The field of Cellular and Molecular Medicine strives to understand the molecular basis of cell physiology and pathology, as well as cellular responses to extracellular stimuli. It integrates molecular cell biology, basic biochemistry and genetics with virology, bacteriology, physiology/pathophysiology, pharmacology, clinical research and bioinformatics. Results from Cellular and Molecular Medicine, along with advances in Genomics and Proteomics, have enabled the development of Precision/Personalized Medicine. A mechanistic understanding of cellular function and molecular interactions is also being used to monitor states of health (state of wellness) and disease, and major international effort has been invested in identifying pre-disease states and in developing ways to prevent progression to overt disease. A continuum can be established in certain cases at the molecular and cellular level between physiology and pathology, with markers, thresholds and a new biology covering those states. One word that captures the area of interest of Journal of Cellular and Molecular Medicine (JCMM) is ‘mechanism’. JCMM aims to publish original and exciting studies that provide a mechanistic understanding of physiological and pathological processes. The review process must analyse results from many experimental systems addressing a wide range of biological questions, and we aim to publish well-executed, novel and original studies that influence progress in the field and have a long-lasting impact. Our review process relies on a group of distinguished Editorial Board Members and Associate Editors, each of which is an expert in their specific area. We have a large database of reviewers with solid credentials in their fields. We work hard to give each manuscript a fair chance, and we review each manuscript in detail in terms of the experimental work carried out, the reproducibility and interpretation of results and the significance of the work. We think individual observations can change the world, provided they are true and valid. We do not aim to rewrite every paper for the authors, nor do we plan their future experiments. We carefully review the merits of the work under analysis. The vast majority of our effort is focussed on primary research papers (especially original articles), but we have published, and will continue to publish, commissioned or spontaneously submitted reviews, provided they offer new information, novel perspectives and authors have previously contributed to the field. Given the broad scope of the journal, and its impact among scientists and clinicians, a major priority is to strengthen the quality of the manuscripts. Like all journals, we need to protect our readers from plagiarism and from misleading papers. That is why we strive to ensure a very thorough and competent review process. We aim to be recognized as a journal that publishes seminal observations that are confirmed and used by others. In other words, we aim to be positively cited. Fast publication is another priority, and we aim to make original observations available to the scientific community as fast as possible so they are of use to other groups in the field. That is why our team works hard to rapidly publish accepted manuscripts online (before they are grouped in formal monthly issues). We do not delay valid and positively reviewed manuscripts that report one novel finding by asking for more complete studies with extensive in vivo transgenic animal model validation. That is not to say that minimal or incomplete data are sufficient, reasonable validation is always required. A journal that focuses on Cellular and Molecular Medicine cannot ignore major unresolved scientific challenges such as understanding the protein folding code, the differentiation code with respect to chromatin spatial structure and gene expression, the molecular basis of communication between stem and progenitor cells, and many others. Results and novel approaches towards tackling these major challenges are within the areas of interest of JCMM. In the same vein, JCMM is interested in publishing studies investigating the mechanisms of action of therapeutics and the molecular and cellular effects of those therapeutics. Recent years have also seen major advances in protein therapeutics such as replacement cytokines and hormones, but also for example, humanized antibodies that are being used for the treatment of many diseases and other protein therapeutics, like single-chain antibodies and diabodies. Developments in this area are as important as the fundamental questions, because novel observations using these agents can help our understanding of cellular functions and the manipulation of cellular functions for therapeutic purposes. Recent years have led to the increased integration of the biomedical field with genomics and proteomics. The successful sequencing of the human genome and developments in bioinformatics allow rapid analysis of proteins and genes studied by mass spectrometry and next-generation sequencing, respectively. We are in the age of mutations and disease where certain mutations explain the phenotype or disease progression. In general, the identification of mutations allowed a paradigm shift in diagnosis and prognosis in many pathological conditions. The unexpected finding that several disease-associated (and causing) mutations can be found in healthy individuals with, for example, clonal haematopoiesis due to ageing, but without pathological features, opened up an entirely new area of investigation whereby mutations alone do not suffice to produce disease. We encourage submission of manuscripts from this research area, provided a mechanism is explored. We target the journal at young and senior researchers in biomedical and clinical research and also aim to attract readers with a broad interest in scientific progress. That is why we will focus on making the manuscripts accessible to the wider scientific community and why we insist on authors obviously explaining their findings so that conceptual advances can be accessible to a broad readership. In short, we will publish original mechanistic observations that are experimentally sound and have potential for a significant impact in medicine. This has been the cornerstone of the journal since its foundation by Professor Laurentiu M. Popescu, a scientist at the forefront of cellular physiology, cell biology and pharmacology, who guided the direction of this journal to publish original and potentially spectacular observations that could inspire others.
No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Jan 2003Urethral Stricture Repair With an Off-the-shelf Collagen Matrix ABDEL W. EL-KASSABY, ALAN B. RETIK, JAMES J. YOO, and ANTHONY ATALA ABDEL W. EL-KASSABYABDEL W. EL-KASSABY , ALAN B. RETIKALAN B. RETIK , JAMES J. YOOJAMES J. YOO , and ANTHONY ATALAANTHONY ATALA View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)64060-8AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: In select patients with urethral strictures in whom genital skin is insufficient alternative tissues are needed for urethral reconstruction. We explored the feasibility of using a bladder submucosa collagen based inert matrix as a free graft substitute for urethral stricture repair. Materials and Methods: A total of 28 patients 22 to 61 years old with a diagnosis of urethral stricture underwent reconstructive surgery using a collagen based inert matrix for urethral repair. The inert collagen matrix was trimmed to size as needed for each patient and the neourethra was created by anastomosing the matrix in an onlay fashion to the urethral plate with continuous 6-zero absorbable sutures. The size of the created neourethra ranged from 1.5 to 16 cm. A voiding history, physical examination, retrograde urethrography, uroflowmetry and cystoscopic examinations were performed preoperatively and postoperatively. Random urethral biopsies were also performed. Results: After a 36 to 48-month followup (mean 37) 24 of the 28 patients had a successful outcome. The remaining 4 patients had a slight caliber decrease at the anastomotic sites on urethrography. A subcoronal fistula developed in 1 patient which closed spontaneously 1 year after repair. Mean maximum urine flow rate increased from the preoperative value of 9 ± 1.29 to 19.7 ± 3.07 ml. per second postoperatively. Cystoscopic studies revealed adequate caliber conduits and normal appearing urethral tissues. Histological examination of the biopsy specimens showed the typical urethral stratified epithelium. Conclusions: Use of an off-the-shelf collagen inert matrix appears to be beneficial for patients with urethral strictures and obviates the need for obtaining an autologous graft, thus eliminating donor site morbidity. References 1 : Preface. Urethral reconstruction. Urol Clin North Am2002; 29: 2. Crossref, Google Scholar 2 : Neourethra with rectum, posterior sagittal approach. In: Reconstructive and Plastic Surgery of the External Genitalia: Adult and Pediatric. Edited by . Philadelphia: W. B. Saunders Co.1999. Google Scholar 3 : Autologous buccal mucosa graft for hypospadias repair: an initial report. J Urol1992; 147: 1081. 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HomeCirculationVol. 141, No. 22Will Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBWill Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Courtney M. Campbell and Rami Kahwash Courtney M. CampbellCourtney M. Campbell Courtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. and Rami KahwashRami Kahwash Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. Originally published9 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047419Circulation. 