Obesity and infectious diseases: pathophysiology and epidemiology of a double pandemic condition.

The current pandemic due to widespread SARS-CoV-19 infection has again highlighted the role of obesity, whose global prevalence increased up to 13%, as a risk factor for both susceptibility to infections and the occurrence of a more severe disease course. To date, this association has not been sufficiently explored. Obesity-related susceptibility to infectious diseases is mostly thought to be due to an impairment of both innate and adaptive immune responses and vitamin D deficiency. Several cofactors can indirectly favour the onset and/or worsening of infectious diseases, such as impairment of respiratory mechanics, skin and subcutaneous tissue homoeostasis, obesity-related comorbidities and inappropriate antimicrobial therapy. Subjects with obesity have a higher incidence of cutaneous infections, probably due to changes in skin barrier functions and wound healing. Excess weight is also associated with an increased risk of urinary tract infection and its recurrence, as well as with a higher prevalence of both lower and higher respiratory tract infections. Moreover, patients with obesity appear to have an increased risk of surgical site infections when undergoing general, orthopaedic, gynaecological, and bariatric surgery. Data concerning the different infectious diseases related to obesity are rather limited since anthropometric parameters are usually poorly recorded. Furthermore, specific therapeutic protocols in subjects with obesity are lacking, especially regarding antibiotic therapy and further supplements. This review summarizes etiopathogenetic and epidemiological evidence and highlights areas of uncertainty in the field of infectious diseases and obesity, which require further research. It is important to raise public awareness of this additional risk related to obesity and to raise awareness among the scientific community to develop specific clinical protocols for subjects with obesity.

The Role of Extracellular Vesicles from Human Macrophages on Host-Pathogen Interaction.

The nano-sized membrane enclosed extracellular vesicles (EVs) released by virtually all cell types play an essential role in intercellular communication via delivering bio-molecules, such as nucleic acids, proteins, lipids, and other molecules to recipient cells. By mediating an active and steady-state cell-to-cell communication, EVs contribute to regulating and preserving cellular homeostasis. On the other hand, EVs can also spread pathogen-derived molecules during infections, subverting the host immune responses during infections and thus worsening pathophysiological processes. In recent years, the biological functioning of EVs has become a widespread research field in basic and clinical branches of medical sciences due to their potential role in therapeutic applications for several diseases. This review aims to summarize the main recent findings regarding the implication of EVs shed by human macrophages (MΦ-EVs) and how they can modulate the host immune response to control or increase the damage caused by infectious agents. We will also present the methods used to describe MΦ-EVs, as well as the potential of these EVs as disease diagnostic tools for some human pathogens. We believe that an in-depth understanding of the host-pathogen interactions mediated by MΦ-EVs may trigger the development of innovative therapeutic strategies against infectious diseases.

Lymphopenia in hospitalized patients and its relationship with severity of illness and mortality.

BACKGROUND: Lymphopenia is associated with various pathologies such as sepsis, burns, trauma, general anesthesia and major surgeries. All these pathologies are clinically expressed by the so-called Systemic Inflammatory Response Syndrome which does not include lymphopenia into defining criteria. The main objective of this work was to analyze the diagnosis of patients admitted to a hospital related to lymphopenia during hospital stay. In addition, we investigated the relationship of lymphopenia with the four levels of the Severity of Illness (SOI) and the Risk of Mortality (ROM). METHOD AND FINDINGS: Lymphopenia was defined as Absolute Lymphocyte Count (ALC) <1.0 x109/L. ALC were analyzed every day since admission. The four levels (minor, moderate, major and extreme risk) of both SOI and ROM were assessed. A total of 58,260 hospital admissions were analyzed. More than 41% of the patients had lymphopenia during hospital stay. The mean time to death was shorter among patients with lymphopenia on admission 65.6 days (CI95%, 57.3-73.8) vs 89.9 (CI95%, 82.4-97.4), P<0.001. Also, patients with lymphopenia during hospital stay had a shorter time to the mortality, 67.5 (CI95%, 61.1-73.9) vs 96.9 (CI95%, 92.6-101.2), P<0.001. CONCLUSIONS: Lymphopenia had a high prevalence in hospitalized patients with greater relevance in infectious pathologies. Lymphopenia was related and clearly predicts SOI and ROM at the time of admission, and should be considered as clinical diagnostic criteria to define SIRS.

Cardiac Arrest Risk During Acute Infections: Systemic Inflammation Directly Prolongs QTc Interval via Cytokine-Mediated Effects on Potassium Channel Expression.

BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections.

