our study provides in vivo evidence for a direct role for Ras in maintenance of metastatic growth via a shift in proliferation/apoptosis balance to favor metastatic growth.
    MeSH term(s) 3T3 Cells ; Animals ; Apoptosis/physiology ; Cell Division/physiology ; Cell Line, Transformed ; Cell Transformation, Neoplastic/pathology ; Gene Expression Regulation, Neoplastic ; Genes, ras/genetics ; Mice ; Mice, SCID ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/pathology ; ras Proteins/biosynthesis ; ras Proteins/genetics ; ras Proteins/physiology
    Chemical Substances ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2002-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Clinical Profile and Predictors of Mortality of Severe Pandemic (H1N1) 2009 Virus Infection Needing Intensive Care: A Multi-Centre Prospective Study from South India.

    Ramakrishna, Kartik / Sampath, Sriram / Chacko, Jose / Chacko, Binila / Narahari, Deshikar L / Veerendra, Hemanth H / Moorthy, Mahesh / Krishna, Bhuvana / Chekuri, Vs / Raju, Rama Krishna / Shanmugasundaram, Devika / Pichamuthu, Kishore / Abraham, Asha M / Abraham, Oc / Thomas, Kurien / Mathews, Prasad / Varghese, George M / Rupali, Priscilla / Peter, John V

    Journal of global infectious diseases

    2012  Volume 4, Issue 3, Page(s) 145–152

    Abstract: Background: This multi-center study from India details the profile and outcomes of patients admitted to the intensive care unit (ICU) with pandemic Influenza A (H1N1) 2009 virus [P(H1N1)2009v] infection.: Materials and methods: Over 4 months, adult ... ...

    Abstract Background: This multi-center study from India details the profile and outcomes of patients admitted to the intensive care unit (ICU) with pandemic Influenza A (H1N1) 2009 virus [P(H1N1)2009v] infection.
    Materials and methods: Over 4 months, adult patients diagnosed to have P(H1N1)2009v infection by real-time RT-PCR of respiratory specimens and requiring ICU admission were followed up until death or hospital discharge. Sequential organ failure assessment (SOFA) scores were calculated daily.
    Results: Of the 1902 patients screened, 464 (24.4%) tested positive for P(H1N1)2009v; 106 (22.8%) patients aged 35±11.9 (mean±SD) years required ICU admission 5.8±2.7 days after onset of illness. Common symptoms were fever (96.2%), cough (88.7%), and breathlessness (85.9%). The admission APACHE-II and SOFA scores were 14.4±6.5 and 5.5±3.1, respectively. Ninety-six (90.6%) patients required ventilation for 10.1±7.5 days. Of these, 34/96 (35.4%) were non-invasively ventilated; 16/34 were weaned successfully whilst 18/34 required intubation. Sixteen patients (15.1%) needed dialysis. The duration of hospitalization was 14.0±8.0 days. Hospital mortality was 49%. Mortality in pregnant/puerperal women was 52.6% (10/19). Patients requiring invasive ventilation at admission had a higher mortality than those managed with non-invasive ventilation and those not requiring ventilation (44/62 vs. 8/44, P<0.001). Need for dialysis was independently associated with mortality (P=0.019). Although admission APACHE-II and SOFA scores were significantly (P<0.02) higher in non-survivors compared with survivors on univariate analysis, individually, neither were predictive on multivariate analysis.
    Conclusions: In our setting, a high mortality was observed in patients admitted to ICU with severe P(H1N1)2009v infection. The need for invasive ventilation and dialysis were associated with a poor outcome.
    Language English
    Publishing date 2012-08-24
    Publishing country India
    Document type Journal Article
    ZDB-ID 2545454-7
    ISSN 0974-8245 ; 0974-777X
    ISSN (online) 0974-8245
    ISSN 0974-777X
    DOI 10.4103/0974-777X.100569
    Database MEDical Literature Analysis and Retrieval System OnLINE

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