Advanced glycation end products (AGE) and receptor for AGE (RAGE) in patients with active tuberculosis
This week we suggest to read an article titled "Advanced glycation end products (AGE) and receptor for AGE (RAGE) in patients with active tuberculosis, and their relationship between food intake and nutritional status", published on the US National Library of Medicine- National Institutes of Health website.
Tuberculosis (TB), caused by Mycobacterium tuberculosis complex, is a major public health problem worldwide, especially in low- and middle-income countries. It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis, and 8 million develop the active form of the disease each year, resulting in 2 million deaths per year. Brazil is in 18th place among the 22 countries responsible for 80% of TB cases globally.
The pathogenesis of the consumptive syndrome, which is long recognized as a characteristic of TB, is largely unknown. The proinflammatory cytokines are the initial candidates as agents causing the metabolic alterations. In addition, cell-mediated immunity and innate immune responses play an important role.
The receptor for advanced glycation end products (RAGE), a pattern-recognition receptor that binds multiple ligands, is expressed in normal lungs and is upregulated during inflammation and infection. AGEs are a heterogeneous group of irreversible products resulting from nonenzymatic glycation between reducing sugars and free amino groups of proteins, nucleic acids, or lipid; carboxymethyl lysine (CML) is the predominant AGE in human plasma, which is over synthesized in conditions of inflammation and lung damage. The interaction between AGEs and RAGE on the plasma membrane causes inflammation, oxidative stress, and apoptosis in lung cells.
Studies investigating the relationship between food intake, nutritional status, AGE and RAGE levels and TB, are mostly with animal models.
The authors reported the results of a prospective case-control (1:1), pilot study, conducted in a general, tertiary care, university-affiliated hospital (Hospital de Clı´nicas de Porto Alegre–HCPA), from June 2017 to June 2018, evaluating AGEs and RAGE levels in adult patients with active TB and healthy controls, and investigating the relationship between food intake and nutritional status with AGEs and RAGE levels.
35 TB patients and 35 controls were enrolled. Demographic data, presence of cough, fever, night sweating, hemoptysis, sputum production, weight loss, dyspnea, chest pain, smoking status, alcohol consumption, drug use, presence of comorbidities, results of the main diagnostic tests, outcome of hospitalization were recorded. Blood sample was collected after an overnight fast.
The authors found that sRAGE levels were higher in TB patients than in controls (p = 0.046). In contrast, only among cases that were current smokers, lower sRAGE levels were associated with weight loss and mortality (p = 0.006). Body Mass Index (BMI) was significantly lower in cases than in controls (p < 0.0001). Also, undernutrition was more frequent in cases than in controls. However, there was no significant correlation between those parameters and CML or sRAGE levels. There was no statistically significant difference in CML levels between cases and controls.
The authors concluded highlighting that, although some limitations (it was a single center study, the higher prevalence of HIV among cases could have been a confounding factor, the US common diets used could be different from the Brailian diet), this was the first study, which generates a hypothesis on the role of CML/RAGE in TB patients and not in animal models.
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AUTHORS: Andrades M, Coutinho SE, de Almeida EGC, Holler SR, Silva DR, Silva LF, Skupien EC, Lazzari TK, Zampieri LR.
Enterovirus D68 – The New Polio?
This week WAidid suggests the article Enterovirus D68 – The New Polio?, recently published on "US National Library of Medicine- National Institutes of Health".
Enterovirus D68 (EV-D68) is a single-stranded positive-sense RNA virus of the Picornaviridae family, belonging to the species EV D, ﬁrst isolated from respiratory samples in 1962 in California, from four pediatric patients with acute respiratory symptoms. EV-D68 is classiﬁed into three genetic clades, A, B and C; subclades A1, A2, B1, and B2 can be further identiﬁed depending on EV typing, targeting either VP1 or VP4-2 capsid protein. EV are transmitted via the fecal-oral route and replicate in the intestine. EV are thought to have existed and coevolved with humanity for thousands of years. The causative agent of poliomyelitis (poliovirus), was not discovered until 1908: it was not only the ﬁrst EV to be discovered, but also caused the most devastating and widespread morbidity and mortality of all the EV genotypes. Over the subsequent years, over 100 EV serotypes have now been discovered with nearly 70 species infecting humans. Non-polio EV can cause a variety of clinical syndromes, ranging from hand-foot and mouth disease to aseptic meningitis.
The introduction of the poliovirus vaccine (inactivated injectable vaccine, developed by Jonas Salk in 1955, and orally vaccine developed by Albert Sabin in 1961), dramatically reduced the incidence of infections globally, with only small clusters sporadically occurring. According to the Global Poliovirus Eradication Initiative (GPEI), only Afghanistan and Pakistan still report endemic wildtype poliovirus in 2018 and only few new cases of vaccine-derived poliovirus in the Democratic Republic of the Congo, Nigeria, Somalia and Papua New Guinea have been reported. Therefore, cases of acute flaccid paralysis (AFP) outside these countries have decreased to very low numbers.
EV-D68 had only been reported sporadically worldwide since 2010. Indeed before 2014, only sporadic outbreaks were reported, but it rapidly became an emerging neuropathogenic threat. Speciﬁc testing for EV-D68 or routine typing for EV are not standard practice in the majority of laboratories, so the true burden of disease is not known.
The authors reported the details about the 2014 outbreak in United States and Canada and the 2016 outbreak in the Netherlands.
Depending on the clinical picture, several diagnostic samples can and should be collected to detect EV: cerebral spinal fluid (CSF), feces, respiratory material and serum/plasma. Molecular testing (RT-PCR targeting the 5’UTR) is recognized as the gold standard for diagnosing an EV infection. Sanger sequencing of the VP1, and occasionally VP4-2 structural proteins, is considered the gold standard for the determination of speciﬁc EV genotype. Next generation sequencing (NGS) allows useful information about changes in tropism or pathogenicity of EV.
The authors reviewed the data about the connection between EV-68 and acute flaccid myelitis (AFM), reporting case definition, use of magnetic resonance in the diagnosis, and highlighting the present lack of the exact pathogenetic mechanism through which EV-D68 instigates infection.
The authors concluded reporting the most important gaps in the EV-D68 management: absence of vaccine and effective treatment (although reporting the most promising therapies, such as 8V-7404, DAS181, Rupintrivir, nerve and muscle transfer), lack of a specific surveillance system, and the necessity of a routinely use of NGS.
Read more here: www.ncbi.nlm.nih.gov/pubmed/30483226
AUTHORS: Cassidy H., Poelman R., Knoester M., Van Leer-Buter C., Niesters H.