ACC/AHA Task Force Members Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair¶ Sana M. Al-Khatib, MD, ...MHS, FACC, FAHA Joshua A. Beckman, MD, MS, FAHA Kim K. Birtcher, MS, PharmD, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA¶ Ralph G. Brindis, MD, MPH, MACC¶ Joaquin E. Cigarroa, MD, FACC Anita Deswal, MD, MPH, FACC, FAHA Lesley H. Curtis, PhD, FAHA¶ Lee A. Fleisher, MD, FACC, FAHA Federico Gentile, MD, FACC Samuel Gidding, MD, FAHA¶ Zachary D. Goldberger, MD, MS, FACC, FAHA Mark A. Hlatky, MD, FACC, FAHA John Ikonomidis, MD, PhD, FAHA José A. Joglar, MD, FACC, FAHA Laura Mauri, MD, MSc, FAHA Barbara Riegel, PhD, RN, FAHA Susan J. Pressler, PhD, RN, FAHA¶ Duminda N. Wijeysundera, MD, PhD¶Former Task Force member; current member during the writing effort.Table of Contents Preamblee93 Introductione95 1.1.Methodology and Evidence Reviewe95 1.2.Organization of the Writing Committeee95 1.3.Document Review and Approvale95 1.4.Scope of the Guidelinee97 1.5.Abbreviationse99 2. Evidence Gaps and Future Research Needse182 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)e214 Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)e216 Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. Adherence to recommendations can be enhanced by shared decision-making between healthcare providers and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities.Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modifies guideline methodology on the basis of published standards from organizations including the Institute of Medicine (P-1,P-2) and on the basis of internal reevaluation. Publication of new, potentially practice-changing study results that are relevant to an existing or new medication, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned.
Phosphatidylserine (PtdSer), an essential constituent of eukaryotic membranes, is the most abundant anionic phospholipid in the eukaryotic cell accounting for up to 10% of the total cellular lipid. ...Much of what is known about PtdSer is the role exofacial PtdSer plays in apoptosis and blood clotting. However, PtdSer is generally not externally exposed in healthy cells and plays a vital role in several intracellular signaling pathways, though relatively little is known about the precise subcellular localization, transmembrane topology and intracellular dynamics of PtdSer within the cell. The recent development of new, genetically-encoded probes able to detect phosphatidylserine is leading to a more in-depth understanding of the biology of this phospholipid. This review aims to give an overview of recent developments in our understanding of the role of PtdSer in intracellular signaling events derived from the use of these recently developed methods of phosphatidylserine detection.
Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) ...overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBMxenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.
ACC/AHA Task Force Members Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair¶ Sana M. Al-Khatib, MD, ...MHS, FACC, FAHA Joshua A. Beckman, MD, MS, FAHA Kim K. Birtcher, MS, PharmD, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA¶ Ralph G. Brindis, MD, MPH, MACC¶ Joaquin E. Cigarroa, MD, FACC Anita Deswal, MD, MPH, FACC, FAHA Lesley H. Curtis, PhD, FAHA¶ Lee A. Fleisher, MD, FACC, FAHA Federico Gentile, MD, FACC Samuel Gidding, MD, FAHA¶ Zachary D. Goldberger, MD, MS, FACC, FAHA Mark A. Hlatky, MD, FACC, FAHA John Ikonomidis, MD, PhD, FAHA José A. Joglar, MD, FACC, FAHA Laura Mauri, MD, MSc, FAHA Barbara Riegel, PhD, RN, FAHA Susan J. Pressler, PhD, RN, FAHA¶ Duminda N. Wijeysundera, MD, PhD¶Former Task Force member; current member during the writing effort.Table of Contents Preamble1679 Introduction1681 1.1.Methodology and Evidence Review1681 1.2.Organization of the Writing Committee1682 1.3.Document Review and Approval1682 1.4.Scope of the Guideline1682 1.5.Abbreviations1684 2. Evidence Gaps and Future Research Needs1725 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)1742 Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)1744 Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. Adherence to recommendations can be enhanced by shared decision-making between healthcare providers and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities.Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modifies guideline methodology on the basis of published standards from organizations including the Institute of Medicine (P-1,P-2) and on the basis of internal reevaluation. Publication of new, potentially practice-changing study results that are relevant to an existing or new medication, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic ...neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SNC, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Much has been learned about the role of exofacial phosphatidylserine (PS) in apoptosis and blood clotting using annexin V. However, because annexins are impermeant and unable to bind PS at low ...calcium concentration, they are unsuitable for intracellular use. Thus little is known about the topology and dynamics of PS in the endomembranes of normal cells. We used two new probes-green fluorescent protein (GFP)-LactC2, a genetically encoded fluorescent PS biosensor, and 1-palmitoyl-2-(dipyrrometheneboron difluoride)undecanoyl-sn-glycero-3-phospho-L-serine (TopFluor-PS), a synthetic fluorescent PS analogue-to examine PS distribution and dynamics inside live cells. The mobility of PS was assessed by a combination of advanced optical methods, including single-particle tracking and fluorescence correlation spectroscopy. Our results reveal the existence of a sizable fraction of PS with limited mobility, with cortical actin contributing to the confinement of PS in the plasma membrane. We were also able to measure the dynamics of PS in endomembrane organelles. By targeting GFP-LactC2 to the secretory pathway, we detected the presence of PS in the luminal leaflet of the endoplasmic reticulum. Our data provide new insights into properties of PS inside cells and suggest mechanisms to account for the subcellular distribution and function of this phospholipid.