2020;141:1739–1741Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 9, 2020: Ahead of Print SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus responsible for the current pandemic, resulting in an escalating number of cases and fatalities worldwide. Despite a high infection rate of coronavirus disease 2019 (COVID-19), only an estimated 15% of patients require hospitalization, with 5% requiring intensive care. Nearly half (49%) of patients requiring intensive care died. How and why patients succumb to SARS-CoV-2 infection is not well understood. A poignant New York Times article described the sudden decompensation and death of a young physician after she had documented viral clearance and was preparing to go home.Several early publications from the Wuhan region of China focused on describing clinical characteristics of hospitalized patients with severe COVID-19 illness. These initial observational studies demonstrate in severe cases evidence of coagulation dysfunction through elevated D-dimer, elevated lactate dehydrogenase, elevated total bilirubin, and decreased platelets with slight or no changes in partial thromboplastin time or activated partial thromboplastin time. In patients with severe or fatal COVD-19, there is also evidence of end-organ damage with acute kidney injury and primarily mildly elevated troponin. In the study by Shi et al,1 a significantly higher percentage of patients with cardiac injury (average troponin I 0.19 µg/L) died compared with those patients without cardiac injury (51.2% versus 4.5%, respectively).The mechanism of cardiac injury for COVID-19 is uncertain. No series of cardiac imaging data, such as echocardiography or cardiac magnetic resonance imaging, has been published for patients with COVID-19. Theories include direct viral damage via the angiotensin-converting enzyme 2 receptor, myocarditis, systemic inflammatory response with cytokine storm, destabilized coronary plaques, and aggravated hypoxia. In case reports of COVID-19–related myocarditis, patients had minimal pulmonary involvement and significant cardiac involvement and recovered from COVID-19. Cardiac biomarkers in the myocarditis cases were much higher than the average values of cardiac injury in patients with COVID-19 reported in the observational studies. Whether myocarditis as a COVID-19 mechanism applies broadly is uncertain. Excessive cytokine release has also been observed in patients with COVID-19. High cytokines were also found in patients with SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus), but subsequent studies demonstrated that corticosteroids did not improve mortality and delayed viral clearance. Tocilizumab, an interleukin-6 inhibitor, is being studied as a potential treatment option. However, elevated cytokines in this context could be a biomarker of critical illness with COVID-19 rather than the pathogenic mediator.In a joint webinar between the Chinese Cardiology Association and the American College of Cardiology on March 28, 2020, the Chinese cardiologists described diffuse microvascular thrombi in multiple organs on autopsy review of COVID-19 nonsurvivors. Given this diffuse thrombosis, Chinese physicians recommended treatment of patients with COVID-19 with systemic anticoagulation, but no trials or publications have evaluated this approach. Similar findings of diffuse multiorgan microvascular thrombosis without viral infiltrates were seen in an autopsy case report for a patient who died of SARS.2Thrombotic microangiopathy (TMA) can occur in many different clinical scenarios, including pathogenic complement activation. The complement system is a mediator of the innate immune response that promotes inflammation, defends against bacterial infections, and often neutralizes infectious viruses. In brief, the complement cascade can be activated via the classical pathway, triggered by antibody-antigen complexes; the alternative pathway, stimulated by specific surface antigens; and the lectin pathway, initiated by binding mannose residues on the pathogen surface. These pathways converge on the common pathway. The common pathway includes production of C3a and C5a inflammatory mediators and C3b-initiated pathogen opsonization and ends in formation of the C5b-9 membrane attack complex, which lyses target cells, resulting in cell death (Figure [A]). Two murine studies directly investigated complement activation in coronavirus infections and asked whether activation of the system would be protective or pathogenic. In a murine model lacking C3 and thus unable to activate the common complement pathway, SARS-CoV infection severity was decreased, with less respiratory dysfunction and lower cytokine levels despite equal viral loads (Figure [C]).2 The authors suggest that a significant portion of SARS-mediated disease is likely immune mediated. In a murine model of MERS-CoV infection, increased concentrations of C5a and C5b-9 were found in sera and lung tissues.4 Blocking C5a with a murine antibody alleviated lung and spleen damage, with decreased cytokine response and viral replication (Figure [D]).Download figureDownload PowerPointFigure. Coronavirus and complement.A, Simplified diagram of the common complement pathway. Eculizumab inhibits C5, preventing breakdown into C5a and C5b, which is an integral component of the membrane attack complex (MAC). B, In humans, overactivation of the complement pathway can lead to thrombotic microangiopathy, resulting in renal and cardiac dysfunction. In atypical hemolytic-uremic syndrome (aHUS), early treatment with eculizumab reverses organ dysfunction. C, On the basis of the mouse model of SARS-CoV (severe acute respiratory syndrome coronavirus)infection described by Gralinski et al,2 lack of the C3 protein results in improved lung function, less cytokine release, and no change in viral load compared with mice with an intact complement system. D, On the basis of the mouse model of MERS-CoV (Middle East respiratory syndrome coronavirus) infection described by Jiang et al,3 antibody blockade of C5 results in improved lung function, less cytokine release, and less viral load compared with untreated mice.In humans, excessive complement activation occurs in a number of pathological settings, leading to diffuse TMA and end-organ dysfunction (Figure [B]). Atypical hemolytic-uremic syndrome (aHUS) is a rare disorder of uncontrolled complement activation characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. TMA in aHUS results in renal dysfunction and, in rare cases, cardiac dysfunction.5 Patients often have an underlying genetic predisposition, with variants in the complement cascade. Alternatively, infection, pregnancy, and certain medications and autoimmune disorders can trigger complement-activating autoantibodies. Importantly, aHUS is treatable with a C5 complement inhibitor, eculizumab. If given early, eculizumab therapy can reverse both renal and cardiac dysfunction.5 Before the introduction of eculizumab, the prognosis of aHUS was poor, with 67% of adults dying within 5 years.Transplant-associated TMA is also thought to be initiated by excessive complement activation, trigged by endothelial injury from chemotherapy, radiation, or viral infection. A recent study showed that 78% of patients with transplant-associated TMA had a pathogenic or likely pathogenic variant in TMA and complement-associated genes.6 Importantly, endothelial injury is a hallmark of COVID-19. Like SARS-CoV, COVID-19 acts primarily through the angiotensin-converting enzyme 2 receptor, which is expressed widely in vascular tissues, including alveolar epithelium and cardiac pericytes.Complement inhibition may be a promising treatment for severe COVID-19 by reducing the innate immune-mediated consequences of severe coronavirus infection, and it would pair well with direct antiviral therapy. The published clinical observations of severe COVID-19 are consistent with excessive complement activation: elevated lactate dehydrogenase, D-dimer, and bilirubin; decreased platelets; mild anemia; renal and cardiac injury; and reportedly diffuse TMA. Patients with severe and fatal cases of COVID-19 might have increased susceptibility to TMA through a genetic predisposition to pathogenic complement activation. Complement inhibition was associated with favorable outcomes in SARS-CoV and MERS-CoV murine models and reversed cardiac dysfunction in aHUS-TMA, which mimics the pathological findings seen in COVID-19. Complement inhibition might be a new target in treating COVID-19–related systemic thrombosis. This approach is worthy of further investigation with a randomized, controlled clinical trial to investigate whether complement inhibition could improve the clinical course for COVID-19 patients with severe disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circCourtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email courtney.campbell@osumc.eduReferences1. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China [published online March 25, 2020].JAMA Cardiol. doi: 10.1001/jamacardio.2020.0950. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524.Google Scholar2. Xiang-Hua Y, Le-Min W, Ai-Bin L, Zhu G, Riquan L, Xu-You Z, Wei-Wei R, Ye-Nan W. Severe acute respiratory syndrome and venous thromboembolism in multiple organs.Am J Respir Crit Care Med. 2010; 182:436–437. doi: 10.1164/ajrccm.182.3.436CrossrefMedlineGoogle Scholar3. Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis.mBio. 2018; 9:e01753-18. doi: 10.1128/mBio.01753-18CrossrefMedlineGoogle Scholar4. Jiang Y, Zhao G, Song N, Li P, Chen Y, Guo Y, Li J, Du L, Jiang S, Guo R, et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.Emerg Microbes Infect. 2018; 7:77. doi: 10.1038/s41426-018-0063-8CrossrefMedlineGoogle Scholar5. Campbell CM, Cassol C, Cataland SR, Kahwash R. Atypical haemolytic uraemic syndrome: a case report of a rare cause of reversible cardiomyopathy.Eur Heart J Case Rep. 2020; 4:1–6. doi: 10.1093/ehjcr/ytaa050CrossrefMedlineGoogle Scholar6. Gavriilaki E, Touloumenidou T, Sakellari I, Batsis I, Mallouri D, Psomopoulos F, Tsagiopoulou M, Koutra M, Yannaki E, Papalexandri A, et al. Pretransplant genetic susceptibility: clinical relevance in transplant-associated thrombotic microangiopathy.Thromb Haemost. March 4, 2020; 120:638–646. doi: 10.1055/s-0040-1702225CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. 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Kutlutürk I, Tokuç E, Karabaş L, Rückert R, Kaya M, Karagöz A and Munk M (2023) How the immune response to the structural proteins of SARS-CoV-2 affects the retinal vascular endothelial cells: an immune thrombotic and/or endotheliopathy process with in silico modeling, Immunologic Research, 10.1007/s12026-023-09412-1, 72:1, (50-71), Online publication date: 1-Feb-2024. Khokhlov R, Yarmonova M and Tribuntseva L (2024) Lesions of the heart and parenchymatous organs in patients with COVID-19 and other acute respiratory infections, Russian Family Doctor, 10.17816/RFD622794, 27:4, (21-32) Rizoli S, Peralta R, Al-Thani H, Ramzee A, El-Menyar A, Asim M, Shahid F, Fino A, Ata Y, El Baba H, Nair A and Al Maslamani M (2023) Descriptive Analysis of Thromboembolic Events in COVID-19 Patients in Qatar, Panamerican Journal of Trauma, Critical Care & Emergency Surgery, 10.5005/jp-journals-10030-1436, 12:3, (120-130), Online publication date: 30-Dec-2023. 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Kawakami E, Saiki N, Yoneyama Y, Moriya C, Maezawa M, Kawamura S, Kinebuchi A, Kono T, Funata M, Sakoda A, Kondo S, Ebihara T, Matsumoto H, Togami Y, Ogura H, Sugihara F, Okuzaki D, Kojima T, Deguchi S, Vallee S, McQuade S, Islam R, Natarajan M, Ishigaki H, Nakayama M, Nguyen C, Kitagawa Y, Wu Y, Mori K, Hishiki T, Takasaki T, Itoh Y, Takayama K, Nio Y and Takebe T (2023) Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19, Cell Stem Cell, 10.1016/j.stem.2023.09.001, 30:10, (1315-1330.e10), Online publication date: 1-Oct-2023. Tomo S, Kiran Kumar P, Yadav D, Sankanagoudar S, Charan J, Purohit A, Nag V, Bhatia P, Singh K, Dutt N, Garg M, Misra S, Sharma P and Purohit P (2023) Association of Serum Complement C3 Levels with Severity and Mortality in COVID 19, Indian Journal of Clinical Biochemistry, 10.1007/s12291-023-01148-x, 38:4, (447-456), Online publication date: 1-Oct-2023. Shama , Mahmood A, Mehmood S and Zhang W (2023) Pathological Effects of SARS-CoV-2 Associated with Hematological Abnormalities, Current Issues in Molecular Biology, 10.3390/cimb45090453, 45:9, (7161-7182) Ge X, Yu Z, Guo X, Li L, Ye L, Ye M, Yuan J, Zhu C, Hu W and Hou Y (2023) Complement and complement regulatory proteins are upregulated in lungs of COVID-19 patients, Pathology - Research and Practice, 10.1016/j.prp.2023.154519, 247, (154519), Online publication date: 1-Jul-2023. Safiriyu I, Fatuyi M, Mehta A, Naser A, Alexander E, Vovan H, Shamaki G and Bob-Manuel T (2023) Impact of COVID-19 Infection on the Clinical Outcomes of Pulmonary Embolism Hospitalizations : A Nationwide Analysis, Current Problems in Cardiology, 10.1016/j.cpcardiol.2023.101669, 48:7, (101669), Online publication date: 1-Jul-2023. Yusharyahya S, Japranata V, Jonlean R, Legiawati L and Astriningrum R (2023) Cutaneous manifestations in elderly patients with confirmed coronavirus disease 2019 and the disease outcomes: A systematic review, The Journal of Dermatology, 10.1111/1346-8138.16722, 50:5, (679-691), Online publication date: 1-May-2023. Purbey P, Roy K, Gupta S and Paul M (2023) Mechanistic insight into the protective and pathogenic immune-responses against SARS-CoV-2, Molecular Immunology, 10.1016/j.molimm.2023.03.009, 156, (111-126), Online publication date: 1-Apr-2023. Iwaniuk A and Jablonska E (2023) Neutrophils in Health and Disease: From Receptor Sensing to Inflammasome Activation, International Journal of Molecular Sciences, 10.3390/ijms24076340, 24:7, (6340) Mocanu A, Bogos R, Lazaruc T, Cianga A, Lupu V, Ioniuc I, Alecsa M, Lupu A, Ivanov A, Miron I and Starcea I (2023) Pitfalls of Thrombotic Microangiopathies in Children: Two Case Reports and Literature Review, Diagnostics, 10.3390/diagnostics13071228, 13:7, (1228) Zhao X, Wu H, Li S, Gao C, Wang J, Ge L, Song Z, Ni B and You Y (2023) The impact of the COVID-19 pandemic on SLE, Modern Rheumatology, 10.1093/mr/road030 Matošević M, Kos I, Davidović M, Ban M, Matković H, Jakopčić I, Vuković Brinar I, Szilágyi Á, Csuka D, Sinkovits G, Prohászka Z, Vrljičak K and Lamot L (2023) Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature, Frontiers in Pediatrics, 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respiratory syndrome coronavirus infection, Frontiers in S, G, G, S, M, E, M and S Previous the of Coronavirus Medical Online publication date: H, M, M, A, M, M, M, S, A and Y and of in Patients with Severe COVID-19 and the Association between the of and The Journal of Critical Care Medicine, Online publication date: Online publication date: A, S, A, M, K, N, E, D, I, G, M, M, S, D, A, P, M, M, S, S, M, F, M, R, P, A, R, El K, R, J, J, A, M, M, F, M, A, A, B, S, A, S, A, D, J, R, J, C, M, Wu H, J, D, A, M, V, A, Gupta G, A, P, C, P, N, X, M, J, M, M, M, G, K, F, Z, S, L, Du R, M, D, R, M, Nguyen T, N, J, J, H, M, N, R, S, A, A and P International controlled study of and outcomes , Journal of Online publication date: Ye J, Yang P, Yang Y and S Complement as a and and Frontiers in Immunology, P, S, M, P and M in COVID-19 – A review of the potential of to disease Molecular Immunology, Online publication date: N, Y, Kumar M, M and L of COVID in A Case in Patients a Indian Journal of and & Surgery, Online publication date: Roy B and S SARS-CoV-2 infection and mechanism of organ Journal of V, Mehta S, S, S and P COVID-19 Effects in and Online publication date: P, F, C, T, C, A, R, B, G, H, J, D, S and B of cardiac evidence for a disease in an autopsy Online publication date: I, A, I, N, and S of of the SARS-CoV-2 A B D and current of the and of and A review, Clinical and Online publication date: N, E, M, P, S, R, A and D Complement A approach in the against in Medical Online publication date: Gavriilaki E, S, Touloumenidou T, E, P, E, E, I, E, E, E, P, C, S, Papalexandri A, M, A, D, E, Sakellari I, A and A of Patients a Complement COVID-19 Current Issues in Molecular Biology, P, A, A, M, K, N, E, I, G, M, M, S, D, A, P, M, M, S, S, M, F, M, D, R, P, A, R, El K, R, B, J, J, A, M, M, F, M, A, A, B, S, A, S, A, D, M, Wu H, J, D, A, M, V, A, Gupta G, A, P, C, P, N, X, M, J, M, M, M, G, K, F, Z, S, L, M, Nguyen T, P, A, J, K, J, H, M, N, R, S and A of a COVID-19 A 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HomeCirculationVol. 142, No. 1Obesity Is a Risk Factor for Severe COVID-19 Infection Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBObesity Is a Risk Factor for Severe COVID-19 InfectionMultiple Potential Mechanisms Naveed Sattar, Iain B. McInnes and John J.V. McMurray Naveed SattarNaveed Sattar Naveed Sattar, MD, Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1604-2593 Institute of Cardiovascular and Medical Sciences (N.S., J.J.V.M.), University of Glasgow, United Kingdom. , Iain B. McInnesIain B. McInnes Institute of Infection, Immunity and Inflammation (I.B.M.), University of Glasgow, United Kingdom. and John J.V. McMurrayJohn J.V. McMurray Institute of Cardiovascular and Medical Sciences (N.S., J.J.V.M.), University of Glasgow, United Kingdom. Originally published22 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047659Circulation. 2020;142:4–6Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 22, 2020: Ahead of Print The coronavirus disease 2019 (COVID-19) pandemic has led to worldwide research efforts to identify people at greatest risk of developing critical illness and dying. Initial data pointed toward older individuals being particularly vulnerable, as well as those with diabetes mellitus or cardiovascular (including hypertension), respiratory, or kidney disease. These problems are often concentrated in certain racial groups (eg, African Americans and Asians), which also appear to be more prone to worse COVID-19 outcomes.1 Increasing numbers of reports have linked obesity to more severe COVID-19 illness and death.1–3 In a French study, the risk for invasive mechanical ventilation in patients with COVID-19 infection admitted to the intensive treatment unit was more than 7-fold higher for those with body mass index (BMI) >35 compared with BMI <25 kg/m2.2 Among individuals with COVID-19 who were <60 years of age in New York City, those with a BMI between 30 to 34 kg/m2 and >35 kg/m2 were 1.8 times and 3.6 times more likely to be admitted to critical care, respectively, than individuals with a BMI <30 kg/m2.3We suggest obesity or excess ectopic fat deposition may be a unifying risk factor for severe COVID-19 infection, reducing protective cardiorespiratory reserve as well as potentiating the immune dysregulation that appears, at least in part, to mediate the progression to critical illness