Podcasts about plasminogen

They say age is just a number…and no concept drives this point home more than biological age. You see, your chronological age isn't the same as the age of your cells. That's why you can have people who look younger (or older) than their stated age.   This has a lot to do with Plasminogen activator inhibitor-1 or PAI-1.   People age at different rates and there are conditions and circumstances that make some age more rapidly than others. From climate, diet, stress and genetics, there are so many factors that impact the health of our cells.   Here's the good news: how long we've been on the planet doesn't have to dictate our health and wellness. There are proactive steps we can take to extend not just the span of our lives but its quality too.   What is plasminogen activator inhibitor-1 and how does it affect aging? Why is there a difference between chronological age and biological age? What can we learn from communities and locations that have longevity?   In this episode, I'm joined by the chairman of the Department of Medicine at Northwestern University, and leader of the Potocsnak Longevity Institute, Dr. Douglas Vaughan. He talks about the strides we've made in understanding biological age and what we can do about it.  Things You'll Learn In This Episode    -The biggest driver of biological age People's biological age can be higher or lower than their stated chronological age. What is plasminogen activator inhibitor-1 (PAI-1) and how does it impact this?    -How to slow aging Every choice we make either ages us faster or it slows down the aging process. How do we make choices that support longevity?    -A convergence of scientific strides We're in the golden age of understanding biological aging. What strides have been made to deepen our knowledge and discover interventions?   Guest Bio   Dr. Douglas E. Vaughan, is chairman of the Department of Medicine and the Irving S. Cutter Professor of Medicine in the Division of Cardiology at Northwestern University Feinberg School of Medicine. He is a fellow of the American College of Cardiology and has been elected to membership in the American Society for Clinical Investigation and the Association of American Physicians. In 2018, Dr. Vaughan led a study that reported the first genetic variation that appears to protect against multiple aspects of biological aging in humans in an extended kindred of Old Order Amish living in the vicinity of Berne, Indiana.   Dr. Vaughan now leads the recently launched Potocsnak Longevity Institute, bringing together scientists and experts across many disciplines to study those populations that seem resistant to negative consequences of aging with a goal of discovering what makes them unique. With a deeper understanding of how aging works, the institute aims to expand the healthspan for all people with future therapies and lifestyle interventions. To learn more, visit https://www.feinberg.northwestern.edu/sites/longevity/index.html.    About Your Host   Hosted by Dr. Deepa Grandon, MD MBA, triple board-certified physician with over 23 years of experience working as a Physician Consultant for influential organizations worldwide. Dr. Grandon is the founder of Transformational Life Consulting (TLC) and an outspoken faith-based leader in evidenced-based lifestyle medicine.   Disclaimer    ​​TLC is presenting this podcast as a form of information sharing only. It is not medical advice or intended to replace the judgment of a licensed physician. TLC is not responsible for any claims related to procedures, professionals, products, or methods discussed in the podcast, and it does not approve or endorse any products, professionals, services, or methods that might be referenced.   Check out this episode on our website, Apple Podcasts, or Spotify, and don't forget to leave a review if you like what you heard. Your review feeds the algorithm so our show reaches more people. Thank you!

On this ID the Future, Michael Behe continues discussing his new book, A Mousetrap for Darwin, with host Eric Anderson. Here the focus is the blood clotting cascade. Behe has argued it’s irreducibly complex, like a mousetrap, and that blind evolution couldn’t build it one small functional step at a time. Behe says a better explanation is that it was intelligently designed. His critics have responded to his argument over the years. Here Behe returns the favor. His most prominent interlocutor on the matter is the recently deceased Russell Doolittle. Behe shows that Doolittle misread the paper he relied on to refute Behe. Professor Behe also responds to Kenneth Miller and Keith Robison. According to Behe, his critics have managed Read More › Source

