Biomedical subjects

Mathilda Mandel

Publications and source records attributed to Mathilda Mandel.

12 recordsLinked to original sources

PubMed2006

Effective prevention of microbial biofilm formation on medical devices by low-energy surface acoustic waves.

Low-energy surface acoustic waves generated from electrically activated piezo elements are shown to effectively prevent microbial biofilm formation on indwelling medical devices. The development of biofilms by four different bacteria and Candida species is prevented when such elastic waves with amplitudes in the nanometer range are applied. Acoustic-wave-activated Foley catheters have all their surfaces vibrating with longitudinal and transversal dispersion vectors homogeneously surrounding the catheter surfaces. The acoustic waves at the surface are repulsive to bacteria and interfere with the docking and attachment of planktonic microorganisms to solid surfaces that constitute the initial phases of microbial biofilm development. FimH-mediated adhesion of uropathogenic Escherichia coli to guinea pig erythrocytes was prevented at power densities below thresholds that activate bacterial force sensor mechanisms. Elevated power densities dramatically enhanced red blood cell aggregation. We inserted Foley urinary catheters attached with elastic-wave-generating actuators into the urinary tracts of male rabbits. The treatment with the elastic acoustic waves maintained urine sterility for up to 9 days compared to 2 days in control catheterized animals. Scanning electron microscopy and bioburden analyses revealed diminished biofilm development on these catheters. The ability to prevent biofilm formation on indwelling devices and catheters can benefit the implanted medical device industry.

Animals↗

PubMed2006

G-CSF enhances the adhesion of encephalitogenic T cells to extracellular matrix components: a possible mechanism for exacerbation of multiple sclerosis.

Autologous stem cell transplantation is being considered as treatment of severe refractory autoimmune disorders, including MS. Stem cell mobilization is achieved with granulocyte-colony stimulating factor (G-CSF), however, G-CSF administration resulted in cases of worsened clinical MS status. We studied autoreactive T-cell properties, which can promote CNS inflammation in MS. We show that G-CSF enhances MS autoreactive T cell line adhesion to the ECM proteins collagen IV and fibronectin as effectively as the proinflammatory IFNgamma and TNFalpha, known to exacerbate MS symptoms. We propose a link between clinical worsening of MS symptoms induced by G-CSF and the hyperstimulation of T cell adhesion to ECM elicited by G-CSF.

Blotting, Western↗

PubMed2005

Anti-angiogenic activities of hypericin in vivo: potential for ophthalmologic applications.

Hypericin, a perihydroxylated dianthraquinone is shown here to be a highly potent inhibitor of angiogenesis in several ocular models examined in rat eyes. Extensive angiogenesis induced in the cornea and iris by intra-ocular administration of FGF-2 was effectively inhibited by a minimum of four dose regimens of hypericin (2 mg/kg) administered via the intraperitoneal route at 48 h intervals. Maximal inhibition was achieved when animal treatment with hypericin was initiated 48 h prior to inoculation of FGF-2. The molecular basis for the hypericin-mediated inhibition of angiogenesis in the anterior eye compartment appears to involve several sites in the cascade leading to angiogenesis. We show that the activating phosphorylation of extracellular signal-regulated MAP kinases (ERK1/2) is inhibited by hypericin in human retinal pigment epithelial cells and in EA.hy926 cells, an endothelial hybridoma expressing endothelial cell properties. ERK1/2 activity is required for the transactivation of hypoxia-inducible factor 1 alpha (HIF-1alpha) and in VEGF-induced blood vessel sprouting. MT1-MMP activity in human microvascular endothelial cells was also inhibited. The findings identify hypericin as a potentially useful agent in the treatment of ophthalmic neovascularization pathogeneses.

Angiogenesis Inducing Agents↗

PubMed2005

Competitive quenching: a possible novel approach in protecting RPE cells from damage during PDT.