and organ failure in a proportion of patients with COVID-19 (Figure). Whether obesity is an independent risk factor for susceptibility to infection requires further research.Download figureDownload PowerPointFigure. Pathways potentially linking obesity or excess ectopic fat to more severe coronavirus disease 2019 (COVID-19) illness. There are multiple pathways by which obesity (or excess ectopic fat) may increase the effect of COVID-19 infection. These include underlying impairments in cardiovascular, respiratory, metabolic, and thrombotic pathways in relation to obesity, all of which reduce reserve and ability to cope with COVID-19 infection and the secondary immune reaction to it. At the same time, there are several reasons why obese individuals may have amplified or dysregulated immune response, linked both to greater viral exposure, as well as the possibility that excess adipose tissue potentiates the immune response. BP indicates blood pressure; COVID-19, coronavirus disease 2019; CV, cardiovascular; FEV1, forced expiratory volume; FVC, forced vital capacity; and SES, socioeconomic status.From a cardiovascular perspective, trial and genetic evidence conclusively show that obesity (and excess fat mass) are causally related to hypertension, diabetes mellitus, coronary heart disease, stroke, atrial fibrillation, renal disease, and heart failure. Obesity potentiates multiple cardiovascular risk factors, the premature development of cardiovascular disease, and adverse cardiorenal outcomes. There is also a metabolic concern. In individuals with diabetes mellitus, or at high risk of diabetes mellitus, obesity and excess ectopic fat lead to impairment of insulin resistance and reduced β-cell function. Both the latter limit ability to evoke an appropriate metabolic response on immunologic challenge, leading some patients with diabetes mellitus to require substantial amounts of insulin during severe infections. Overall, the integrated regulation of metabolism required for the complex cellular interactions, and for effective host defense, is lost, leading to functional immunologic deficit. COVID-19 may also directly disrupt pancreatic β-cell function through an interaction with angiotensin-converting enzyme 2. Furthermore, obesity enhances thrombosis, which is relevant given the association between severe COVID-19 and prothrombotic disseminated intravascular coagulation and high rates of venous thromboembolism.Beyond cardiometabolic and thrombotic consequences, obesity has detrimental effects on lung function, diminishing forced expiratory volume and forced vital capacity (Figure). Higher relative fat mass is also linked to such adverse changes, perhaps relevant to emerging reports of greater critical illness from COVID-19 in certain ethnicities, eg, Asians.1 Asians often display lower cardiorespiratory fitness and carry proportionally more fat tissue at lower BMIs. With extreme obesity (eg, BMI >40 kg/m2), care for individuals admitted to intensive therapy units is often impeded as these patients are more difficult to image, ventilate, nurse, and rehabilitate.With respect to the immune response, there is a clear association between obesity and basal inflammatory status characterized by higher circulating interleukin 6 and C-reactive protein levels. Adipose tissue in obesity is "proinflammatory," with increased expression of cytokines and particularly adipokines. There is also dysregulated tissue leukocyte expression, and inflammatory macrophage (and innate lymphoid) subsets replace tissue regulatory (M2) phenotypic cells. Obesity per se is an independent and causal risk factor for the development of immune-mediated disease, eg, psoriasis,4 suggesting that such adipose state may have systemic immune consequence on additional environmental provocation. In terms of host defense, obesity impairs adaptive immune responses to influenza virus5 and conceivably could do so in COVID-19. Obese individuals may exhibit greater viral shedding, suggesting potential for great viral exposure, especially if several family members are overweight. This may be aggravated in overcrowded multigenerational households, which are more common in the socioeconomically deprived communities in which obesity is prevalent. All these observations point toward a potential for obesity to give rise to a more adverse virus versus host immune response relationship in COVID-19. Poorer nutritional status and hyperglycemia may further aggravate the situation in some obese individuals.Much of the focus of COVID-19 has been on older people. However, it is important to remember that weight and muscle mass start to decline at advanced age but relative fat mass increases, particularly in those with comorbid diseases such as cardiovascular and respiratory conditions. Older age is also associated with more hypertension and diabetes mellitus because of stiffer vessels and impaired metabolic efficiency, respectively. People who are older (eg, >70 years of age), similar to younger obese individuals, have less cardiorespiratory reserve to cope with COVID-19 infection. Immune senescence is well recognized, as is the concept of inflammaging, and both may influence virus–host dynamics in the elderly and infection outcomes.What are the implications of these emerging observations for future research and public health messaging? With respect to research, predictive instruments for those most at risk of severe outcomes should consider BMI. Mechanistic understanding of the relationship between obesity and COVID-19 may suggest therapeutic interventions (eg, proven weight loss drugs, low-calorie diets) to potentially reduce the risk of developing severe COVID-19 illness. With respect to public health, it is important to communicate risks without causing anxiety. People worldwide should be encouraged to improve their lifestyle to lessen risk both in the current and subsequent waves of COVID-19. In addition to increasing activity levels, there should be improved messaging on better diet, focusing on simpler advice to help people adopt sustainable changes. This is particularly challenging with current stay-at-home rules limiting activity levels—the lockdown cost of weight gain. Even more worrying is that the resultant economic downturn may worsen obesity, especially in the most vulnerable individuals, a risk that governments need to address after the current pandemic. Indeed, this pandemic has highlighted that more—not less—must be done to tackle and prevent obesity in societies for the prevention of chronic disease and greater adverse reactions to viral pandemics.AcknowledgmentsThe authors thank Liz Coyle from the University of Glasgow for her excellent technical assistance in the preparation of this article.Sources of FundingThe work in this study is supported by the British Heart Foundation Center of Research Excellence Grant RE/18/6/34217.DisclosuresDr Sattar reports personal fees from Amgen, AstraZeneca, Eli Lilly, Novo Nordisk, Pfizer, and Sanofi and personal fees and research grants from Boehringer Ingelheim outside the submitted work. Drs McInnes and McMurray report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circNaveed Sattar, MD, Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Email naveed.sattar@glasgow.ac.ukReferences1. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell LF, Chernyak Y, Tobin K, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.BMJ2020; 369:m1966. doi: 10.1136/bmj.m1966CrossrefMedlineGoogle Scholar2. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, Labreuche J, Mathieu D, Pattou F, Jourdain M, Lille Intensive Care COVID-19 and Obesity Study Group. 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Obesity impairs the adaptive immune response to influenza virus.Ann Am Thorac Soc. 2017; 14(suppl 5):S406–S409. doi: 10.1513/AnnalsATS.201706-447AWCrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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The Journal of Bone and Joint Surgery. British volumeVol. 70-B, No. 4 ArticlesFree AccessDoes corrosion matter?J BlackJ BlackSearch for more papers by this authorPublished Online:1 Aug 1988https://doi.org/10.1302/0301-620X.70B4.3403590AboutSectionsPDF/EPUB ToolsAdd to FavouritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byPediatric fractures following implant removal: A systematic review10 November 2022 | Journal of Children's Orthopaedics, Vol. 6Effect of boron oxide on mechanical and thermal properties of bioactive glass coatings for biomedical applications7 March 2022 | Journal of the American Ceramic Society, Vol. 105, No. 6Titanium Wear of Dental Implants from Placement, under Loading and Maintenance Protocols21 January 2021 | International Journal of Molecular Sciences, Vol. 22, No. 3IN VITRO STUDY AND MECHANICAL CHARACTERISTICS OF DENTAL IMPLANTS MADE OF VARIOUS MATERIALS AND FABRICATION METHODS18 February 2021 | Journal of Mechanics in Medicine and Biology, Vol. 21, No. 01Coatings on orthopedic implants to overcome present problems and challenges: A focused reviewMaterials Today: Proceedings, Vol. 45Hardware removal rates after surgical treatment of proximal femur fractures21 January 2020 | Archives of Orthopaedic and Trauma Surgery, Vol. 140, No. 8Recent advancements in Fe-based biodegradable materials for bone repair19 October 2018 | Journal of Materials Science, Vol. 54, No. 3Mandibular Osteotomies1 August 2019Biodegradation of gold and platinum implants in rats studied by electron microscopy27 November 2019 | International Journal of Physics Research and