Virulence factors of the mycobacterium tuberculosis complex

The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world. Introduction.Fil: Forrellad, Marina Andrea. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Klepp, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Gioffré, Andrea Karina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Sabio y García, Julia Verónica. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Morbidoni, Héctor Ricardo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Escuela de Ciencias Médicas. Cátedra de Microbiología, Parasitología y Virología; ArgentinaFil: Santangelo, María de la Paz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Cataldi, Ángel Adrián. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Impact of the deletion of the six mce operons in Mycobacterium smegmatis

The Mycobacterium smegmatis genome contains six operons designated mce (mammalian cell entry). These operons, which encode membrane and exported proteins, are highly conserved in pathogenic and non-pathogenic mycobacteria. Although the function of the Mce protein family has not yet been established in Mycobacterium smegmatis, the requirement of the mce4 operon for cholesterol utilization and uptake by Mycobacterium tuberculosis has recently been demonstrated. In this study, we report the construction of an M. smegmatis knock-out mutant deficient in the expression of all six mce operons. The consequences of these mutations were studied by analyzing physiological parameters and phenotypic traits. Differences in colony morphology, biofilm formation and aggregation in liquid cultures were observed, indicating that mce operons of M. smegmatis are implicated in the maintenance of the surface properties of the cell. Importantly, the mutant strain showed reduced cholesterol uptake when compared to the parental strain. Further cholesterol uptake studies using single mce mutant strains showed that the mutation of operon mce4 was reponsible for the cholesterol uptake failure detected in the sextuple mce mutant. This finding demonstrates that mce4 operon is involved in cholesterol transport in M. smegmatis.Fil: Klepp, Laura Ines. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Forrellad, Marina Andrea. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Osella, Ana Virginia. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blanco, Federico Carlos. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Stella, Emma Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Bianco, María Verónica. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; ArgentinaFil: Santangelo, María de la Paz. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Sassetti, Cristopher. Massachusetts Institute of Technology; Estados UnidosFil: Jackson, Mary. State University of Colorado - Fort Collins; Estados UnidosFil: Cataldi, Ángel Adrián. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bigi, Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. CNIA Castelar. Centro de Investigación en Ciencias Veterinarias y Agronómicas; ArgentinaFil: Morbidoni, Héctor Ricardo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Gout, hyperuricemia and cardio-vascular risk

Concern about gout-related increase in risk of hypertension and cardiovascular diseases has been raising in recent years. A similar relationship has been postulated even for asymptomatic hyperuricemia. The aims of this review are to appraise the available evidence about: 1. the relationship between hyperuricemia itself and/or gout and cardiovascular diseases; 2. the effect of decreasing serum acid uric level on the rate of cardiovascular events. To meet this purpose, we did an extensive analysis of literature, limiting the search to articles in English, indexed in Medline and published in the last 17 years. Most of the retrieved studies were conducted on surrogate outcomes, whereas randomized trials on clinically relevant outcomes are few and of questionable quality. Based on the available data, we may conclude that hyperuricemia itself is a probable, although weak, risk factor for hypertension and increases the risk of nephropathy in patients with type 2 diabetes mellitus. Moreover, symptomatic gout significantly increases the risk of cardiovascular events, particularly of myocardial infarction and mainly in young-adult and people without other risk factors. Regarding the effectiveness of urate-lowering drugs in the prevention of myocardial infarction, the strongest evidence supports their use in subjects affected by gout. A probable efficacy in controlling hypertension, especially in young subjects and women, as well as in preventing nephropathy in type 2 diabetic patients has also been reported. Interestingly, allopurinol administered at doses ≤300 mg/day seems to protect from myocardial infarction, hypertension, total and serious cardiovascular events; preliminary evidences suggest a protective effect of febuxostat on major adverse cardiovascular events in high-risk gouty patients

Clinical practice guidelines adaptation for internists - An EFIM methodology

The rising number of clinical guidelines poses a new challenge to the internists. The main problems are: 1) available documents suffer from heterogeneous methodological quality, and 2) most of clinical guidelines target an 'ideal' patient affected by a single condition, while in real practice internists must face with comorbid patients typically undergoing a polypharmacy. To help address this challenge, EFIM Clinical Practice Working Group started a project aimed to answer a series of relevant clinical questions, by selecting the best available guidance containing recommendations applicable to complex patients under polypharmacy. The project started with the creation of a research protocol containing details about all the steps needed to write the Clinical Practice Guideline Summary. In particular, this methodological document specifies the rules: 1) to select topics and clinical questions; 2) to build up a panel of experts, carefully managing eventual conflict of interests; 3) to critically appraise clinical guidelines (using a validated tool as AGREE II), selecting the most valid and applicable to the common clinical practice (using ADAPTE; 4) to address and solve potential disagreements among the selected documents

A new score to predict Clostridioides difficile infection in medical patients: a sub-analysis of the FADOI-PRACTICE study

