No abstract

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing an unprecedented global pandemic demanding the urgent development of therapeutic strategies. Microarray binding experiments, using an extensive heparan sulfate (HS) oligosaccharide library, showed that the receptor binding domain (RBD) of the spike of SARS-CoV-2 can bind HS in a length- and sequence-dependent manner. A hexasaccharide composed of IdoA2S-GlcNS6S repeating units was identified as the minimal binding epitope. Surface plasmon resonance showed the SARS-CoV-2 spike protein binds with a much higher affinity to heparin ( K D = 55 nM) compared to the RBD ( K D = 1 μM) alone. It was also found that heparin does not interfere in angiotensin-converting enzyme 2 (ACE2) binding or proteolytic processing of the spike. However, exogenous administered heparin or a highly sulfated HS oligosaccharide inhibited RBD binding to cells. Furthermore, an enzymatic removal of HS proteoglycan from physiological relevant tissue resulted in a loss of RBD binding. The data support a model in which HS functions as the point of initial attachment allowing the virus to travel through the glycocalyx by low-affinity high-avidity interactions to reach the cell membrane, where it can engage with ACE2 for cell entry. Microarray binding experiments showed that ACE2 and HS can simultaneously engage with the RBD, and it is likely no dissociation between HS and RBD is required for binding to ACE2. The results highlight the potential of using HS oligosaccharides as a starting material for therapeutic agent development.

Chronic pain in the Ehlers–Danlos syndromes (EDS) is common and may be severe. According to one study, nearly 90% of patients report some form of chronic pain. Pain, which is often one of the first symptoms to occur, may be widespread or localized to one region such as an arm or a leg. Studies on treatment modalities are few and insufficient to guide management. The following is a discussion of the evidence regarding the underlying mechanisms of pain in EDS. The causes of pain in this condition are multifactorial and include joint subluxations and dislocations, previous surgery, muscle weakness, proprioceptive disorders, and vertebral instability. Affected persons may also present with generalized body pain, fatigue, headaches, gastrointestinal pain, temporomandibular joint pain, dysmenorrhea, and vulvodynia. Pain management strategies may be focused around treating the cause of the pain (e.g., dislocation of a joint, proprioceptive disorder) and minimizing the sensation of pain. Management strategies for chronic pain in EDS includes physical therapy, medications, as well as durable medical equipment such as cushions, compressive garments, and braces. The different modalities are discussed in this paper. © 2017 Wiley Periodicals, Inc.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing an unprecedented global pandemic demanding the urgent development of therapeutic strategies. Microarray binding experiments using an extensive heparan sulfate (HS) oligosaccharide library showed the spike of SARS-CoV-2 can bind HS in a length-and sequence-dependent manner. Hexa-and octasaccharides composed of IdoA2S-GlcNS6S repeating units were identified as optimal ligands. Surface plasma resonance (SPR) showed the SARS-CoV-2 spike protein binds with higher affinity to heparin (KD 55 nM) compared to the receptor binding domain (RBD, KD 1 µM) alone. An octasaccharide composed of IdoA2S-GlcNS6S could inhibit spike-heparin interaction with an IC50 of 38 nM. Our data supports a model in which the RBD of the spike of SARS-CoV-2 confers sequence specificity for HS expressed by target cells whereas an additional HS binding site in the S1/S2 proteolytic cleavage site enhances the avidity of binding. Collectively, our results highlight the potential of using HS oligosaccharides as a therapeutic agent by inhibiting SARS-CoV-2 binding to target cells. KEYWORDSSARS-CoV-2, coronavirus, heparan sulfate, heparin, spike glycoprotein, microarray, surface plasma resonances was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