PURPOSE: The purpose of this study is to demonstrate feasibility of using our novel concept, termed competitive quenching, for protecting the choroidal extravascular compartment and retinal pigment epithelium (RPE) from verteporfin (VP)-induced phototoxicity using hypericin. Furthermore, we aim to achieve partitioning of the quencher, hypericin, in the extravascular space and VP within the microvascular compartment of the chorio-retinal complex in vivo. METHODS: We protect RPE cells from damage inflicted by photoactivated VP by introducing hypericin into these cells prior to photosensitization to quench the photosensitizing activity of VP. Cell protection levels were measured by MTT and Hemacolor viability assays. Wavelength range used for VP photoexcitation (700 +/- 40 nm) excludes the absorption range of hypericin, preventing the latter from photoactivation. Pharmacokinetic conditions, in which hypericin spreads throughout the choroidal and retinal extravascular space while VP is confined to the vasculature, are delineated using double-fluorescence imaging. RESULTS: Cell viability increased 3- to 5-fold when 10-20 microM hypericin were present in RPE cells during photosensitization with 0.1-0.5 microM VP. VP fluorescence intensity was unchanged by the presence of hypericin in the cells. Hypericin administered intravenously to rats was confined to the choroidal vasculature after 15 min to 2 hr. Subsequently, hypericin partitioned to the choroidal and retinal extravascular space. VP administered at this time was confined to the microvasculature. CONCLUSIONS: RPE and choroid may potentially be protected by compartmentalizing hypericin to the extravascular compartment while VP administered shortly before photosensitization is confined to the microvasculature. Adverse photodynamic therapy (PDT) damage to choroidal tissues adjacent to neovasculature targeted for photoablation have the potential of being prevented by competitive quenching with hypericin.

Animals↗

PubMed2005

Unique gene expression patterns in human T-cell lines generated from multiple sclerosis patients by stimulation with a synthetic MOG peptide.

Multiple sclerosis (MS) is an autoimmune disease where T-cells activated against myelin antigens are involved in myelin destruction. Yet, healthy subjects also harbor T-cells responsive to myelin antigens, suggesting that MS patient-derived autoimmune T-cells might bear functional differences from T-cells derived from healthy individuals. We addressed this issue by analyzing gene expression patterns of myelin oligodendrocytic glycoprotein (MOG) responsive T-cell lines generated from MS patients and healthy subjects. We identified 150 transcripts that were differentially expressed between MS patients and healthy controls. The most informative 43 genes exhibited > 1.5-fold change in expression level. Eighteen genes were upregulated including BCL2, lifeguard, IGFBP3 and VEGF. Twenty five genes were down-regulated, including apoptotic activators like TNF and heat shock protein genes. This gene expression pattern was unique to MOG specific T-cell lines and was not expressed in T-cell lines reactive to tetanus toxin (TTX). Our results indicate that activation in MS that promotes T-cell survival and expansion, has its own state and that the unique gene expression pattern that characterize autoreactive T-cells in MS represent a constellation of factors in which the chronicity, timing and accumulation of damage make the difference between health and disease.

Base Sequence↗

PubMed2004

Antimetastatic activity of the photodynamic agent hypericin in the dark.

A unique property of the photodynamic signal transduction inhibitor hypericin (HY) is high functionality in the dark, which has been shown to result in portfolio of anticancer activities both in vitro and in vivo. Here we show that treatment with HY significantly reduces growth rate of metastases in 2 murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2). Focus on metastases was achieved by resection of primary tumors at stages in which micrometastases exist in lungs. Long-term animal survival in DA3 tumor-excised groups increased from 15.6% in controls to 34.5% following supplementary treatment with HY. In mice bearing SQ2 tumor metastases, therapy with HY increased animal survival from 17.7% in controls to 46.1%. Using Laser-induced fluorescence and multipixel spectral image analyses, we demonstrate that HY has a high tendency to accumulate in primary and metastatic tumors; HY content in lungs bearing metastases was approximately 2-fold higher than in the lungs of healthy animals. The tendency of HY to preferentially concentrate in lung metastases, combined with its potent antiproliferative activities, may render HY as a useful supplementary modality in the treatment of metastatic cancer irrespective of photoactivation.