Applications, Vol. 2, No. 1Artificial neural network based optimization of prerequisite properties for the design of biocompatible titanium alloysComputational Materials Science, Vol. 149Detection of Titanium Particles in Soft Tissues Adjacent to the Fixators in Patients with Facial Fractures and Bone Defects30 March 2018 | Journal of Diagnostics and Treatment of Oral and Maxillofacial Pathology, Vol. 2, No. 1Metal-on-Metal Hip Implants: Progress and Problems25 February 2018Dual-surface modification of titanium alloy with anodizing treatment and bioceramic particles for enhancing prosthetic devices21 April 2017 | Journal of Materials Science, Vol. 52, No. 15In Vivo Damage of the Head-Neck Junction in Hard-on-Hard Total Hip Replacements: Effect of Femoral Head Size, Metal Combination, and 12/14 Taper Design1 July 2017 | Materials, Vol. 10, No. 7Influence of process parameters on plasma electrolytic surface treatment of tantalum for biomedical applicationsApplied Surface Science, Vol. 407Fabrication and apatite inducing ability of different porous titania structures by PEO treatmentMaterials Science and Engineering: C, Vol. 66Inorganic characterizations and filler particles morphology of self-adhesive cementsInternational Journal of Adhesion and Adhesives, Vol. 68Study of the bioactivity, wettability and hardness behaviour of the bovine hydroxyapatite-diopside bio-nanocomposite coatingJournal of the Taiwan Institute of Chemical Engineers, Vol. 60Chapter 4 Immune Response12 June 2016Tribocorrosion and TMJ TJR DevicesAnodisation and Sol–Gel Coatings as Surface Modification to Promote Osseointegration in Metallic Prosthesis10 August 2016Corrosion at the Head-Neck Taper Interface Affects the Prognosis of Hip Revision Surgery29 January 2016Is Taper Fretting Corrosion a Threat to the Clinical Performance of Large-Diameter Hips with Highly Crosslinked Polyethylene Bearings?29 January 2016In vivo electrochemical corrosion study of a CoCrMo biomedical alloy in human synovial fluidsActa Biomaterialia, Vol. 21Metal Removal29 October 2014Do Ceramic Femoral Heads Reduce Taper Fretting Corrosion in Hip Arthroplasty? 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Particle microanalysis and histopathological findings.The Journal of Bone & Joint Surgery, Vol. 76, No. 9Intramedullary bone formation after polylactic acid wire implantationJournal of Materials Science: Materials in Medicine, Vol. 5, No. 6-7In vivo corrosion of modular hip prosthesis components in mixed and similar metal combinations. The effect of crevice, stress, motion, and alloy couplingJournal of Biomedical Materials Research, Vol. 27, No. 12The Rationale for Cemented Total Hip ArthroplastyOrthopedic Clinics of North America, Vol. 24, No. 4Current Concepts in Orthopaedic Biomaterials and Implant FixationThe Journal of Bone & Joint Surgery, Vol. 75, No. 7Evaluation of wear in an all-polymer total knee replacement. Part 2: Clinical evaluation of wear in a polyethylene on polyacetal total kneeClinical Materials, Vol. 14, No. 2Biodegradation of orthodontic appliances. Part I. Biodegradation of nickel and chromium in vitroAmerican Journal of Orthodontics and Dentofacial Orthopedics, Vol. 103, No. 1Acrylic bone cements: Residuals and extractability of methacrylate monomers and aromatic aminesJournal of Applied Biomaterials, Vol. 3, No. 1Observations on removal of metal implantsInjury, Vol. 23, No. 1The biologic responses to orthopedic implants and their wear debrisClinical Materials, Vol. 9, No. 3-4Severe metallosis due to abnormal abrasion of the femoral head in a dual bearing hip prosthesisThe Journal of Arthroplasty, Vol. 7Foreign-body reactions to polyglycolide screws8 July 2009 | Acta Orthopaedica Scandinavica, Vol. 63, No. 2Genotoxicity of Acrylic Bone CementsPharmacology & Toxicology, Vol. 69, No. 5Dental implant materials. I. Some effects of preparative procedures on surface topographyJournal of Biomedical Materials Research, Vol. 25, No. 9Fracture-associated SarcomasVeterinary Clinics of North America: Small Animal Practice, Vol. 21, No. 4Systemic effects of implanted prostheses made of cobalt-chromium alloysArchives of Orthopaedic and Trauma Surgery, Vol. 110, No. 2CANCER RISK AFTER MCKEE-FARRAR TOTAL HIP REPLACEMENTOrthopedics, Vol. 14, No. 2Rigid Internal Fixation Facts Versus FallaciesOral and Maxillofacial Surgery Clinics of North America, Vol. 2, No. 4Metal materials biodegradation: a chronoamperometric studyJournal of Materials Science: Materials in Medicine, Vol. 1, No. 2Forearm fracture plates: To remove or not to removeThe Journal of Hand Surgery, Vol. 15, No. 2Niomaterials Highlights II. Materials for Biomedical Applications — High Long-Term Success Rates might pose new ProblemsAngewandte Chemie, Vol. 101, No. 7Materials for biomedical application- high long-term success rates might pose new problemsAdvanced Materials, Vol. 1, No. 7Blood Analysis for Trace Metals in Patients with Different Bearings in Total Hip ArthroplastyMandibular Osteotomies and Considerations for Rigid Internal Fixation Vol. 70-B, No. 4 Metrics History Published online 1 August 1988 Published in print 1 August 1988 InformationCopyright © 1988, The British Editorial Society of Bone and Joint Surgery: All rights reservedPDF download
BioTechniquesVol. 30, No. 1 BenchmarksOpen AccessMicroplate Assay for the Measurement of Hydroxyproline in Acid-Hydrolyzed Tissue SamplesSharon Brown, Michael Worsfold & Christopher SharpSharon Brown*Address correspondence to Ms. Sharon Brown, Charles Salt Centre, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG, UK. e-mail: E-mail Address: sharon.rowbotham@rjahoh-tr.wmids.nhs.ukRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, ShropshireUniversity College Chester, Chester, Cheshire, UK, Michael WorsfoldRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire & Christopher SharpRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, ShropshirePublished Online:5 Sep 2018https://doi.org/10.2144/01301bm06AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit FiguresReferencesRelatedDetailsCited ByCollagen fibrils from both positional and energy-storing tendons exhibit increased amounts of denatured collagen when stretched beyond the yield pointActa Biomaterialia, Vol. 155Unraveling the effect of collagen damage on bone fracture using in situ synchrotron microtomography with deep learning21 October 2022 | Communications Materials, Vol. 3, No. 1Collagen Molecular Damage is a Hallmark of Early Atherosclerosis Development12 September 2022 | Journal of Cardiovascular Translational Research, Vol. 286Biomechanical, biochemical, and near infrared spectral data of bovine knee ligaments and patellar tendonData in Brief, Vol. 36Mouse Models of Lung Fibrosis25 May 2021Near-Infrared Spectroscopy for Mapping of Human Meniscus Biochemical Constituents27 July 2020 | Annals of Biomedical Engineering, Vol. 49, No. 1Structure, composition and fibril-reinforced poroviscoelastic properties of bovine knee ligaments and patellar tendon27 January 2021 | Journal of The Royal Society Interface, Vol. 18, No. 174Comparison of water, hydroxyproline, uronic acid and elastin contents of bovine knee ligaments and patellar tendon and their relationships with biomechanical propertiesJournal of the Mechanical Behavior of Biomedical Materials, Vol. 104Effect of centrifugal force on the development of articular neocartilage with bovine primary chondrocytes23 October 2018 | Cell and Tissue Research, Vol. 375, No. 3Favorable outcomes of metformin on coronary microvasculature in experimental diabetic cardiomyopathy13 October 2018 | Journal of Molecular Histology, Vol. 49, No. 6Effectiveness of vinpocetine and isosorbide-5-mononitrate on experimental schistosomiasis mansoni: Biochemical and immunohistochemical studyActa Tropica, Vol. 186Residual feed intake, carcass traits and meat quality in Nellore cattleMeat Science, Vol. 128A hydrolytically-tunable photocrosslinked PLA-PEG-PLA/PCL-PEG-PCL dual-component hydrogel that enhances matrix deposition of encapsulated chondrocytes27 November 2014 | Journal of Tissue Engineering and Regenerative Medicine, Vol. 11, No. 3Establishing a live cartilage-on-cartilage interface for tribological testingBiotribology, Vol. 9Hydrocortisone effect on hyaluronate synthesis in a self-assembled human dermal equivalent16 August 2013 | Journal of Tissue Engineering and Regenerative Medicine, Vol. 10, No. 10Cationic Contrast Agent Diffusion Differs Between Cartilage and Meniscus29 April 2016 | Annals of Biomedical Engineering, Vol. 44, No. 10Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats8 August 2015 | Inflammation, Vol. 39, No. 1Bone Fracture Toughness and Strength Correlate With Collagen Cross-Link Maturity in a Dose-Controlled Lathyrism Mouse Model16 February 2015 | Journal of Bone and Mineral Research, Vol. 30, No. 3Hydrocortisone and triiodothyronine regulate hyaluronate synthesis in a tissue-engineered human dermal equivalent through independent pathwaysJournal of Bioscience and Bioengineering, Vol. 119, No. 2Xenogeneic Acellular Conjunctiva Matrix as a Scaffold of Tissue-Engineered Corneal Epithelium6 November 2014 | PLoS ONE, Vol. 9, No. 11All-trans retinoic acid is an effective inhibitor of hyaluronate synthesis in a human dermal equivalent6 April 2014 | Archives of Dermatological Research, Vol. 306, No. 7Mechanical Properties of Native and Tissue-Engineered Cartilage Depend on Carrier Permeability: A Bioreactor StudyTissue Engineering Part A, Vol. 19, No. 13-14Triiodothyronine (T3) inhibits hyaluronate synthesis in a human dermal equivalent