Protein myristoylation, the addition of a 14-carbon saturated acyl group, is an abundant modification implicated in biological events as diverse as development, immunity, oncogenesis, and infections. N-Myristoyltransferase (NMT) is the enzyme that catalyzes this modification. Many elegant studies have established the rules guiding the catalysis including substrate amino acid sequence requirements with the indispensable N-terminal glycine, and a co-translational mode of action. Recent advances in technology such as the development of fatty acid analogs, small molecule inhibitors, and new proteomic strategies, allowed a deeper insight into the NMT activity and function. Here we focus on discussing recent work demonstrating that NMT is also a lysine myristoyltransferase, the enzyme's regulation by a previously unnoticed solvent channel, and the mechanism of NMT regulation by protein-protein interactions. We also summarize recent findings on NMT's role in cancer, immunity, and infections and the advances in pharmacological targeting of myristoylation. Our analyses highlight opportunities for further understanding and discoveries.

Fatal pediatric Stevens-Johnson syndrome/toxic epidermal necrolysis: Three case reports.

RATIONALE: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are extremely rare but potentially life-threatening disorders. We presented 3 fatal pediatric SJS/TEN cases. PATIENT CONCERNS: Our patients had some severe complications such as septic shock, respiratory failure and obliterans bronchiolitis (BO) etc. DIAGNOSIS:: Three patients diagnosed SJS/TEN with clinical symptoms that were triggered by antibiotics, nonsteroidal anti-inflammatory drugs, previous infection, or neoplasms. INTERVENTIONS: All of them accepted mechanical ventilation, intravenous immunoglobulin (IVIG), blood transfusion, glucocorticoid, and multi-anti-infectious therapy. OUTCOMES: They all died because of out-of-control severe infections. In Patient 1, he died 6 days after being admitted to the PICU on the 28th day from onset. In Patient 2, he died on the 211th day from the onset of illness during the third time of PICU admission. In Patient 3, she died 12 days after PICU admission on the 87th day from onset. LESSONS: We should be aware that mucosal damage occurs on the skin and within the mucosa of visceral organs, leading to the occurrence of bronchiectasia, BO, enterocolitis, acute renal failure, and severe secondary infections. Establish a clinically predictive score that includes severe infection for pediatric patients to evaluate the risk of mortality in children in order to improve poor outcomes.

Extra-cardiac endovascular infections in the critically ill.

Vascular infections are associated with high complication rates and mortality. While there is an extensive body of literature surrounding cardiac infections including endocarditis, this is less so the case for other endovascular infections. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe vascular infections exclusive of those involving the heart. Endovascular infections may involve either the arterial or venous vasculature and may arise in native vessels or secondary to implanted devices. Management is complex and requires multi-disciplinary involvement from the outset. Infective arteritis or device-related arterial infection involves removal of the infected tissue or device. In cases where complete excision is not possible, prolonged courses of antimicrobials are required. Serious infections associated with the venous system include septic thrombophlebitis of the internal jugular and other deep veins, and intracranial/venous sinuses. Source control is of paramount importance in these cases with adjunctive antimicrobial therapy. The role of anticoagulation is controversial although recommended in the absence of contraindications. An improved understanding of the management of these infections, and thus improved patient outcomes, requires multi-center, international collaboration.

Human body cell membranes and antigen control.

The variables involved in the initiation and operation of the human immune system are considered. It is shown that the number of variations associated with disease and other detrimental conditions exceeds the number of lymphocyte cells available for control of these conditions. It is proposed that the immune system functions by changes in the ionic strength of metabolic fluids which in turn control the formation and stability of cell membranes. The application of these conditions to the control of bacterial, virus particle and other antigens is detailed. Observations supporting the proposals are presented.

The role of hepcidin in regulating iron homeostasis in selected diseases.

Iron is an element whose content in the human organism remains under strict control not only due to its involvement in many life processes but also because of its potential toxicity. The latest studies in iron metabolism, especially the involvement of hepcidin, which is the main regulator of iron homeostasis, broadened our knowledge in many medical fields (immunology, nephrology, hematology, gastrology). The present paper is a review of the literature devoted to the importance of hepcidin under selected conditions.

Neutrophil heterogeneity and its role in infectious complications after severe trauma.