Animals↗

PubMed2004

Blood transcriptional signatures of multiple sclerosis: unique gene expression of disease activity.

Multiple sclerosis (MS) is a central nervous system disease with an unpredictable course and outcome. Peripheral blood mononuclear cells (PBMCs) are involved in the disease pathogenesis and induce active demyelination. Using oligonucleotide microarrays, we identified a statistically significant transcriptional signature of 1,109 genes in PBMCs from 26 MS patients, irrespective of disease activation state or immunomodulatory treatment. This signature contains genes that implicate underlying processes involved in MS pathogenesis including T-cell activation and expansion, inflammation, and apoptosis. Another transcriptional signature of 721 genes involved in cellular recruitment, epitope spreading, and escape from regulatory immune surveillance identified MS patients in acute relapse compared with remission. Our results offer new opportunity for understanding the mechanisms involved in MS and indicate that gene expression patterns in PBMCs contain information about a remote-target disease process that may be useful for diagnosis and future tailoring of therapeutic strategies for MS.

Adjuvants, Immunologic↗

PubMed2004

The metabolic effects of fresh versus old stored blood in the priming of cardiopulmonary bypass solution for pediatric patients.

OBJECTIVES: Pediatric cardiopulmonary bypass involves the creation of a large obligatory priming reservoir. Packed red blood cells are an essential part of the cardiopulmonary bypass priming solution in children. The storage media in packed red blood cells might cause significant acid-base, glucose, and electrolyte imbalances, which have been associated with severe complications. The purpose of the present study was to evaluate the metabolic effects of fresh (< or =5 days) versus old (>5 days) stored packed red blood cells added to the priming solutions of pediatric patients undergoing cardiac surgery. METHODS: Blood samples were drawn from cardiopulmonary bypass priming of 30 consecutive pediatric patients undergoing cardiac surgery. Patients were divided into 2 groups. Fresh (< or =5 days old) stored packed red blood cells were added to the priming solution in group 1, and old (>5 days old) stored packed red blood cells were added to the priming solution in group 2. In each group blood samples were drawn from the packed red blood cells on arrival to the operating room and from the priming solution immediately after packed red blood cells were added and after 20 minutes of prime circulation. Samples were also collected at the beginning of cardiopulmonary bypass and after 30 minutes. The last sample was collected on arrival to the pediatric intensive care unit. The levels of potassium, glucose, and lactate and the acid-base balance were analyzed in each sample. RESULTS: There was a linear increase in potassium levels in packed red blood cell samples with increasing packed red blood cell age, ranging from 5.4 to 18.4 mEq/L. Significant differences in the concentrations of potassium, glucose, and lactate and the acid-base balance were found when comparing old and fresh packed red blood cells in samples taken during the packed red blood cell and early prime time. Those differences resolved after 20 minutes of reconstitution of the priming solution. The age of the packed red blood cells had no effect on the samples taken during bypass and those taken in the pediatric intensive care unit. CONCLUSION: The significantly higher concentration of potassium and lactate and lower pH in old stored packed red blood cells has a minimal effect on the final constitution of priming solution before and during cardiopulmonary bypass in children undergoing corrective cardiac surgery.

Acid-Base Equilibrium↗

PubMed2004

T-cell vaccination in multiple sclerosis.

T cells that are autoreactive against myelin antigens play a pivotal role in the pathogenesis of multiple sclerosis (MS). The concept of T cell vaccination (TCV) has been developed to generate an immune response against these autoreactive pathogenic T cells. Immunologic data accumulated so far demonstrates depletion of T cells reactive against immunodominant myelin peptides after immunization in the animal model of experimental autoimmune encephalomyelitis, as well as in vaccinated MS patients. Clinical trials have confirmed the safety and efficacy of TCV in a small number of immunized MS patients. TCV resulted in reduced relapse rates and slowed the progression of neurological disability and MRI brain lesion load. Recently, there have been several double-blind, placebo-controlled studies initiated to evaluate the role of TCV in MS. Specifically, it is important to examine the effect of early TCV, given after the first episode suggestive of the disease, in order to prevent the process of epitope spreading.