Medical divisions are at high risk of Clostridioides difficile infection (CDI) due to patients' frailty and complexity. This sub-analysis of the FADOI-PRACTICE study included patients presenting with diarrhea either at admission or during hospitalization. CDI diagnosis was confirmed when both enzyme immunoassay and A and B toxin detection were found positive. The aim of this sub-analysis was the identification of a new score to predict CDI in hospitalized, medical patients. Five hundred and seventy-two patients with diarrhea were considered. More than half of patients was female, 40% on antibiotics in the previous 4 weeks and 60% on proton pump inhibitors (PPIs). CDI diagnosis occurred in 103 patients (18%). Patients diagnosed with CDI were older, more frequently of female sex, recently hospitalized and bed-ridden, and treated with antibiotics and PPIs. Through a backward stepwise logistic regression model, age > 65 years, female sex, recent hospitalization, recent antibiotic therapy, active cancer, prolonged hospital stay (> 12 days), hypoalbuminemia (albumin < 3 g/dL), and leukocytosis (white blood cells > 9 x 10<^>9/L) were found to independently predict CDI occurrence. These variables contributed to building a clinical prognostic score with a good sensitivity and a modest specificity for a value > 3 ( 79% and 58%, respectively; AUC 0.75, 95% CI 0.71-0.79, p < 0.001), that identified low-risk (score <= 3; 42.5%) and high-risk (score > 3; 57.5%) patients. Although some classical risk factors were confirmed to increase CDI occurrence, the changing landscape of CDI epidemiology suggests a reappraisal of common risk factors and the development of novel risk scores based on local epidemiology

Pulmonary embolism - an EFIM guideline critical appraisal and adaptation for practicing clinicians

Several trials have been conducted in the last decades that challenged the management of patients with acute pulmonary embolism (PE) in terms of diagnosis and treatment. Updated international clinical practice guidelines (CPGs) endorsed the evidence from these trials. The aim of this document was to adapt recommendations from existing CPGs to assist physicians in decision making concerning specific and complex scenarios related to acute PE. The flow for the adaptation procedure was first the identification of unsolved clinical issues in patients with acute PE (PICOs), then critically appraise the existing CPGs and choose the recommendations, which are the most applicable to these specific and complex scenarios. Five PICOs were identified and CPGs appraisal was performed. Concerning diagnosis of PE when computed tomographic pulmonary angiography is not available/contraindicated and d-dimer is less specific, perfusion lung scan is the preferred option in the majority of clinical scenarios. For the treatment of PE when relevant clinical conditions like pregnancy or severe renal failure are present heparin is to be used. Poor evidence and low-level recommendations exist on the best bleeding prediction rule in patients treated for PE. The duration of anticoagulation needs to be tailored concerning the presence of predisposing factors for index PE and the consequent risk for recurrence. Finally, recommendations on the opportunity to screen for cancer and thrombophilia patients without recognized thrombosis risk factors for PE are reported. Overall, 35 recommendations were endorsed and the rationale for the selection is reported in the main text. By the use of proper methodology for the adaptation process, this document offers a simple and updated guide for practicing clinicians dealing with complex patients

Virulence factors of the Mycobacterium tuberculosis complex

The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world.Instituto de BiotecnologíaFil: Forrellad, Marina Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; ArgentinaFil: Klepp, Laura Ines. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; ArgentinaFil: Gioffre, Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; ArgentinaFil: Sabio y Garcia, Julia Veronica. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; ArgentinaFil: Morbidoni, Hector R. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Cátedra de Microbiología; ArgentinaFil: Santangelo, María De La Paz. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina.Fil: Cataldi, Angel Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; ArgentinaFil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentin

The discharge of patients with diabetes from Internal Medicine Units: a clinical audit

The aim of the present study was to address it by conducting a clinical audit, one that focused on the quality evaluation of the assistance given to patients with diabetes at the moment of their discharge from hospital. The clinical audit was structured in 5 phases: i) preparation; ii) definition of criteria, indicators and standards; iii) retrospective data collection; iv) data analysis, identification of main deviations from standards; v) implementation of corrective measures. Twenty Departments of Internal Medicine from 10 Italian regions retrospectively reviewed medical reports obtaining a data collection from 1332 discharged patients with diabetes. Patients receiving instructions for home glycemic control/discharged patients, showed a mean performance =41.6% (range: 5.0-89.9); patients receiving instructions for hypoglycemic treatment/discharged patients, =32.4% (range: 0.0-92.1); patients receiving instructions for subcutaneous insulin administration/discharged patients, =60.4% (range: 56.5-100.0); patients receiving nutritional scheme or advice/discharged patients, =24.8 (range: 25.4-76.6); patients addressed to ambulatory control/discharged patients, =60.7% (range: 65.6-100.0); and finally patients with HbA1c reported in discharge report/discharged patients, =40.6% (range: 1.75-98.0). Results confirmed that all the levels are well below 70%, the acceptable level of quality. The clinical audit provided data that allows for better identification of deficient clinical behaviors and the addressing of them with specific ameliorative actions; a continuing process of check, re-check and feedback in order to further enhance the quality of assistance given to patients with diabetes discharged from hospital