by downregulation of HAS29 February 2013 | In Vitro Cellular & Developmental Biology - Animal, Vol. 49, No. 3Tissue-engineered fetal dermal matrices6 September 2012 | In Vitro Cellular & Developmental Biology - Animal, Vol. 48, No. 8Role of Endoplasmic Reticulum Stress in Age-Related Susceptibility to Lung FibrosisAmerican Journal of Respiratory Cell and Molecular Biology, Vol. 46, No. 6Telomerase deficiency does not alter bleomycin-induced fibrosis in mice6 March 2012 | Experimental Lung Research, Vol. 38, No. 3Ultrasound speed varies in articular cartilage under indentation loading [Coresspondence]IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol. 58, No. 12Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs13 June 2011 | Proceedings of the National Academy of Sciences, Vol. 108, No. 26TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitmentAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 300, No. 6High Amplitude Direct Compressive Strain Enhances Mechanical Properties of Scaffold-Free Tissue-Engineered CartilageTissue Engineering Part A, Vol. 17, No. 9-10Simultaneous ultrasound measurement of articular cartilage and subchondral boneOsteoarthritis and Cartilage, Vol. 18, No. 12Anti-Inflammatory Effects of the Neurotransmitter Agonist Honokiol in a Mouse Model of Allergic Asthma1 November 2010 | The Journal of Immunology, Vol. 185, No. 9Early predictors of cardiac decompensation in experimental volume overload7 January 2010 | Molecular and Cellular Biochemistry, Vol. 338, No. 1-2Depth-wise progression of osteoarthritis in human articular cartilage: investigation of composition, structure and biomechanicsOsteoarthritis and Cartilage, Vol. 18, No. 1The use of phospholipase A2 to prepare acellular porcine corneal stroma as a tissue engineering scaffoldBiomaterials, Vol. 30, No. 21Strain-Dependent Modulation of Ultrasound Speed in Articular Cartilage Under Dynamic CompressionUltrasound in Medicine & Biology, Vol. 35, No. 7Influence of Donor Age on the Biomechanical and Biochemical Properties of Human Meniscal Allografts31 March 2009 | The American Journal of Sports Medicine, Vol. 37, No. 5High levels of glucosamine-chondroitin sulfate can alter the cyclic preload and acute overload responses of chondral explants16 October 2008 | Journal of Orthopaedic Research, Vol. 27, No. 3Effect of intermittent cyclic preloads on the response of articular cartilage explants to an excessive level of unconfined compression3 June 2008 | Journal of Orthopaedic Research, Vol. 26, No. 12Increased longitudinal growth in rats on a silicon-depleted dietBone, Vol. 43, No. 3The Effect of Timing of Mechanical Stimulation on Proliferation and Differentiation of Goat Bone Marrow Stem Cells Cultured on Braided PLGA ScaffoldsTissue Engineering Part A, Vol. 14, No. 8Stress–relaxation of human patellar articular cartilage in unconfined compression: Prediction of mechanical response by tissue composition and structureJournal of Biomechanics, Vol. 41, No. 9Effect of human trabecular bone composition on its electrical propertiesMedical Engineering & Physics, Vol. 29, No. 8Acoustic Properties of Trabecular Bone—Relationships to Tissue CompositionUltrasound in Medicine & Biology, Vol. 33, No. 9Effect of Transforming Growth Factor-Beta and Growth Differentiation Factor-5 on Proliferation and Matrix Production by Human Bone Marrow Stromal Cells Cultured on Braided Poly Lactic-Co-Glycolic Acid Scaffolds for Ligament Tissue EngineeringTissue Engineering, Vol. 13, No. 7Early lung injury contributes to lung fibrosis via AT1 receptor in ratsActa Pharmacologica Sinica, Vol. 28, No. 2Development and characterisation of a full-thickness acellular porcine bladder matrix for tissue engineeringBiomaterials, Vol. 28, No. 6Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosisAtherosclerosis, Vol. 189, No. 1Functional changes in bladder tissue from type III collagen-deficient miceMolecular and Cellular Biochemistry, Vol. 283, No. 1-2Alveolar Surfactant Protein D Content Modulates Bleomycin-induced Lung InjuryAmerican Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 7Identification of potent and selective MMP-13 inhibitorsBioorganic & Medicinal Chemistry Letters, Vol. 15, No. 18Tissue Engineering of Ligaments: A Comparison of Bone Marrow Stromal Cells, Anterior Cruciate Ligament, and Skin Fibroblasts as Cell SourceTissue Engineering, Vol. 10, No. 5-6Differently cross-linked and uncross-linked carboxy-terminal telopeptides of type I collagen in human mineralised boneBone, Vol. 34, No. 4Effects of Dexamethasone Application in Growing Pigs on Hormones, N-retention and Other Metabolic ParametersJournal of Veterinary Medicine Series A, Vol. 51, No. 3Increased content of type III collagen at the rupture site of human Achilles tendon1 January 2006 | Journal of Orthopaedic Research, Vol. 20, No. 6Oxidant-induced Vascular Endothelial Growth Factor Expression in Human Keratinocytes and Cutaneous Wound HealingJournal of Biological Chemistry, Vol. 277, No. 36Characterization of myocardium, isolated cardiomyocytes, and blood pressure in WKHA and WKY ratsAmerican Journal of Physiology-Heart and Circulatory Physiology, Vol. 282, No. 1 Vol. 30, No. 1 Follow us on social media for the latest updates Metrics Downloaded 654 times History Published online 5 September 2018 Published in print January 2001 Information© 2018 Author(s)PDF download
Dear Editor: In a recent issue of the Journal of Cellular and Molecular Medicine, it was reported that the tyrosine kinase inhibitor nilotinib (AMN-107, Tasigna®; Norvartis Pharmaceuticals, Basel, Switzerland), used for the treatment of chronic myeloid leukaemia, is able to inhibit the function of normal human T lymphocytes in vitro[1]. In addition, this group demonstrated nilotinib inhibits T-cell receptor (TCR) activation and the phosphorylation of signalling proteins involved in TCR activation. We have also investigated the effects of nilotinib on T cells and have expanded on the findings of Chen et al. by demonstrating that like imatinib [2], nilotinib is able to inhibit LCK, a Src-family kinase that plays a critical role in TCR activation [3]. Experiments were performed using normal human peripheral blood mononuclear cells (PBMCs) isolated by density centrifugation. Experimental use of human material was approved by the Royal Adelaide Hospital Ethics Committee and blood was collected with informed consent. 5’6 carboxyfluorescein diacetate succin-imidyl ester (CFSE) staining of human PBMCs was performed as described previously [4]. In the presence of varying concentrations of nilotinib and imatinib (Novartis Pharmaceuticals), T cells were stimulated with 10 μg/ml phytohaemagglutinin (PHA) or Concanavalin A (ConA) (Sigma, St. Louis, MO, USA) or directly using 75 ng/ml of an anti-CD3 antibody (Mabtech, Stockholm, Sweden). Following a 5-day incubation, the proliferation of T cells determined by analysing CFSE dye dilution in cells stained positive by an anti-CD3 PE antibody (BD Biosciences, San Jose, CA, USA) (Fig. 1A). T-cell data were then analysed by Modfit analysis program (Verity Software, Topsham, ME, USA) and the proliferation index determined for each sample. Graphing these values allowed IC50 values for each drug to be determined. Inhibition of LCK by nilotinib and imatinib was analysed by evaluating the effects of each drug on LCK phosphorylation of a substrate peptide. Active LCK kinase (Cell Signaling, Danvers, MA, USA) was incubated with varying concentrations of both drugs in a standard kinase reaction buffer containing a mix of unlabelled and γ32p labelled ATP and a Src-family kinase peptide substrate (Upstate Biotechnology, Lake Placid, NY, USA). The level of γ32pATP labelled substrate, and hence LCK activity, was determined by blotting reactions on p81 filter paper (Whatman, Kent, UK) and determining radioactivity of each sample using a bench top scintillation β-counter. Nilotinib inhibits T-cell proliferation and LCK activity. Following PHA stimulation, nilotinib was able to strongly inhibit the proliferation of T cells as determined by CFSE tracking (A). Using this CFSE data, the proliferation index at various drug concentrations was determined and used to calculate IC50 values for the inhibition of proliferation (B). Values represent the mean from five donors each analysed in different experiments and significant donor variability was seen as represented by large standard deviations. The effects of varying concentrations of nilotinib and imatinib on LCK kinase activity was determined and normalized to a percentage of maximum kinase activity when no drug was present allowing IC50 values to be determined (C). Data presented represent the mean of three independent experiments. Nilotinib inhibited T-cell proliferation at IC50's of 2–5 μM depending on the stimulus used (Fig. 1B). The IC50 values were roughly half that we observed with imatinib. We also observed a similar effect of nilotinib on T-cell activation marker expression and cytokine production (data not shown). LCK kinase activity was inhibited by nilotinib with an IC50 of 550 nM (Fig. 1C). Imatinib inhibited LCK at a similar concentration as reported in the literature [2] with an IC50 of 1250 nM, approximately twice the IC50 of nilotinib. In contrast to our findings, another group [5] found nilotinib to inhibit LCK weakly with an IC50 of 5200 nM. While this is somewhat less potent inhibition to that we obtained, the different IC50s could be due to technical differences in the kinase assays used. Abl has also been implicated in T-cell function [6–8] and it is possible that Abl inhibition by nilotinib may cause, or add to LCK blockade for the inhibitory effect on T-cell function. Nilotinib has 20-fold increased potency against Abl compared with imatinib [9] and we found it to have twice the potency against LCK. As nilotinib inhibited T cells approximately twice as strongly as imatinib, not 20 times as strongly, our data would suggest LCK inhibition may be the main mechanism by which the drug inhibits T-cell activation. Our findings agree well with those of Chen et al.[1] and expand on their results by demonstrating nilotinib inhibits the activity of the Src-family kinase LCK, and propose inhibition of LCK as the likely mechanism by which nilotinib interrupts TCR signalling and the function of T cells. We would like to thank Novartis for supplying the nilotinib used in these experiments. One of the authors, Professor Tim Hughes, is on the Advisory Board of Novartis Pharmaceuticals and also receives research funding from the company.