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.05.325688v1?rss=1 Authors: Florova, G., Girard, R. A., Azghani, A. O., Sarva, K., Buchanan, A., Karandashova, S., DeVera, C. J., Hill, D., Chamiso, M., Koenig, K., Cines, D. B., Idell, S., Komissarov, A. A. Abstract: Plasminogen activator inhibitor-1 (PAI-1) is an endogenous irreversible inhibitor of tissue-type (tPA) and urokinase (uPA) plasminogen activators. PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) is designed to decrease the therapeutic dose of tPA and uPA to attenuate the risk of bleeding and other complications. The docking site peptide (DSP) is a part of the PAI-1 reactive center loop, which interacts with plasminogen activators, thus affecting the PAI-1 mechanism. We used DSP for PAI-1-TFT in two rabbit models: chemically-induced pleural injury and Streptococcus pneumoniae induced empyema. PAI-1-TFT with DSP combined with single chain uPA or tPA resulted in an up to 8-fold decrease in the minimal effective therapeutic dose of plasminogen activator and induced no bleeding. An increase in the level of PAI-1 in infectious pleural injury, when compared to chemically-induced injury, coincided with an increase in the minimal effective dose of plasminogen activator and DSP. PAI-1 is a valid molecular target in S. pneumoniae empyema model in rabbits, which closely recapitulates key characteristics of empyema in humans. Low dose PAI-1-TFT is a novel precise interventional strategy that may improve fibrinolytic therapy of empyema in clinical practice. Copy rights belong to original authors. Visit the link for more info

Finally got hold of the man who more than anyone, has deep-dived into the root causes of heart disease - without bias - just fixated with finding the truth. I'm of course referring to Dr. Malcolm Kendrick, who has created the 65-part (and growing) series "What Causes Heart Disease?". See index below for a gist of what we covered (hint - it was A LOT!) VIDEO PODCAST: https://www.youtube.com/watch?v=8wkxp-l2c68 INDEX/CONTENTS: 00:00:40 Are the causes we talk about “necessary and sufficient”? 00:04:45 What does Sickle Cell Disease prove about heart disease cause? 00:09:33 Kawasaki Disease illuminates the true causes of heart disease 00:14:45 Vein/artery differences, blood pressure & turbulence - speak volumes 00:20:14 Damage and repair – it's the imbalance that is the problem 00:24:34 Steroids, inflammation and …Cushing's Disease – what do they say? 00:28:12 Blood glucose, insulin resistance and their effects - a pivotal axis 00:31:54 Pollution, leaded petrol – and the surprising effect of Chelation 00:35:50 Bias, homocysteine, drug treatments - and the research world behaving badly 00:46:01 LDL importance…versus blood clotting factors 00:49:40 Atherosclerosis is the result of endothelial damage & blood clotting processes –root mechanisms 00:53:08 Sun, Nitric Oxide – and taking Viagra…! 00:56:53 Magnesium, salts, nitric oxide – and why your arteries fail you 01:02:06 Blood clotting is at the very core of heart disease – deep-dive 01:09:05 LDL, Lp(a) – and what cholesterol crystals in plaque really say! 01:15:05 Lp(a0, Vitamin C and Plasminogen – putting it all together 01:22:45 Familial Hypercholesterolemia….and what's actually occurring all along 01:25:39 The mechanisms of statins and other drugs – beyond the old LDL story 01:34:48 “Well, they can't all be wrong, can they?” – but history has shown how often this has been the case 01:43:04 We're building a cathedral of wisdom - at least on the root causes of heart disease!

If you talk to people about the topic of thrombolysis in PE they'll tell you about the controversy of the submassive category, but there's a universal acceptance that thrombolysing massive PE's is well evidenced and straight forward. In this episode we delve back into the literature and not only explore massive PE thrombolysis, but also the gold standard to which it is judged upon, heparin. Have a listen to the podcast and as always we would love to hear your thoughts. Enjoy! Simon & Rob References & Further Reading 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism British Thoracic Society guidelines for the management of suspected acute pulmonary embolism; 2003 Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report; 2016 Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension. A Scientific Statement From the American Heart Association. 2011 Venous thromboembolic diseases: diagnosis, management and thrombophilia testing; NICE. 2012 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438862/pdf/jrsocmed00257-0051.pdfValue of anticoagulants in the treatment of pulmonary embolism: a discussion paper. Paul Egermayer. Journal of the Royal Society of Medicine 1981. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. BARRITT DW. Lancet. 1960 Treatment of pulmonary embolism in total hip replacement. Johnson R. Clin Orthop Relat Res. 1977 PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. Dalla-Volta S. J Am Coll Cardiol. 1992  Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Goldhaber SZ. Lancet. 1993 Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism.  A Meta-Analysis of the Randomized Controlled Trials. Susan Wan. 2004 Massive PE and cardiogenic shock. To thrombolyse or not to thrombolyse, that is the question. Francoise Ticehurst. BestBets. 2004  

