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"Dengue is the leading mosquito-borne viral illness infecting humans !"
Dengue is caused by infection with any of the four dengue virus serotypes. This review highlights the mechanisms underlying the clinical course of a dengue infection, which can range from mild febrile illness through to hemorrhagic fever and circulatory shock. It also outlines the epidemiology, pathogenesis, diagnosis and management of dengue infection.
Key phases of dengue infection
Dengue is a mosquito-borne disease caused by infection with dengue virus (DENV). Clinically, the disease can range from a mild febrile illness (previously called dengue fever) through to dengue with warning signs and severe dengue, which includes what were previously called dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
DENVs belong to the genus Flavivirus of the Flaviviridae family. The four serotypes are enveloped, spherical viral particles with a diameter of approximately 500 Å20. The genome of each serotype comprises approximately 11 kb of positive-sense, single-stranded RNA that encodes ten proteins. The three structural proteins encoded by the genome are the membrane (M) protein, envelope (E) protein and capsid (C) protein; the non-structural (NS) proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5.
"The viral receptor on human cells plays a critical role in disease progression !"
Viruses enter cells and initiate infection by binding to their cognate cell surface receptors. The expression and distribution of viral entry receptors therefore regulates their tropism, determining the tissues that are infected and thus disease pathogenesis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus known to co-opt the peptidase angiotensin-converting enzyme 2 (ACE2) for cell entry. The interaction between SARS-CoV-2 and ACE2 is critical to determining both tissue tropism and progression from early SARS-CoV-2 infection to severe coronavirus disease 2019 (COVID-19). Understanding the cellular basis of SARS-CoV-2 infection could reveal treatments that prevent the development of severe disease, and thus reduce mortality.
Key phases of disease progression
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2). Initial infection of cells in the upper respiratory tract may be asymptomatic, but these patients can still transmit the virus. For those who develop symptoms, up to 90% will have pneumonitis, caused by infection of cells in the lower respiratory tract. Some of these patients will progress to severe disease, with disruption of the epithelial-endothelial barrier, and multi-organ involvement.
As with all coronaviruses, SARS-CoV-2 cell entry is dependent on its 180-kDa spike (S) protein, which mediates two essential events: binding to ACE2 by the amino-terminal region, and fusion of viral and cellular membranes through the carboxyl-terminal region. Infection of lung cells requires host proteolytic activation of spike at a polybasic furin cleavage site. To date, this cleavage site is found in all spike proteins from clinical SARS-CoV-2 isolates, as well as some other highly pathogenic viruses (e.g., avian influenza A), but it is absent from SARS-CoV and is likely to have been acquired by recombination between coronaviruses in bats. Cleavage by the furin protease therefore expands SARS-CoV-2 cell tropism and may have facilitated transmission from bats to humans. Membrane fusion also requires cleavage by additional proteases, particularly transmembrane protease serine 2 (TMPRSS2), a host cell surface protease that cleaves spike shortly after binding ACE2. SARS-CoV-2 tropism is therefore dependent on expression of cellular proteases, as well as ACE2.
Scientists’ understanding of the genetics/genomics of breast cancer continues to grow; a revolution is underway both in terms of categorizing breast cancers and targeting treatment that will be effective in individual cases. New perspectives are being offered on the interpretation of biopsies, too. Here is a round-up of some very recent studies.
Genetic variants alter cells’ response to estrogen
An international study of almost 120,000 women has newly identified five genetic variants affecting risk of breast cancer, all of which are believed to influence how breast cells respond to the female sex hormone estrogen.
Estrogen acts as a trigger, binding to a molecule known as an estrogen receptor in most breast cells and triggering a cascade of signals that cause the cell to behave normally. However, the estrogen receptor is switched off in some cells and these do not respond to the hormone.
Vitamin D is a precursor of the steroid hormone calcitriol that is crucial for bone and mineral metabolism. Both the high prevalence of vitamin D deficiency in the general population and the identification of the vitamin D receptor in the heart and blood vessels raised interest in the potential cardiovascular effects of vitamin D. Experimental studies have demonstrated various cardiovascular protective actions of vitamin D, but vitamin D intoxication in animals is known to induce vascular calcification. In meta-analyses of epidemiological studies, vitamin D deficiency is associated with an increased cardiovascular risk. Findings from Mendelian randomization studies and randomized, controlled trials (RCTs) do not indicate significant effects of a general vitamin D supplementation on cardiovascular outcomes. Previous RCTs, however, were not adequately designed to address extra skeletal events, and did not focus on vitamin D-deficient individuals. Therefore, currently available evidence does not support cardiovascular benefits or harms of vitamin D supplementation with the commonly used doses, and whether vitamin D has cardiovascular effects in individuals with overt vitamin D deficiency remains to be evaluated. Here, we provide an update on clinical studies on vitamin D and cardiovascular risk, discuss ongoing vitamin D research, and consider the management of vitamin D deficiency from a cardiovascular health perspective.
Key points
The vitamin D receptor (VDR) and enzymes for vitamin D metabolism are expressed throughout the cardiovascular system
VDR and 1α-hydroxylase knockout mice have hypertension with myocardial hypertrophy and increased activity of the renin–angiotensin–aldosterone system
The molecular effects of VDR activation indicate various anti-atherosclerotic and protective effects on the heart and on common cardiovascular risk factors
Observational studies have shown that low 25-hydroxyvitamin D levels are associated with an adverse cardiovascular risk profile and significantly increased risk of cardiovascular events
Mendelian randomization studies and randomized clinical trials have not shown significant effects of vitamin D on cardiovascular events, but these trials were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals
Vitamin D supplementation is currently not indicated for the purpose of cardiovascular disease prevention, but treatment of vitamin D deficiency is critical for skeletal health
Introduction
The critical involvement of vitamin D in bone and mineral metabolism is historically known. The identification of the vitamin D receptor (VDR) in almost all human organs including the heart and the blood vessels, and observations that individuals deficient in vitamin D are at increased risk of various extraskeletal diseases, stimulated research on the role of vitamin D for overall and cardiovascular health. In this Review, we summarize the existing knowledge on the effects of vitamin D on cardiovascular diseases and associated risk factors, with a particular focus on meta-analyses of large, epidemiological studies and randomized, controlled trials (RCTs). First, we provide a short summary of vitamin D metabolism and current vitamin D guidelines, a historical perspective on vitamin D and cardiovascular diseases, and a brief overview on the mechanistic effects of VDR activation on cardiovascular risk factors, the blood vessels, and the heart. The principal aspect of this Review is an update on observational studies, Mendelian randomization studies, and RCTs on vitamin D and cardiovascular risk. Finally, we outline and discuss ongoing vitamin D research, including large RCTs, and present our conclusions on how to deal with the management of vitamin D deficiency from a public health and cardiovascular health perspective.