INSULIN-like growth factor-I (IGF-I) and its structural homologue, IGF-II, are low molecular weight peptides that promote cellular mitosis and differentiation in a variety of systems and are believed to play a role in cyclic ovarian follicular development. In 1978, IGF-I and IGF-II were purified and sequenced by Rinderkneckt and Humbel (1, 2), and since that time there has been an exponential accumulation of information regarding these peptides, as well as their receptors, and their binding proteins (IGFBPs), constituents of the "IGF autocrine/paracrine system." These constituents have been examined in various tissues in vivo under a variety of physiological conditions and in vitro in numerous cell and tissue culture systems in several species (for review see Refs. 3–9). A decade ago, research on the IGFs focused on skeletal growth in childhood, a subspecialty of pediatric endocrinology. In the intervening years, the arena of research inquiry extended to other disciplines, including nephrology, ophthalmology, adult endocrinology, surgery, genetics, and reproductive endocrinology. Adashi and colleagues (10) published in 1985, in this journal, an elegant and comprehensive monograph describing what was known at that time about the IGFs and their roles as intraovarian regulators of granulosa cell growth and function. New information on the IGF system in the ovary has been accumulating rapidly during the years since Adashi's review, mainly due to two major advances in science and medicine. First, advances in molecular biology have provided details of the structures of the IGFs, IGFBPs, and IGF receptors. Complementary and genomic DNA for most of the components of the IGF system have been cloned and sequenced (reviewed in Refs. 3–9), opening the way for understanding regulation and function of these peptides and proteins in the ovary, as well as in other tissues. Second, the clinical practice of reproductive endocrinology has been revolutionized by the advent of in vitro fertilization and embryo transfer (IVF-ET) as treatment for infertility due to a variety of causes. Follicular growth, in response to exogenous gonadotropin administration, can be observed by ultrasound, and human granulosa cells, components of follicular aspirates during oocyte retrieval for IVF-ET, have become plentiful for examination in the laboratory. In addition, the repertoire of agents used for ovulation induction for IVF-ET has increased, and GH, the main regulator of serum IGF-I levels, has been included as an adjunct to gonadotropins in some ovulation induction protocols. Along with studies on human follicular constituents and granulosa cells obtained from follicles exposed to a variety of ovulation induction agents, continued basic research in animal models has brought comparative physiology of normal and abnormal ovarian function into a new age of investigation.
OBJECTIVES: The present manuscript aims to critically detail the physiologic process of socket healing, in the absence or presence of grafting materials or platelet concentrates, addressing the associated molecular and cellular events that culminate in the restoration of the lost tissue architecture and functionality. MATERIAL AND METHODS: An electronic search in the National Library of Medicine database MEDLINE through its online site PubMed and Web of Science from inception until May 2019 was conducted to identify articles concerning physiologic process of socket healing, in the absence or presence of grafting materials or platelet concentrates. The search was restricted to English language articles without time restriction. Additionally, a hand search was carried out in oral surgery, periodontology and dental implants related journals. RESULTS: In total, 122 literature sources were obtained and reviewed. The detailed biological events, at the molecular and cellular level, that occur in the alveolus after tooth extraction and socket healing process modulated by grafting materials or autologous platelet concentrates were presented as two entities. CONCLUSIONS: Tooth extraction initiates a convoluted set of orderly biological events in the alveolus, aiming wound closure and socket healing. The healing process comprises a wide range of events, regulated by the interplay of cytokines, chemokines and growth factors that determine cellular recruitment, proliferation and differentiation in the healing milieu, in a space- and time-dependent choreographic interplay. Additionally, the healing process may further be modulated by the implantation of grafting materials or autologous platelet concentrates within the tooth socket, aiming to enhance the regenerative outcome.
Alzheimer disease (AD) is characterized by the presence of two aberrant histopathological structures: the senile plaques and the neurofibrillary tangles. In the decade of the 1980s it was described that Aβ peptide is the major component of senile plaques [1]. Also, in the same decade, the pioneer works of Grundke-Iqbal et al. described the presence of tau [2], in hyperphosphorylated form [3], in the neurofibrillary tangles. Thus, two main features appear to be related with the tau pathology found in AD: tau phosphorylation and tau aggregation. Whereas the toxicity of tau aggregates is discussed at the present, there are some indications of a toxic behaviour for hyperphosphorylated tau (P-tau). In fact, it has been described that P-tau can sequester different microtubule-associated proteins, affecting the neuronal microtubule network [4], and, very recently, toxicity has been demonstrated in some animal models [5]. Also, the presence of P-tau has been correlated with cognitive impairment [6]. The level of P-tau is a consequence of the action of protein kinases, which favour tau phosphorylation, and of protein phosphatases, which decrease this post-translational modification. Tau kinases has been classified as proline-directed (PDPK) and non-proline-directed protein kinases (NPDPK) [7], one of the PDPK being glycogen synthase kinase 3 (GSK-3), the enzyme that could modify more sites in tau molecule [8]. Some of these sites are modified as well in mouse models overexpressing GSK3 [9]. On the other hand, tau phosphatases have also been described [10], the most significant one being protein phosphatase 2A (PP2A), a protein that accounts for more than 70% of the total phosphatase activity found in human brain [11]. One of the main objectives to understand tau pathology associated to AD is to identify the external signals that could favour the increase of tau phosphorylation. For instance, it was described that starvation may induce tau hyperphosphorylation in mouse brain [12]. Thus, alterations in glucose metabolism that induce hypothermia lead to tau hyperphosphorylation, mainly by inhibition of tau phosphatases [13]. More recently, it has also been reported that insulin dysfunction (a feature that has been related to AD [14]), may induce in vivo tau hyperphosphorylation [15]. Insulin dysfunction results in a decrease of both tau kinases and tau phosphatases (Fig. 1). In the case of tau phosphatase PP2A, composed of a catalytic subunit (PP2Ac) and two regulatory subunits, A and B, it was described that in peripheral tissues PP2Ac could be modified at tyrosine residues in response to insulin [16–18]. Tyrosine phosphorylation of PP2Ac mainly occurs at tyrosine 307, located at the C-terminus of the molecule, close to the carboxy-terminal end (residue 309), where a leucine residue, which could be modified by methylation, is present [19]. Thus, the analysis of tyrosine 307 phosphorylation could be an important task to understand tau phosphorylation in AD. Insulin (or related compounds) signalling could affect, in two opposite ways, to tau phosphorylation. In one way (left), it will inhibit the main tau kinase (GSK3), decreasing the modification in tau molecule. On the other hand (right), it will decrease PP2A activity, increasing the level of tau phosphorylation. It seems that the overall effect, from these opposite effects, is an increase in tau phosphorylation. In a work that is published in this issue of the Journal of Cellular and Molecular Medicine, Liu et al.[20] describe the presence of PP2Ac tyrosine phosphorylation in AD brains, a finding that could further explain tau hyperphosphorylation found in AD. For a future work it will be of interest to analyse if there is a decrease in this tyrosine phosphorylation process in response to external stimuli that could result in a dysfunction of insulin (or related factors) signalling pathways.