Prometic Life Sciences is developing both plasma-derived and small molecule therapeutics to address a number of rare diseases that are today without therapies. Its lead experimental therapeutic is Ryplazim, which is purified human plasminogen that is being developed to treat congenital plasminogen deficiency. Plasminogen is a naturally occurring protein that plays a critical role in wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis. We spoke to Pierre Laurin, president and CEO of Prometic, about Ryplazim, the challenges and benefits of deriving products from human plasma, and what else is moving through the company’s pipeline.

ProMetic Life Science hits two significant clinical milestones, Antibe Therapeutics reports promising Phase 2 results, In BC researchers, take a closer look at the DNA of the world’s greatest wines, and using genomics to treat and track tuberculosis We have this and more on this week’s Biotechnology Focus Podcast! Welcome to Biotechnology Focus Podcast. I’m your host Shawn Lawrence. Story 1 We start this week’s show in beautiful British Columbia, highlighting two local projects with an international flavor. The first story sees UBC researchers Dan Durall and Mansak (Ben) Tantikachornkiat getting ever closer to identifying the biological personalities of the world’s greatest wines. In a recent study, published in the International Journal of Food Microbiology , the duo developed a technique that combines a process to identify the full spectrum of DNA in yeast and bacteria samples with a technique that distinguishes between live and dead micro-organisms. As Durall, an associate professor of biology at UBC’s Okanagan campus, explains, since only live micro-organisms are relevant in the various stages of fermentation as they relate to the senses, this study provides some of the important tools that will be necessary to determine why different types of wine taste and smell as they do. Their findings could also lead to the identification and elimination of micro-organisms that are responsible for spoilage. In undertaking the study, the pair used a number of different kinds of yeast and bacteria specimens, including those typically found in wine fermentations. Key in the development of the new scientific technique was the use of a light-sensitive dye, propidium monoazide, which binds to dead DNA and prevents it from being detected. This allows scientists to identify and focus on the more relevant aspects of a test sample. According to Tantikachornkiat, this technique has allowed them to quickly and accurately monitor in one experiment what previously could have taken multiple experiments and months of trial and error. The next stages of their research will focus this technique on different types of wine making methods to see how they change micro-organisms that affect the final wine product. Story 2 Our second BC story focuses on a new collaborative project involving the BC Centre for Disease Control (BCCDC), Oxford University and Public Health England (PHE). Together they are working to build data-sharing capacity between eachother to accelerate the use of genomics as a tool for the diagnosis, treatment and tracking of tuberculosis (TB). Led by Dr. Jennifer Gardy at BCCDC and Dr. Derrick Crook, University of Oxford and PHE, the research project is exploring how to communicate the complex data from a genomics-based test in a simple and effective laboratory report allowing clinicians, many of whom have not worked with genomic data before, to quickly and easily find the information and get the interpretation they need to ensure a direct benefit for patients. Funded in part by Genome BC, the project also supports PHE and BCCDC’s efforts to validate the use of a genomic platform in a clinical setting through developing user-friendly reports to assist doctors in faster and more effective diagnosis and treatment. The use of genomics in the clinic means patients will have access to the most effective treatment several weeks earlier. Through a previous collaboration, the researchers have already demonstrated that using genomics to diagnose and characterize TB infections can reduce the time to diagnose and fully characterize an infection from an average of 31 days to just five days. Genomics also provides important information on the drug resistance profile of the tuberculosis strain, which helps doctors to identify the best treatment and avoid using antibiotics that will not be effective. Valued at $168,000, the initiative called SMAC: Sharing Mycobacterial Analytic Capacity will use techniques from the field of information visualization to design the better laboratory reporting form. Through a series of online surveys and iterative designs, the researchers hope to develop a simple, two-page report that describes a patient’s diagnosis, the antibiotics that are predicted to work to treat the infection, and whether or not the patient is part of an outbreak. As part of