There is increasing amount of evidence pointing toward a high prevalence of psychiatric conditions among individuals with hypermobile type of Ehlers-Danlos syndrome (JHS/hEDS). A literature review confirms a strong association between anxiety disorders and JHSh/hEDS, and there is also limited but growing evidence that JHSh/ hEDS is also associated with depression, eating, and neuro-developmental disorders as well as alcohol and tobacco misuse. The underlying mechanisms behind this association include genetic risks, autonomic nervous system dysfunction, increased exteroceptive and interoceptive mechanisms and decreased proprioception. Recent neuroimaging studies have also shown an increase response in emotion processing brain areas which could explain the high affective reactivity seen in JHS/hEDS. Management of these patients should include psychiatric and psychological approaches, not only to relieve the clinical conditions but also to improve abilities to cope through proper drug treatment, psychotherapy, and psychological rehabilitation adequately coupled with modern physiotherapy. A multidimensional approach to this "neuroconnective phenotype" should be implemented to ensure proper assessment and to guide for more specific treatments. Future lines of research should further explore the full dimension of the psychopathology associated with JHS/hEDS to define the nature of the relationship. © 2017 Wiley Periodicals, Inc.KEY WORDS: joint hypermobility; anxiety; psychopathology; neuroconnective phenotype; hypermobile Ehlers-Danlos syndrome Professor Antonio Bulbena, M.D., M.Sc, Ph.D., is the Chair of the Department of Psychiatry at the Autonoma University of Barcelona with clinical, academic, and administrative contributions particularly in the area of psychosomatic medicine and anxiety disorders, dementia, chocolate and carbohydrates, clinical measurement in psychiatry, phobias, seasonality, and biometeorology. Has recently developed the Neuroconnective Phenotype and has published numerous books, book chapters, and scientific articles in peer-reviewed journals.Carolina Baeza-Velasco, Ph.D., is a clinical psychology at the Paris Descartes University, with important contributions in the area of psychological assessment and treatment of patients with comorbid anxiety disorders and joint hypermobility among other conditions. Has published several articles about the psychological factors of EDS and related conditions. Andrea Bulbena-Cabre, M.D., M.Sc., is a Psychiatry Research Fellow at the Icahn School of Medicine at Mount Sinai/J. J. Peters Bronx VA Hospital. She has specialized in psychosomatic medicine and is currently studying the anxiety-joint hypermobility phenomena in bipolar and psychotic spectrum disorders. Other research interests include substance abuse, especially in synthetic cannabis and psychosis.Guillem Pailhez, M.D., Ph.D., is an Assistant Professor at the Department of Psychiatry at the Autonoma University of Barcelona, has devoted his career in the study of the interactions between mind and body ...

Background. Choledochal cyst, a rare congenital cystic dilatation of biliary tree, is uncommon in adults. Their presentations differ from children and surgical management has evolved. Methods. A retrospective review of the records of all the patients above 15 years, who underwent therapeutic intervention in our hospital, was carried out. Results. Ten cases of choledochal cyst were found; 8 female, with mean age 31 years. These included 8 cases of Todani type I and one case each of type II and type III. The predominant symptoms were abdominal pain and jaundice. Abdominal mass and past history of cholangitis and pancreatitis were seen in 2 patients. Investigations included ultrasound in 8 patients, CT in 7, ERCP in 3, and MRCP in 5. Surgical intervention included complete excision of the cyst with hepaticojejunostomy and cholecystectomy (type I), excision of the diverticulum (type II), and ERCP sphincterotomy (type III). Malignancy was not seen in any patients. The long-term postoperative complications included cholangitis in two patients. Conclusion. Choledochal cyst is rare in adults. The typical triad of abdominal pain, jaundice, and mass is uncommon in adults. The surgical strategy aims for single stage complete excision of the cyst with hepaticojejunostomy.

Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9–1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.

Humans express seven heparan sulfate (HS) 3-O-sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3-O-sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3-O-sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented for binding is largely unknown. We describe herein a modular synthetic approach that can provide structurally diverse HS oligosaccharides with and without 3-OS. The methodology was employed to prepare 27 hexasaccharides that were printed as a glycan microarray to examine ligand requirements of a wide range of HS-binding proteins. The binding selectivity of antithrombin-III (AT-III) compared well with anti-Factor Xa activity supporting robustness of the array technology. Many of the other examined HS-binding proteins required an IdoA2S-GlcNS3S6S sequon for binding but exhibited variable dependence for the 2-OS and 6-OS moieties, and a GlcA or IdoA2S residue neighboring the central GlcNS3S. The HS oligosaccharides were also examined as inhibitors of cell entry by herpes simplex virus type 1, which, surprisingly, showed a lack of dependence of 3-OS, indicating that, instead of glycoprotein D (gD), they competitively bind to gB and gC. The compounds were also used to examine substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase II is influenced by 3-OS, while digestion by lyase I is only affected by 2-OS. Lyase III exhibited sensitivity to both 3-OS and 2-OS.