Background: Trauma leads to a complex inflammatory cascade that induces both immune activation and a refractory immune state in parallel. Although both components are deemed necessary for recovery, the balance is tight and easily lost. Losing the balance can lead to life-threatening infectious complications as well as long-term immunosuppression with recurrent infections. Neutrophils are known to play a key role in these processes. Therefore, this review focuses on neutrophil characteristics and function after trauma and how these features can be used to identify trauma patients at risk for infectious complications. Results: Distinct neutrophil subtypes exist that play their own role in the recovery and/or development of infectious complications after trauma. Furthermore, the refractory immune state is related to the risk of infectious complications. These findings change the initial concepts of the immune response after trauma and give rise to new biomarkers for monitoring and predicting inflammatory complications in severely injured patients. Conclusion: For early recognition of patients at risk, the immune system should be monitored. Several neutrophil biomarkers show promising results and analysis of these markers has become accessible to such extent that they can be used for point-of-care decision making after trauma.

Potential Therapies for Infectious Diseases Based on Targeting Immune Evasion Mechanisms That Pathogens Have in Common With Cancer Cells.

Many global infectious diseases are not well-controlled, underlining a critical need for new, more effective therapies. Pathogens and pathogen-infected host cells, like cancer cells, evade immune surveillance via immune evasion mechanisms. The present study indicates that pathogenic bacteria, endoparasites, and virus-infected host cells can have immune evasion mechanisms in common with cancers. These include entry into dormancy and metabolic reprogramming to aerobic glycolysis leading to excessive secretion of lactic acid and immobilization of local host immunity. The latter evasion tactic provides a therapeutic target for cancer, as shown by our recent finding that patient-derived cancer xenografts can be growth-arrested, without major host toxicity, by inhibiting their lactic acid secretion (as mediated by the MCT4 transporter)-with evidence of host immunity restoration. Accordingly, the multiplication of bacteria, endoparasites, and viruses that primarily depend on metabolic reprogramming to aerobic glycolysis for survival may be arrested using cancer treatment strategies that inhibit their lactic acid secretion. Immune evasion mechanisms shared by pathogens and cancer cells likely represent fundamental, evolutionarily-conserved mechanisms that may be particularly critical to their welfare. As such, their targeting may lead to novel therapies for infectious diseases.

Epidemiología del VIH en Venezuela desde 1983 a 2016 / Epidemiology of HIV Infection in Venezuela since the year 1983 to the year 2016

Hay en el mundo, grandes avances en la lucha contra el Virus de Inmunodeficiencia Humana (VIH). En Venezuela el primer paciente con SIDA fue evaluado por el Dr. Manuel Guzmán en el año 1983, estimándose para el año 2016 120.000 personas infectadas Objetivo: describir los indicadores epidemiológicos del VIH en Venezuela desde el año 1983 hasta el año 2016. Metodología: se revisaron documentos del Programa Nacional de VIH/SIDA/ITS del MPPS (PNS), ONUSIDA, OPS, OMS y otros documentos científicos. También los datos epidemiológicos, y el acceso a la carga viral (CV) de VIH, CD4, test de resistencia y tratamiento antirretroviral (TARV). Resultados: Venezuela enfrenta una epidemia con- centrada, con prevalencia mayor de 5% en grupos vulnerables como los HSH y se desconoce la preva- lencia en otros grupos vulnerables. La prevalencia del VIH en los indígenas waraos es de 9.5 %, una de las más altas de América Latina, cuya situación ha sido catalogada como dramática. El número de mujeres infectadas va en ascenso, la mayoría son amas de casa con, instrucción de educación prima- ria y transmisión principalmente sexual. No hay datos de prevalencia de VIH de las embarazadas a nivel nacional y la tasa de transmisión vertical esti- mada para el 2013 fue de 21.8 %. La tasa de mor- talidad general por VIH/SIDA para el año 2015 fue de 8.3 por 100.000 habitantes, un aumento de 94 % con respecto a 1996 (4,14 x 100.000 habitantes). La tasa promedio de mortalidad por VIH/SIDA en niños < de 5 años, es mayor en los menores de un año, con una tasa de 3,46 por 1.000 recién nacidos vivos. El índice de mortalidad en los hombres aumentó 1.8 veces y en la mujer 3.9. El acceso a las pruebas diagnósticas, CV de VIH, lin-focitos CD4 y test de resistencia está seriamente limitado. Para el año 2016, de 120 mil personas con VIH , 59% tenía acceso al TARV y solo 7 % tenían supresión viral. Venezuela es el país de América Latina, que ha experimentado más interrupciones del TARV, agravándose dicha situación durante 2017 y 2018, con un acceso a tratamiento de 16 %en abril de 2018, y desde esa fecha, 58.000 pacien-tes estaban en falta absoluta de TARV. Gracias al Plan Maestro, el acceso a TARV fue reiniciado en febrero del 2019. Conclusión: después de 30 años de la epidemia del VIH en Venezuela, las políticas sanitarias no han sido suficientes para detener el avance de la enfermedad, lo que evidencia el fraca-so del PNS. Es urgente y prioritario, cumplir las recomendaciones del Plan Maestro, así como otras expuestas en el presente documento(AU)