SMAC, the UK and Canadian teams are also sharing resources and expertise in TB genomics and bioinformatics in order to accelerate the clinical validation and implementation of genomics-based TB diagnostics, first in the UK, and ultimately in BC. The partnership is a product of a MOU signed by Genome British Columbia and Genomics England last year to improve diagnostic capability and outcomes for patients with cancer, rare diseases and infectious diseases. Story 3 In Atlanta, Georgia, Toronto based med tech company Synaptive Medical has launched a revolutionary brain surgery technology at Emory University Hospital. The technology, called BrightMatter™ is an innovative neurosurgery solution that offers advanced imaging, surgical planning and navigation through robotic visualization. Synaptive’s technology shares a common imaging hub, which analyzes and assesses the quality of imaging scans in real-time prior to surgical planning and creates the foundation for a clinically-integrated imaging informatics research platform. Using an imaging method called diffusion tensor imaging, or DTI, BrightMatter enhances MRI images of the entire brain’s pathways, allowing physicians to consider approaches for navigating around critical structures in neurological surgery. Synaptive’s integrated imaging and navigation systems allow physicians to see details that can’t be seen with the naked eye or a standard MRI, and may allow access to brain locations previously deemed inoperable. The automatic positioning system with an attached camera follows the physician’s tools, showing an image of the patient’s anatomy with unprecedented detail. This robotic arm includes a hands-free optical visualization system that allows for better surgical ergonomics, facilitates collaboration with operating room staff, and consumes less surgical time without the need to manipulate cumbersome optics. Dr. Gustavo Pradilla, an Emory assistant professor of Neurosurgery, and chief of neurosurgery for Grady, co-director of the Grady Skull Base Center, and director of the Cerebrovascular Research Laboratory said that acquiring Synaptive’s platform will bring innovative neurosurgical treatments that are the next technological frontier in intraoperative navigation, robotic-assisted visualization, corridor-based neurosurgery and clinical informatics. He adds that the technology will expand the hospitals ability to treat previously inoperable lesions in delicate areas of the brain, leading to safer and more efficient procedures, smaller incisions, shorter hospital stays. Story 4 In clinical trial news, Toronto’s Antibe Therapeutics Inc. has posted positive results from its Phase 2 clinical trial of ATB-346 in osteoarthritis (OA). ATB-346, is an NSAID (non-steroidal anti-inflammatory drug), and a hydrogen sulfide-releasing derivative of naproxen, the most-prescribed NSAID in North America. As part of the trial, 12 patients with OA of the knee were treated once daily for 10 days with the drug at a dose of 250 mg. The dose contains one-sixth of the typical daily dose of naproxen for treating OA. According to the company, the lower dose was found to be very effective at reducing pain, and equal to or better than naproxen or celecoxib in comparable studies. The drug was also found to be safe and well-tolerated. As part of the trial, patients recorded their level of pain one day prior to starting treatment and again on days four and 10 of treatment. The “WOMAC pain scale”, the gold standard in arthritis clinical trials, was used as the measure of beneficial effect. The enhanced effectiveness of ATB-346 as compared to the market-leading drugs for osteoarthritis was a pleasant surprise, particularly considering the low dose of ATB-346 that was used said both the company’s chief science officer John Wallace and the company’s CEO Dan Legault. Legault added that the company plans to expeditiously perform additional clinical trials to confirm the results seen in this phase 2 study, and explore the effectiveness of even lower doses of ATB-346. The Phase 2 clinical trial was carried out in Toronto, Canada by Topstone Research Ltd. Story 5 A research team at the Krembil Research Institute has discovered a pair of tissue biomarkers that directly contribute to the harmful joint degeneration associated with spine osteoarthritis. In a study study, published in the Journal of Clinical Investigation Insight, the researchers were able to show that elevated levels of both of these biomarkers cause inflammation, cartilage destruction and collagen depletion. Osteoarthritis affects about three million Canadians and is characterized by a breakdown of the protective cartilage found in the body’s spine, hand, knee and hip joints. There is no known cure. The study involved tissue biopsies from 55 patients undergoing decompression or discectomy at the Krembil Neuroscience Centre at Toronto Western Hospital. As part of the study, the research team – led by Dr. Mohit Kapoor