We report the preparation of hybrid self-assembled microgel beads by combining the low molecular weight gelator (LMWG) DBS-CONHNH
2
and the natural polysaccharide calcium alginate polymer gelator ...(PG). Microgel formulations based on LMWGs are extremely rare due to the fragility of the self-assembled networks and the difficulty of retaining any imposed shape. Our hybrid beads contain interpenetrated LMWG and PG networks, and are obtained by an emulsion method, allowing the preparation of spherical gel particles of controllable sizes with diameters in the mm or μm range. Microgels based on LMWG/alginate can be easily prepared with reproducible diameters <1 μm (
ca.
800 nm). They are stable in water at room temperature for many months, and survive injection through a syringe. The rapid assembly of the LMWG on cooling plays an active role in helping control the diameter of the microgel beads. These LMWG microbeads retained the ability of the parent gel to deliver the bioactive molecule heparin, and in cell culture medium this enhanced the growth of human mesenchymal stem cells. Such microgels may therefore have future applications in tissue repair. This approach to fabricating LMWG microgels is a platform technology, which could potentially be applied to a variety of different functional LMWGs, and hence has wide-ranging potential.
We report microgel beads with diameters of
ca.
800 nm based on interpenetrating networks of a low-molecular-weight gelator and a polymer gelator, and demonstrate their use as heparin delivery vehicles to enhance stem cell growth.
Summary
Background: Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations ...and relatively low selectivity for the M1 muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin.
Methods: Cognitive function studies evaluating darifenacin, oxybutynin, tolterodine, solifenacin and/or trospium were identified from publications databases (Medline, Biosis and Embase) and congress s. Preclinical studies and randomised controlled trials in adults were reviewed.
Results: Five randomised, double‐blind, multiple‐dose studies of cognitive function were identified. Oxybutynin was consistently associated with cognitive deficit (four studies), whereas darifenacin did not impair cognition (three studies). These findings were supported by data from sleep/attention and EEG studies. Tolterodine data were limited to one small study with each formulation. For solifenacin and trospium, there were no human studies evaluating memory, the cognitive function most vulnerable to CNS anticholinergics.
Conclusions: There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M1 muscarinic receptor sparing. The risk of CNS impairment is of particular concern for vulnerable populations such as the elderly (a substantial proportion of the OAB population), and CNS‐compromised neurogenic bladder patients such as those with multiple sclerosis or Parkinson’s disease.
We evaluated the therapeutic potential of mesenchymal stem cell-conditioned medium (CM-MSC) as an alternative to cell therapy in an antigen-induced model of arthritis (AIA). Disease severity and ...cartilage loss were evaluated by histopathological analysis of arthritic knee joints and immunostaining of aggrecan neoepitopes. Cell proliferation was assessed for activated and naïve CD4+ T cells from healthy mice following culture with CM-MSC or co-culture with MSCs. T cell polarization was analysed in CD4+ T cells isolated from spleens and lymph nodes of arthritic mice treated with CM-MSC or MSCs. CM-MSC treatment significantly reduced knee-joint swelling, histopathological signs of AIA, cartilage loss and suppressed TNFα induction. Proliferation of CD4+ cells from spleens of healthy mice was not affected by CM-MSC but reduced when cells were co-cultured with MSCs. In the presence of CM-MSC or MSCs, increases in IL-10 concentration were observed in culture medium. Finally, CD4+ T cells from arthritic mice treated with CM-MSC showed increases in FOXP3 and IL-4 expression and positively affected the Treg:Th17 balance in the tissue. CM-MSC treatment reduces cartilage damage and suppresses immune responses by reducing aggrecan cleavage, enhancing Treg function and adjusting the Treg:Th17 ratio. CM-MSC may provide an effective cell-free therapy for inflammatory arthritis.
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