Immunodeficiency Virus (HIV). The first patient with AIDS in Venezuela, was evaluated by Dr. Manuel Guzmán in 1983 and in the year 2016 the number of infected people was estimated in 120,000. Objective: to describe the epidemiological indicators of HIV in Venezuela from 1983 to 2016. Methodology, the reviewed documents were: National HIV / AIDS / STI Program of the Ministry of Popular Power for Health (PNS), UNAIDS/ WHO/PAHO Master Plan for fortifying the response to HIV, tuberculosis and malaria in our country from a public health perspective (Master Plan), and other scientific publications. Epidemiological data were reviewed as well as the access to viral load (VL) of HIV, CD4, resistance test, and antiretroviral treatment (ART). Results: Venezuela faces a concentrated epidemic, with a prevalence of more than 5% in vulnerable groups and the prevalence in other groups is unknown. The prevalence of HIV in the Waraos Indigenous people is 9.5%, one of the highest in Latin America, the situation has been named as dramatic. Infected women are on the rise, with the majority being housewives, with elementary schooling and, mainly by sexual transmission. There are no HIV prevalence data of pregnant women nationwide and the estimated vertical transmission rate for 2013 was 21.8%. The overall mortality rate for HIV / AIDS for the year 2015 was 8.3 per 100.000 inhabitants, an increase of 94% compared to 1996 (4.14 x 105). The mortality index in men increased 1.8 times and in women 3.9. The average mortality rate for HIV / AIDS in children under 5 years of age is higher in those under one year of age, with a rate of 3.46 per 1000 live births. In 2014, maternal deaths due to AIDS represented 2.5%, there are no updated data. Access to diagnostic tests, VL, lymphocyte CD4 and resistance test is severely limited. For the year 2016, 120.000 persons were living with HIV in Venezuela, 59% had access to ART, but only 7% had suppression of LV. Venezuela is the country in Latin America, which has experienced more interruptions of ART. Aggravating this situation during 2017 and 2018, with an access to treatment of 16 % in April 2018. Since then, approximately 58,000 patients receive no ART at all. Thanks to the Master Plan access to ART was reinitiated in February 2019. Conclusions: more than 30 years after the HIV epidemic in Venezuela, health policies have been sufficient to stop the progression of the disease, which shows the failure of the National HIV /AIDS / STI Program. It is a priority to comply with the recommendations of the Master Plan, as well as others set out in this document(AU)

Giant-cell arteritis-related mortality in France: A multiple-cause-of-death analysis.

OBJECTIVES: Giant-cell arteritis (GCA) is a large vessel vasculitis. Data regarding mortality are controversial. We describe the mortality data of the French death certificates for the period of 2005 to 2014. METHODS: Using multiple-cause-of-death (MCOD) analysis, we calculated age-adjusted mortality rates for GCA, examined differences in mortality rates according to age and gender and analyzed the underlying causes of death (UCD). RESULTS: We analyzed 4628 death certificates listing a diagnosis of GCA as UCD or non-underlying cause of death (NUCD). The mean age of death was 86 (±6.8) years. The overall age-standardized mortality rate among GCA patients was 7.2 per million population. Throughout the study period, the mean age of death was significantly increased (r = 0.17, p < .0001) in both genders. There was no significant difference with age repartition of death in the general population (p = .26). When GCA was listed as the UCD, most frequent associated diseases were cardiovascular (79%) and infectious diseases (35%). When GCA was reported as the NUCD, the listed UCD was a cardiovascular event in 40% of cases, neoplasm in 13%, neurodegenerative disorder in 11% and infectious disease in 10%. When GCA was the UCD or NUCD, an age-adjusted observed/expected ratio > 1 in GCA-associated mortality compared with the general population mortality was observed for tuberculosis, pneumonia and cardiovascular diseases. CONCLUSION: In this analysis of French death certificates mentioning GCA, we observed a stable standardized mortality rate between 2005 and 2014. The most frequent associated diseases were cardiovascular diseases and infections.

HIF-1alpha and infectious diseases: a new frontier for the development of new therapies.