at the Krembil Research Institute and comprising Dr. Akihiro Nakamura, a post-doctoral fellow, and Dr. Y. Raja Rampersaud, a clinical expert and spine surgeon – explored the role, function and signaling mechanisms of two tissue biomarkers: microRNA-181a-5p and microRNA-4454. The study screened 2,100 microRNAs and found that measuring the levels of these two specific biomarkers can help clinicians determine the stage to which the disease has progressed, and provide a tool for determining the degree of cartilage destruction. Dr. Kapoor discusses his team’s discovery of the pair of tissue biomarkers in the following audio provided by (Video: UHN From 0:26-1:09,1:30-2:02). The discovery represents the end of the first stage of research. The team is now investigating whether these biomarkers can be detected in the blood – which would help clinicians more simply determine the stage of spine osteoarthritis – and whether further studying the biomarkers will allow researchers to halt and reverse spine degeneration. Story 6 It’s been a week filled with successful milestones for Laval, QC’s ProMetic Life Sciences. A developer of products used in the purification of biologics, drug development, proteomics and the removal of pathogens, the company announced on August 9th it had completed enrollment of the adult patient cohort for its pivotal intravenous immunoglobulin (IVIG) Phase3 clinical trial for the treatment of primary immunodeficiency diseases (PIDD). The company also announced on August 11 that it had completed patients enrolment of the congenital plasminogen deficient patients in its pivotal phase 2/3 clinical trial required for the accelerated regulatory approval pathway with the U.S. Food and Drug Administration In terms of the Phase 3 trial, completion of enrollment for the adult patient population is five months ahead of schedule and puts the company on the fast track to becoming the first Canadian-based company to locally produce IVIG. It’s also a further indication of the near-term commercial prospect of what will be the company’s second plasma protein. According to company CEO and president Pierre Laurin, Canadian patients are amongst the largest consumers of IVIG on a per capita basis worldwide and the demand continues to grow at a rapid pace. He believes that the manufacturing advantages provided by the company’s proprietary PPPS™ technology can help alleviate Canada’s current dependence on foreign plasma derived therapeutics. IVIG is a preparation of antibodies purified from plasma donations from normal individuals. It is indicated for the maintenance treatment of patients with primary immunodeficiencies including common variable immunodeficiency, X-linked agammaglobulinemia, severe combined immunodeficiency and as a treatment of immune thrombocytopenic purpura (ITP). It is also used for the treatment of many other autoimmune diseases, including Guillain-Barré syndrome, Kawasaki disease. The Phase 3 trial is an open label, single arm, two-cohort multicenter study investigating the safety, tolerability, efficacy and pharmacokinetics of ProMetic’s plasma derived IVIG in a total of 75 patients suffering from PIDD, and the adult cohort includes the 50 enrolled adults (cohort 1) and will also include 25 children (cohort 2). ProMetic anticipates the completion of enrollment for cohort 2 to go quickly with completion of the IVIG Phase 3 clinical trial expected in the second half of 2017. As for the second trial, the FDA has agreed to an accelerated regulatory approval pathway, given the rarity of the condition and the related unmet medical need. To secure an accelerated pathway approval, a drug must treat a serious condition, provide a meaningful advantage over available therapies and demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. Dr John Moran, Chief Medical Officer of ProMetic commented that the ongoing clinical trial has enabled ProMetic to meet the primary end-point of achieving the targeted increase in plasma concentration of plasminogen and to define the optimal treatment regimen. Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. Plasminogen is therefore vital in wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis. ProMetic's Plasminogen has received an Orphan Drug Designation by the FDA and the European Commission for the US and the European markets respectively. ProMetic also received a Fast Track Designation by the FDA, a process designed to facilitate the development and expedite review of drugs and biologics intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. With that we’ve come to the end of this week’s program. We hope you enjoyed it. Thanks to Laskey Hart our production manager. You can find us online at www.biotechnologyfocus.ca and we’re always looking for your feedback, story ideas and suggestions so we’d love to hear from you. Simply reach out to us on twitter: @BiotechFocus . For all of us here at Biotechnology Focus, thank you for listening.

