Sunil J. Wimalawansa

Bio: Sunil J. Wimalawansa is an academic researcher from Rutgers University. The author has contributed to research in topics: Calcitonin gene-related peptide & Calcitonin. The author has an hindex of 46, co-authored 167 publications receiving 7426 citations. Previous affiliations of Sunil J. Wimalawansa include Hammersmith Hospital & University of British Columbia.

Calcitonin Gene-Related Peptide and Its Receptors: Molecular Genetics, Physiology, Pathophysiology, and Therapeutic Potentials

Abstract: I. Introduction THE calcitonin (CT) and calcitonin gene-related peptide (CGRP) are derived from the CT/CGRP gene, which is localized in chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. This alternative tissue-specific processing of primary mRNA from the α-CT/CGRP gene in rats generates two distinct peptides, CT and CGRP (1, 2). CGRP is a 37-amino acid neuropeptide expressed predominantly in the nervous system and CT is expressed mainly in the thyroid gland. CGRP receptors, widely distributed in the body, are the most potent endogenous vasodilatory peptides that have been discovered. Derived from the C cells of the thyroid gland, CT is the most potent peptide inhibitor of osteoclast-mediated bone resorption and is involved primarily in protecting the skeleton during periods of “calcium stress” such as growth, pregnancy, and lactation (3). In 1961, Copp and colleagues (4) postulated the existence of the calcium-lo...

Amylin, Calcitonin Gene-Related Peptide, Calcitonin, and Adrenomedullin: A Peptide Superfamily

Abstract: The calcitonin gene peptide superfamily consists of calcitonin (CT), calcitonin gene-related peptide (CGRP), and amylin. CT and CGRP derive from the CT/CGRP gene, which is encoded on chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. CGRP (a 37-amino-acid neuropeptide) and its receptors are widely distributed in the body, and it is the most potent endogenous vasodilatory peptide discovered so far. CT (a 32-amino-acid peptide) is, however, a hormone primarily involved in protecting the skeleton during periods of "calcium stress" such as growth, pregnancy, and lactation. CT derives from the C cells of the thyroid gland and is the most potent peptide inhibitor of osteoclast-mediated bone resorption. Therefore, treatment with CT is highly effective for conditions associated with increased bone turnover such as Paget's disease, osteoporosis, Sudeck's atrophy, and hypercalcemia. Amylin (a 37-amino-acid peptide) is generated from a gene located on chromosome 12 (thought to be an evolutionary duplication of chromosome 11) and shares 46% amino acid sequence homology with CGRP and 20% with human CT. Amylin is predominantly located in the beta cells of the islets of the pancreas and may be involved in the pathogenesis of type II diabetes by deposition as amyloid within the pancreas, leading to beta cell destruction. Adrenomedullin, a recently discovered 52-amino-acid vasoactive peptide from adrenal tissue, shares 24% homology with CGRP and is also a member of this superfamily of peptides. A portion of the B-chain of insulin is strongly homologous to these four peptides. Not only does adrenomedullin (13-52) show 24% amino acid homology with CGRP, it also has a biological activity profile similar to that of CGRP.CGRP, CT, and amylin are related to the insulin gene superfamily of peptides, which may all have diverged from a common ancestral gene during evolution. When the crystallographic- and nuclear magnetic resonance-based molecular modeling of the three-dimensional structure of CGRP, CT, amylin, and adrenomedullin peptides and their receptors is available, it will lead to a greater understanding of the involvement of this family of peptides in pathophysiology. Together, CGRP, CT, amylin and adrenomedullin have overlapping biological effects owing to their structures and cross-reactivity between receptors. I propose that CT, CGRP, adrenomedullin, and amylin belong to a family of G-protein-coupled receptors (an "insulin superfamily" of peptides) and therefore share some of the characteristics of insulin, such as growth factor-like effects, and possible interaction at insulin receptor sites as an antagonist.

Nitric oxide and bone.

Abstract: Age-associated decrease in nitric oxide (NO) production may be related to an increase in cardiovascular events, sexual dysfunction, and osteoporosis. Relative NO deficiency is a plausible biological basis for NO replacement therapy. Hormone replacement therapy (HRT) enhances local NO production and rectifies NO deficiency in postmenopausal women. However, excess local production of NO aggravates bone destruction in inflammatory arthropathies. In addition to its use in alleviating angina and erectile dysfunction, NO compounds could be a valuable supplemental therapy for chronic conditions including osteoporosis. Estrogen mediates its beneficial effects in bone, in part via the NO/cGMP pathway; hence NO donor therapy is an alternative to estrogen, estrogen agonists-antagonists, and androgen receptor modulator therapy in the prevention and treatment of osteoporosis. Large numbers of animal studies and human pilot studies support the concept of using NO donors for preventing bone loss. Administration of exogenous NO or prolonging endogenous NO activity are practical ways to supplement NO.

Vitamin D Deficiency: Effects on Oxidative Stress, Epigenetics, Gene Regulation, and Aging.

Abstract: Recent advances in vitamin D research indicate that this vitamin, a secosteroid hormone, has beneficial effects on several body systems other than the musculoskeletal system. Both 25 dihydroxy vitamin D [25(OH)2D] and its active hormonal form, 1,25-dihydroxyvitamin D [1,25(OH)2D] are essential for human physiological functions, including damping down inflammation and the excessive intracellular oxidative stresses. Vitamin D is one of the key controllers of systemic inflammation, oxidative stress and mitochondrial respiratory function, and thus, the aging process in humans. In turn, molecular and cellular actions form 1,25(OH)2D slow down oxidative stress, cell and tissue damage, and the aging process. On the other hand, hypovitaminosis D impairs mitochondrial functions, and enhances oxidative stress and systemic inflammation. The interaction of 1,25(OH)2D with its intracellular receptors modulates vitamin D–dependent gene transcription and activation of vitamin D-responsive elements, which triggers multiple second messenger systems. Thus, it is not surprising that hypovitaminosis D increases the incidence and severity of several age-related common diseases, such as metabolic disorders that are linked to oxidative stress. These include obesity, insulin resistance, type 2 diabetes, hypertension, pregnancy complications, memory disorders, osteoporosis, autoimmune diseases, certain cancers, and systemic inflammatory diseases. Vitamin D adequacy leads to less oxidative stress and improves mitochondrial and endocrine functions, reducing the risks of disorders, such as autoimmunity, infections, metabolic derangements, and impairment of DNA repair; all of this aids a healthy, graceful aging process. Vitamin D is also a potent anti-oxidant that facilitates balanced mitochondrial activities, preventing oxidative stress-related protein oxidation, lipid peroxidation, and DNA damage. New understandings of vitamin D-related advances in metabolomics, transcriptomics, epigenetics, in relation to its ability to control oxidative stress in conjunction with micronutrients, vitamins, and antioxidants, following normalization of serum 25(OH)D and tissue 1,25(OH)2D concentrations, likely to promise cost-effective better clinical outcomes in humans.

Harrison's Principles of Internal Medicine

Abstract: The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Vitamin D deficiency.

Abstract: admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.