The aim of this review is to show the significant role of HIF-1alpha in inflammatory and infectious diseases. Hypoxia is a physiological characteristic of a wide range of diseases from cancer to infection. Cellular hypoxia is sensed by oxygen-sensitive hydrolase enzymes, which control the protein stability of hypoxia-inducible factor alpha 1 (HIF-1alpha) transcription factors. When stabilized, HIF-1alpha binds with its cofactors to HIF-responsive elements (HREs) in the promoters of target genes to organize a broad ranging transcriptional program in response to the hypoxic environment. HIF-1alpha also plays a regulatory function in response to a diversity of molecular signals of infection and inflammation even under normoxic conditions. HIF-1alpha is stimulated by pro-inflammatory cytokines, growth factors and a wide range of infections. Its induction is a general element of the host response to infection. In this review, we also discuss recent advances in knowledge on HIF-1alpha and inflammatory responses, as well as its direct influence in infectious diseases caused by bacteria, virus, protozoan parasites and fungi.

Humanised mouse models for haematopoiesis and infectious diseases.

"Humanised" mouse models have emerged over past years as powerful tools for investigating human haematopoiesis and immunity. They allowed the identification of key factors for the maintenance and function of normal and leukaemic human haematopoietic stem cells. These findings have been widely used to dissect the pathogenesis of multiple myeloid and lymphoid neoplasms, such as acute myeloid leukaemia and acute lymphoblastic leukaemia. Furthermore, these models can serve as a stepping-stone to clinical trials by testing novel drugs that target leukaemic stem cells. The investigation of human immunity in vivo is also of great interest in both the context of understanding the innate and adaptive immune system and responses to viral infections with exclusive human tropism, such as Epstein-Barr virus and human immunodeficiency virus. This review focuses on recent advances in the study of human haematopoiesis and immunity in humanised mouse models, underlining their relevance and limitations.

Immunogenetic profiling of 23 SNPs of cytokine and chemokine receptor genes through a minisequencing technique: Design, development and validation.

The minisequencing technique offers accuracy and robustness to genotyping of polymorphic DNA variants, being an excellent option for the identification and analyses of prognostic/susceptibility markers in human diseases. Two multiplex minisequencing assays were designed and standardized to screen 23 candidate SNPs in cytokine, chemokine receptor and ligand genes previously associated with susceptibility to cancer and autoimmune disorders as well as to infectious diseases outcome. The SNPs were displayed in two separate panels (panel 1-IL2 rs2069762, TNFα rs1800629, rs361525; IL4 rs2243250; IL6 rs1800795; IL10 rs1800896, rs1800872; IL17A rs8193036, rs2275913 and panel 2-CCR3 rs309125, CCR4 rs6770096, rs2228428; CCR6 rs968334; CCR8 rs2853699; CXCR3 rs34334103, rs2280964;CXCR6 rs223435, rs2234358; CCL20 rs13034664, rs6749704; CCL22 rs4359426; CXCL10/IP-10 rs3921, rs56061981). A total of 305 DNA samples from healthy individuals were genotyped by minisequencing. To validate the minisequencing technique and to encompass the majority of the potential genotypes for all 23 SNPs, 20 of these samples were genotyped by Sanger sequencing. The results of both techniques were 100% in agreement. The technique of minisequencing showed high accuracy and robustness, avoiding the need for high quantities of DNA template samples. It was easily to be conducted in bulk samples derived from a highly admixed human population, being therefore an excellent option for immunogenetic studies.

The Prevention of Venous Thromboembolism in Surgical Patients.

Patients undergoing surgery are at an increased risk of VTE. Since the early 1990s the prevention of VTE has been dominated by the administration of low-molecular weight heparin during admission. New oral anticoagulants have been extensively researched and have increased in popularity. This chapter reviews why surgical patients are at increased risk of VTE and summaries both the pharmacological and mechanical methods of prophylaxis available.

A scoping review of anorexia of aging correlates and their relevance to population health interventions.

Anorexia of aging (AA, i.e., loss of appetite and/or reduction of food intake with aging) is an important public health issue. It leads to unintentional weight loss, which is an independent risk factor for morbidity and mortality among seniors. AA has mainly been studied from a biological perspective and regarded as a normal physiological consequence of aging, rather than a negative health outcome with underlying determinants. Some potentially modifiable correlates have however been found to be associated with this geriatric condition. Here, we conducted a scoping review of the literature to: 1) identify AA correlates, and 2) discuss their relevance to population health interventions. Our results indicate two main categories of AA correlates, namely, physiopathological and non-physiopathological. The first category relates to physiological dysfunctions, pathologies involving (or culminating in) biomarker dysregulation, and polypharmacy. These correlates are difficult to modify, especially through population health interventions. The second category, which contains fewer correlates, includes potentially modifiable public health targets, such as food-related properties, psychological, sociocultural, and environmental issues. We conclude that there are several AA correlates. Some of them are modifiable and could be targeted for development and implementation as appropriate population health interventions to prevent appetite loss and promote maintenance of adequate food intake in aging.