Filmed live at ASM Biodefense 2016 with special guests: Rebekah Kading and Wyndham Lathem. From the ASM Biodefense and Emerging Diseases Research meeting, Vincent Racaniello speaks with Rebekah and Wyndham about their work on Rift Valley Fever virus and other vector-borne pathogens, and the evolution and pathogenesis of Yersinia pestis, the agent of plague. Links for this episode  Rift Valley fever virus risk (Emerg Micr Inf) Predicting Rift Valley fever virus transmission (PLoS NTD) Culex in New York City (BioOne) Early emergence of Y. pestis (Nature Comm) Pneumonic plague (Trends Micro) Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Don't miss an episode of MicrobeWorld Video. Subscribe for free using iTunes or help support our work by purchasing the MicrobeWorld podcast application for iPhone and Android devices in the iTunes or Android app stores. Send your microbiology questions and comments (email or mp3 file) to twim@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twim. Subscribe to TWiM (free) on iTunes, Stitcher, Android, RSS, or by email. You can also listen on your mobile device with the Microbeworld app.

Filmed live at ASM Biodefense 2016 with special guests: Rebekah Kading and Wyndham Lathem. From the ASM Biodefense and Emerging Diseases Research meeting, Vincent Racaniello speaks with Rebekah and Wyndham about their work on Rift Valley Fever virus and other vector-borne pathogens, and the evolution and pathogenesis of Yersinia pestis, the agent of plague. Links for this episode  Rift Valley fever virus risk (Emerg Micr Inf) Predicting Rift Valley fever virus transmission (PLoS NTD) Culex in New York City (BioOne) Early emergence of Y. pestis (Nature Comm) Pneumonic plague (Trends Micro) Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Don't miss an episode of MicrobeWorld Video. Subscribe for free using iTunes or help support our work by purchasing the MicrobeWorld podcast application for iPhone and Android devices in the iTunes or Android app stores. Send your microbiology questions and comments (email or mp3 file) to twim@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twim. Subscribe to TWiM (free) on iTunes, Stitcher, Android, RSS, or by email. You can also listen on your mobile device with the Microbeworld app.

Filmed live at ASM Biodefense 2016 with special guests: Rebekah Kading and Wyndham Lathem. From the ASM Biodefense and Emerging Diseases Research meeting, Vincent Racaniello speaks with Rebekah and Wyndham about their work on Rift Valley Fever virus and other vector-borne pathogens, and the evolution and pathogenesis of Yersinia pestis, the agent of plague. See the video version at microbeworld.org/mwv

Host: Vincent Racaniello Special guests: Rebekah Kading and Wyndham Lathem From the ASM Biodefense and Emerging Diseases Research meeting, Vincent speaks with Rebekah and Wyndham about their work on Rift Valley Fever virus and other vector-borne pathogens, and the evolution and pathogenesis of Yersinia pestis, the agent of plague. Subscribe to TWiM (free) on iTunes, Stitcher, Android, RSS, or by email. You can also listen on your mobile device with the Microbeworld app. Links for this episode  Rift Valley fever virus risk (Emerg Micr Inf) Predicting Rift Valley fever virus transmission (PLoS NTD) Culex in New York City (BioOne) Early emergence of Y. pestis (Nature Comm) Pneumonic plague (Trends Micro) Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Send your microbiology questions and comments (email or mp3 file) to twim@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twim.

