Interleukin-6 and -27 as potential novel biomarkers for human pleural tuberculosis regardless of the immunological status.

Tuberculosis (TB) is the leading cause of pleural exudative effusions. Inflammatory markers, such as IFNγ and ADA, have been used as proxies for its diagnosis. We evaluated ex vivo levels of several cytokines in 83 pleural effusion specimens from patients with TB (including 10 with HIV co-infection) and 26 patients with other pleuritis using multiplex and ELISA assays. IL-6 and IL-27 levels were higher (p ≤ 0.04) in TB patients, regardless of the HIV status and the approach. IL-2, IL-4, IL-8, IFNγ, TNF and G-CSF showed variable results depending on the assay. This warranty these markers to be further validated.

Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination.

Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.

Monomicrobial Pseudomonas necrotizing fasciitis: a case of infection by two strains and a review of 37 cases in the literature.

Necrotizing fasciitis due to Pseudomonas aeruginosa is rare. We report a case of monomicrobial Pseudomonas necrotizing fasciitis and review 37 cases in the literature. The mortality rate was 30%, and most infections occurred in the immunocompromised. Clinicians should consider empiric pseudomonal antibiotic coverage in the severely immunocompromised with potentially necrotizing infections.

The BCG Moreau Vaccine Upregulates In Vitro the Expression of TLR4, B7-1, Dectin-1 and EP2 on Human Monocytes.

Background: Tuberculosis (TB) is currently the second greatest killer worldwide and is caused by a single infectious agent. Since Bacillus Calmette−Guérin (BCG) is the only vaccine currently in use against TB, studies addressing the protective role of BCG in the context of inducible surface biomarkers are urgently required for TB control. Methods: In this study, groups of HIV-negative adult healthy donors (HD; n = 22) and neonate samples (UCB; n = 48) were voluntarily enrolled. The BCG Moreau strain was used for the in vitro mononuclear cell infections. Subsequently, phenotyping tools were used for surface biomarker detection. Monocytes were assayed for TLR4, B7-1, Dectin-1, EP2, and TIM-3 expression levels. Results: At 48 h, the BCG Moreau induced the highest TLR4, B7-1, and Dectin-1 levels in the HD group only (p-value < 0.05). TIM-3 expression failed to be modulated after BCG infection. At 72 h, BCG Moreau equally induced the highest EP2 levels in the HD group (p-value < 0.005), and higher levels were also found in HD when compared with the UCB group (p-value < 0.05). Conclusions: This study uncovers critical roles for biomarkers after the instruction of host monocyte activation patterns. Understanding the regulation of human innate immune responses is critical for vaccine development and for treating infectious diseases.

Impact of the complex humanitarian crisis on the epidemiology of the cardiometabolic risk factors in Venezuela.

BACKGROUND: The complex humanitarian crisis (CHC) in Venezuela is characterized by food insecurity, hyperinflation, insufficient basic services, and the collapse of the healthcare system. The evolution of the epidemiology of cardiometabolic risk factors in this context is unknown. AIM: To compile the last 20 years evidence on the prevalence of cardiometabolic risk factors in adults of Venezuela in the context of the CHC. METHODS: A comprehensive literature review of population-based studies of adults in Venezuela from 2000 to 2020. RESULTS: Seven studies (National EVESCAM 2014-2017, 3 regions VEMSOLS 2006-2010, Maracaibo city 2007-2010, Merida city 2015, Mucuchies city 2009, Barquisimeto city CARMELA 2003-2005, and Zulia state 1999-2001) with samples sizes ranging from 109 to 3414 subjects were included. Over time, apparent decrease was observed in smoking from 21.8% (2003-2005) to 11.7% (2014-2017) and for obesity from 33.3% (2007-2010) to 24.6% (2014-2017). In contrast, there was an apparent increase in diabetes from 6% (2003-2005) to 12.3% (2014-2017), prediabetes 14.6% (2006-2010) to 34.9% (2014-2017), and hypertension 24.7% (2003-2005) to 34.1% (2014-2017). The most prevalent dyslipidemia - a low HDL-cholesterol - remained between 65.3% (1999-2001) and 63.2% (2014-2017). From 2006-2010 to 2014-2017, the high total cholesterol (22.2% vs 19.8%, respectively) and high LDL-cholesterol (23.3% vs 20.5%, respectively) remained similar, but high triglycerides decreased (39.7% vs 22.7%, respectively). Using the same definition across all the studies, metabolic syndrome prevalence increased from 35.6% (2006-2010) to 47.6% (2014-2017). Insufficient physical activity remained steady from 2007-2010 (34.3%) to 2014-2017 (35.2%). CONCLUSION: Changes in the prevalence of cardiometabolic risk factors in Venezuela are heterogeneous and can be affected by various social determinants of health. Though the Venezuelan healthcare system has not successfully adapted, the dynamics and repercussions of the CHC on population-based cardiometabolic care can be instructive for other at-risk populations.