Animals↗

PubMed2004

[Multiple sclerosis and anti-phospholipid syndrome--one or two diseases?].

Multiple sclerosis is an autoimmune central nervous system disease that affects young adults and causes inflammation, demyelination and axonal loss. Within the common relapsing-remitting course of the disease patients develop various neurological symptoms that lead to significant disability overtime. The anti-phospholipid syndrome, similarly to multiple sclerosis, appears in young adults and is characterized by thromboembolic events and pregnancy complications. The overlay between these two diseases and the ability to correctly diagnose or differentiate between them is sometimes difficult. The current review approaches this problem and discusses whether multiple sclerosis and anti-phospholipid syndrome are actually one or two diseases.

Antiphospholipid Syndrome↗

PubMed2003

Enhanced ubiquitinylation of heat shock protein 90 as a potential mechanism for mitotic cell death in cancer cells induced with hypericin.

A unique property of the photodynamic signal transduction inhibitor hypericin is functionality in the dark. We show in tumor cells that hypericin targets the heat shock protein (Hsp) 90 chaperone but not Hsp70 (Hsc70) to enhanced ubiquitinylation. As a consequence Hsp90 chaperone functionality is abrogated and the client proteins, mutant p53, Cdk4, Raf-1, and Plk, are displaced from complexes with Hsp90, destabilized, and degraded via a proteasome-independent pathway. Decline in Raf-1 prevents downstream activation of extracellular signal-regulated kinase 1/2 kinases, the Ras/Raf pathway is inhibited, and tumor cell proliferation is arrested. The cells exhibit multiple aberrations including retardation at G(2)-M, increased cell volume, and multinucleation, all of which are hallmarks of mitotic cell death. The studies demonstrate that ubiquitinylation of Hsp90 inactivates the chaperone, destabilizes the plethora of client proteins, and creates deficiencies in multiple unrelated cellular functions. This combination constitutes a mechanism by which hypericin generates mitotic cell death in cancer cells.

Animals↗

PubMed2002

Interaction of disease-related antigen-reactive T-cell lines from multiple sclerosis patients with type IV collagen: role of integrin VLA-1 and effects of irradiation.

Multiple sclerosis (MS), a chronic demyelinating disease, is thought to be initiated by pathogenic T cells that transmigrate the vascular endothelium and enter the brain through vascular and parenchymal basement membranes (BM). Vaccination with T-cell lines reactive with myelin basic protein (MBP) and myelin oligodendrocytic glycoprotein (MOG) epitopes, expanded with interleukin-2 (IL-2), and attenuated by ionizing radiation is currently being evaluated as a therapeutic modality for this disease. We examined mechanisms potentially involved in pathogenic cell migration into the central nervous system (CNS) and the influence of irradiation on these processes. Seven of 7 autoantigen-responsive T-cell lines from MS patients adhered to collagen IV, the major collagenous constituent of BMs. This adhesion was inhibited almost completely by monoclonal antibody (MAb) to very late antigen (VLA)-1 and partially by anti-VLA-2. T-cell lines from healthy donors adhered more variably to collagen IV. Furthermore, patient derived T cells actively transmigrated through a collagen IV gel toward medium containing TNF-a, in a process that was inhibited by MAbs to VLA-1. Ionizing radiation at the dose used in vaccine preparation, inhibited morphological polarization associated with migratory capability, induced integrin clustering on the cell membrane, and abrogated adhesion to collagen IV. These findings may have important implications for understanding the pathogenesis of MS and how irradiation of potentially pathogenic T cells produces a reagent with possible therapeutic effects in T-cell vaccination (TCV).

Adolescent↗