Thu, 22 Oct 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18849/ https://edoc.ub.uni-muenchen.de/18849/1/Uhl_Bernd.pdf Uhl, Bernd

Interview with Gregg C. Fonarow, MD, author of Door-to-Needle Times for Tissue Plasminogen Activator Administration and Clinical Outcomes in Acute Ischemic Stroke Before and After a Quality Improvement Initiative

Interview with Jeffrey L. Saver, MD, author of Time to Treatment With Intravenous Tissue Plasminogen Activator and Outcome From Acute Ischemic Stroke

Background/Aims: Viral infections are a major problem worldwide and many of them are complicated by virally induced glomerulonephritides. Progression of kidney disease to renal failure is mainly attributed to the development of renal fibrosis characterized by the accumulation of extracellular matrix components in the mesangial cell compartment and the glomerular basement membrane. Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) are major regulators of plasmin generation and play an important role in generation and degradation of glomerular extracellular matrix components. Viral receptors expressed by mesangial cells (MC) are known to be key mediators in immune-mediated glomerulonephritis. We investigated the effect of stimulation of the viral receptors toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I) on the expression of PAI-1 and t-PA. Methods: Expression of PAI-1 and t-PA in immortalized human MC stimulated with polyriboinosinic: polyribocytidylic acid {[}poly(I:C)] RNA and cytokines were analyzed by real-time RT-PCR and ELISA. Results: Incubation of MC with poly(I:C) RNA to activate the viral receptors TLR3 and RIG-I upregulates the expression of PAI-1 and t-PA. Knockdown of viral receptors with specific siRNA abolishes the induction of PAI-1 and t-PA. Conclusion: For the first time a link between the activation of viral receptors on MC and potentially causative agents in the development of glomerulosclerosis and tubulointerstitial fibrosis is shown. The progression of inflammatory processes to glomerulosclerosis can be postulated to be directly enhanced by viral infection. Copyright (C) 2009 S. Karger AG, Basel

Zum Nachweis von PrPc und PrPsc wurde eine Kapillarelektrophorese-Immunofluoreszenz-Methode (CE-LIF) etabliert und mit konventionellen Verfahren (ELISA, Westernblot, Dot-EIA) verglichen. Zur CE-LIF wurde der monoklonale Antikörper F89 und ein Fluoreszenz-markiertes Peptid (FITC-P3) eingesetzt. Die Nachweisgrenze für rekombinantes bovines PrPc liegt bei 1 pg/Test. Zur Anreicherung von PrPsc aus Hirn und Liquor wurden (Ultra-) Zentrifugations-, Extraktions- (HFIP) und Chromatographieverfahren (HPLC, Festphasenextraktion) einzeln oder in Kom-binationen geprüft; darüber hinaus wurden Anreicherungsversuche mit Affinität- bzw. Immu-nomagnetischer Separation vorgenommen. Die Überprüfung des PrPsc-Gehaltes ausgewählter Extrakte im Vergleich zum Ausgangsma-terial mittels ELISA ergab deutliche Substanzverluste. Eine selektive Bindung von PrPsc an Dynabeads® gekoppeltem Plasminogen konnte nicht nachgewiesen werden. Dagegen wurde eine Anlagerung an Antikörper-beschichteten Beads festgestellt. Allerdings war die Bin-dungskapazität der Beads bei Versuchen in mit in PBS gelöstem PrPc oder PrPsc höher als bei vergleichbaren Versuchen mit Liquor. Bei der kapillarelektrophoretischen Analyse erwiesen sich alle mittels einfacher Probenauf-bereitung hergestellten Extrakte als ungeeignet. Sie führten entweder zu technischen Prob-lemen (Verstopfung der Kapillare; Durchbrennen) oder zu Interferenzen im Elektrophe-rogramm, die eine Auswertung nicht ermöglichten. Die Aufbereitung mittels HPLC ergab zwar verwendbare Präparationen, allerdings variierte die Retentionszeit von PrPsc derart stark, dass dieses Verfahren nicht weiter eingesetzt wurde. Bezüglich der Verwertbarkeit von CE-LIF wurden die besten Resultate mit Hilfe einer Aufreinigung nach Bio-Rad® mit an-schließender Festphasenextraktion erzielt. Während der Nachweis von PrPsc mittels CE-LIF aus Hirngewebe eindeutig gelang, führte die Untersuchung des Liquors eines bekannt BSE-positiven Tieres zu keinem eindeutigen Ergebnis. Prinzipiell ist die CE-LIF zum Nachweis von PrPsc geeignet. Allerdings handelt es sich dabei um ein sehr störanfälliges Verfahren. Die Sensitivität kann deutlich erhöht werden, wenn die Konzentration von PrPsc in kleine Volumina noch besser gelingt.