Journal Article Mitochondrial DNA Polymorphism in Candida albicans Get access Paul D. Olivo, Paul D. Olivo Research Service, Middleton Veterans Hospital, and the Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin; and the Department of Microbiology and the Graduate Program in Cellular, Molecular, and Developmental Biology, University of Tennessee, Knoxville, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward J. McManus, Edward J. McManus Research Service, Middleton Veterans Hospital, and the Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin; and the Department of Microbiology and the Graduate Program in Cellular, Molecular, and Developmental Biology, University of Tennessee, Knoxville, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Stuart Riggsby, W. Stuart Riggsby Research Service, Middleton Veterans Hospital, and the Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin; and the Department of Microbiology and the Graduate Program in Cellular, Molecular, and Developmental Biology, University of Tennessee, Knoxville, Tennessee Search for other works by this author on: Oxford Academic PubMed Google Scholar Jeffrey M. Jones Jeffrey M. Jones Research Service, Middleton Veterans Hospital, and the Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin; and the Department of Microbiology and the Graduate Program in Cellular, Molecular, and Developmental Biology, University of Tennessee, Knoxville, Tennessee Please address requests for reprints to Dr. Jeffrey M. Jones, Medical Service, Middleton Veterans Hospital, 2500Overlook Terrace, Madison, Wisconsin 53705. Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 156, Issue 1, July 1987, Pages 214–215, https://doi.org/10.1093/infdis/156.1.214 Published: 01 July 1987 Article history Received: 27 October 1986 Revision received: 19 January 1987 Published: 01 July 1987
Objective The Journal of Basic and Clinical Physiology and Pharmacology ( JBCPP ) is a peer-reviewed bi-monthly published journal in experimental medicine. JBCPP publishes novel research in the physiological and pharmacological sciences, including Emergency Medicine, Oncology, Hematology and Coagulation disorders, Vascular Medicine, Gastroenterology, Liver Disease, Neurology and Cerebrovascular Diseases, Gender Medicine, Endocrinology, Diabetology and Metabolism, Cardiovascular Diseases, Heart Failure, Respiratory Disease, Geriatrics, Immunology and Rheumatology. Moreover, Manuscripts regarding basic and laboratory sciences will be very welcome. As the borders between physiology, pharmacology and biochemistry become increasingly blurred, we also welcome papers using cutting-edge techniques in cellular and/or molecular biology to link descriptive or behavioral studies with cellular and molecular mechanisms underlying the integrative processes. Topics Emergency Medicine Oncology Hematology and Coagulation disorders Vascular Medicine Gastroenterology Liver Disease Neurology and Cerebrovascular Diseases Gender Medicine Endocrinology Diabetology and Metabolism Cardiovascular Diseases Heart Failure Respiratory Disease Geriatrics Immunology Rheumatology Article formats Research Articles, Reviews and Mini Reviews, Short Communications, Editorials and Letters to the Editor
The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the 'Warburg effect' of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and parasite infections, neurons, stem cell potency and cancer metabolism.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, and open access journal with aims at promoting and accelerating the translation of preclinical research to a clinical application and the communication between basic and clinical scientists. The journal emphasizes clinical potential and application of new biotechnologies, biomaterials, bioengineering, disease-specific biomarkers, cellular and molecular medicine, omics science, bioinformatics, applied immunology, molecular imaging, drug discovery and development, and regulation and health policy. The journal is focused on the bench to bedside approach, favoring studies and clinical observations which generate hypotheses and questions relevant to the patient and disease, and guide the investigations of cellular and molecular medicine. Clinical and Translational Medicine welcomes submissions from clinicians, researchers, policymakers, and the industry.
The fields of tissue engineering (TE) and regenerative medicine (RegMed) are yet to bring about the anticipated therapeutic revolution. After two decades of extremely high expectations and often disappointing returns both in the medical as well as in the financial arena, this scientific field reflects the sense of a new era and suggests the feeling of making a fresh start although many scientists are probably seeking reorientation. Much of research was industry driven, so that especially in the aftermath of the recent financial meltdown in the last 2 years we have witnessed a biotech asset yard sale. Despite any monetary shortcomings, from a technological point of view there have been great leaps that are yet to find their way to the patient. RegMed is definitely bound to play a major role in our life because it embodies one of the primordial dreams of mankind, such as: everlasting youth, flying, remote communication and setting foot on the moon. The Journal of Cellular and Molecular Medicine has been at the frontier of these developments in TE and RegMed from its beginning and reflects recent scientific advances in both fields. Therefore this review tries to look at RegMed through the keyhole of history which might just be like looking 'back to the future'.
The number of citations a work has received is a measure of its impact. We identified the top cited works in Parkinson's disease. A Web of Science search was performed for articles including the keyword "Parkinson*" in the title (the asterisk was included in the search string as a wild card character). Articles with more than 400 citations, the threshold to be considered a "citation classic," were identified and analyzed. The 107 articles identified appeared in 33 different journals, with clinical articles primarily appearing in the New England Journal of Medicine and Lancet, and scientific articles primarily in Nature, Science, and the Proceedings of the National Academy of Sciences. There were 52 laboratory studies, 38 clinical studies, 12 review articles, and 5 classifications of disease. The clinical studies included evaluation of medical and surgical therapies, and the laboratory studies included gene discovery, molecular biology, and cellular biology, as well as animal models and neuropathological studies. High impact topics included deep brain stimulation, levodopa therapy and related adverse effects, MPTP-based animal studies, discovery and evaluation of genetic mutations, and pathogenesis related to oxidative degeneration. More than half of the articles identified in this study have been published in the past 20 years. Prior to 1990, highly cited articles in Parkinson's disease tended to be those that evaluated medical therapies and defined the clinical and neuropathological characteristics of the disease. Since 1990, a high proportion of the citation classics address the genetic characterization of and surgical treatments for the disease suggesting that these are the most significant recent developments and main drivers of impact in this field.
To introduce this special issue of the Journal of Molecular Recognition dedicated to the applications of atomic force microscopy (AFM) in life sciences, this paper presents a short summary of the history of AFM in biology. Based on contributions from the first international conference of AFM in biological sciences and medicine (AFM BioMed Barcelona, 19-21 April 2007), we present and discuss recent progress made using AFM for studying cells and cellular interactions, probing single molecules, imaging biosurfaces at high resolution and investigating model membranes and their interactions. Future prospects in these different fields are also highlighted.
There has been increasing interest in the research on flavonoids from plant sources because of their versatile health benefits reported in various epidemiological studies. Since flavonoids are directly associated with human dietary ingredients and health, there is need to evaluate structure and function relationship. The bioavailability, metabolism, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about their nuclear structure. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. Most recent researches have focused on the health aspects of flavonoids for humans. Many flavonoids are shown to have antioxidative activity, free radical scavenging capacity, coronary heart disease prevention, hepatoprotective, anti-inflammatory, and anticancer activities, while some flavonoids exhibit potential antiviral activities. In plant systems, flavonoids help in combating oxidative stress and act as growth regulators. For pharmaceutical purposes cost-effective bulk production of different types of flavonoids has been made possible with the help of microbial biotechnology. This review highlights the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production.