Plasminogen wird durch verschiedene Proteasen proteolytisch gespalten. Zu den Enzymen, von denen bekannt ist, daß sie Plasminogen an definierten Peptidbindungen prozessieren können, gehören Elastase aus polymorphnukleären Neutrophilen (PMN) und Metallo-Elastase aus Makrophagen. Ein Spaltprodukt ist Miniplasminogen, das die proteolytische Domäne und den Kringel 5 umfaßt. Die Spaltstelle bei Val441 ist charakterisiert und ein Sandwich-ELISA gegen die Neodeterminante ist etabliert. Das dabei entstehende Counterpart besteht aus den Kringeln1-4. Es wird Angiostatin genannt, weil es hemmend auf die Neubildung von Gefäßen wirkt. Im Rahmen dieser Arbeit sollte untersucht werden, ob Miniplasminogen unter pathologischen Bedingungen wie Sepsis, Peritonitis und Tumorerkrankungen auftritt, um daraus einerseits den Einfluß der Elastase abzuleiten und Einblicke in die pathophysiologischen Abläufe bei Entzündung und Tu-morgeschehen unter Betrachtung der Plasminogenspaltprodukte in Korre-lation zu anderen Parametern zu gewinnen. In Vorversuchen konnte gezeigt werden, daß unter dem Einfluß von aktivierten polymorph-nukleären Neutrophilen Miniplasminogen aus Plas-minogen generiert wird. Von den potentiell an der Proteolyse beteiligten En-zymen konnte in vitro nur bei dem Einsatz von PMN-Elastase Mini-plasminogen nachgewiesen werden, nicht jedoch von MMP-2, -8 und -9. In Untersuchungen zur Stabilität von Miniplasminogen unter verschiedenen Blutabnahmebedingungen waren Citrat-Proben den anderen Systemen (EDTAPlasma, Serum) überlegen. In Proben von gesunden Probanden konnte in keinem Fall Miniplasminogen über der Nachweisgrenze des ELISAs gemessen werden.Es wurden Proben aus klinischen Studien zu Sepsis, Peritonitis und Mammakarzinom ausgewählt, die auf Grund einer hohen PMN-Elastase-Konzentration ein Entstehen von Miniplasminogen erwarten lassen konnten. Ein Ausscheiden von Miniplasminogen über die Niere konnte durch Messungen im Urin ausgeschlossen werden. In Citratplasma-Proben von Peritonitispatienten war kein Miniplasminogen nachweisbar, in Peritonitisexsudaten desselben Patientenkollektivs waren Miniplasminogenwerte bis 90 ng/ml meßbar. Es zeigte sich allerdings keine Korrelation zu anderen Parametern (Elastase-Konzentration, Plasminogenkonzentration). Signifikante Unterschiede der Miniplasminogenkonzentrationen konnten zwischen den Mittelwerten der Proben der Patientengruppe, bei der therapeutisch Fresh-Frozen-Plasma intraabdominell appliziert wurde, und der Kontrollgruppe, sowie zwischen den Gruppen mit und ohne Tumorerkrankung nachgewiesen werden. Bei der Evaluierung von Serumproben aus einem Mammakarzinom-Kollektiv wurden Werte bis 52 ng/ml gemessen. Eine Korrelation mit anderen Parametern oder signifikante Unterschiede in den verschiedenen Subgruppen konnten auch hier nicht gezeigt werden. Ein Zusammenhang zwischen der proteolytischen Kapazität in den Exsudaten und der MPlg-Entstehung ließ sich nicht zweifelsfrei beweisen. MPlg ist daher – im Gegensatz zu dem Elastase-spezifischen Spaltprodukt des Fibrinogens (FEP) (Gippner-Steppert, 1991) - als ein spezifisches Spaltprodukt des Plg nicht für den indirekten Nachweis der proteolytischen Aktivität der PMNElastase geeignet. Erfolgversprechend könnten ggf. immunhistochemische Untersuchungen von Tumormaterial in Hinblick auf das lokale Entstehen von Miniplasminogen sein.