Time to face the proofs: the BCG Moreau vaccine promotes superior inflammatory cytokine profile in vitro when compared with Russia, Pasteur, and Danish strains.

Tuberculosis (TB) has been a major public health problem worldwide, and the Bacillus Calmette-Guérin (BCG) vaccine is the only available vaccine against this disease. The BCG vaccine is no longer a single organism; it consists of diverse strains. The early-shared strains of the BCG vaccine are stronger immunostimulators than the late-shared strains. In this study, we have employed a simple in vitro human model to broadly evaluate the differences among four widely used BCG vaccines during the characterization of strain-specific host immune responses. In general, the BCG Moreau vaccine generated a higher inflammatory cytokine profile and lower TGF-ß levels compared with the Russia, Pasteur, and Danish strains in the context of early sensitization with TB; however, no changes were observed in the IL-23 levels between infected and noninfected cultures. Unsurprisingly, the BCG vaccines provided different features, and the variances among those strains may influence the activation of infected host cells, which ultimately leads to distinct protective efficacy to tackle TB.

Management of symptomatic uterine fibroids with ulipristal acetate: A retrospective, multicentric and nationwide study.

OBJECTIVE: To evaluate symptomatic uterine fibroid outcomes following at least one course of ulipristal acetate (UPA) 5 mg/day therapy in the hospital setting, during the year 2017. STUDY DESIGN: A retrospective and descriptive analysis involving women with symptomatic fibroids was conducted in 15 hospital centers in Portugal in 2017 to assess fibroid size, bleeding control and hemoglobin levels following at least one course of UPA 5 mg/day. Secondary outcomes were the reasons for the treatment, type of surgery, fibroid classification, patient satisfaction with the treatment, and adverse events. RESULTS: Five-hundred and twenty-six patients were enrolled in this survey, and 93 % of the women completed, at least, 1 treatment course with UPA. Uterine bleeding control was achieved in 81 % of the cases. A significant increase (p < 0.001) in hemoglobin levels and a reduction (p < 0.001) in uterine fibroid size was observed after treatment, with a median reduction of 24 % from the baseline. Forty-seven percent of the patients underwent subsequent surgery and there were no serious adverse events reported in this multicentric nationwide study. CONCLUSIONS: So far, this is the largest case series reporting on symptomatic uterine fibroid outcomes after UPA therapy in Portugal. Our data are in line with published literature and confirm favorable outcomes after UPA therapy for women of childbearing age and premenopausal.

The in vitro Mycobacterium bovis BCG Moreau infection of human monocytes that induces Caspase-1 expression, release and dependent cell death is mostly reliant upon cell integrity.

BACKGROUND: Caused by Mycobacterium tuberculosis, tuberculosis (TB) is an extremely contagious disease predominantly affecting the lungs. TB is found worldwide and has a major impact on public health safety primarily due to its high mortality rate. Applied for over a hundred years as a preventive measure, Mycobacterium bovis BCG remains the only available TB vaccine. Only one seminal study about the apoptotic pathways induced by this vaccine in the monocytic lineage of the host cell has found the effects of BCG on regulation of apoptosis. The aim of this study was to explore beyond that pioneer study the pathway related to the in vitro cell-death pattern and the inflammatory response to the BCG vaccine in human monocytes. METHODS: Cohorts of HIV-negative volunteers were enrolled: adult Healthy Donors (HD) and neonates' Umbilical Cord Blood (UCB) individuals. Host mononuclear cells were infected with the M. bovis Moreau strain of BCG vaccine at 16, 24, 48, and 72 h. The Real-Time RT-PCR for TRADD, Bcl-2, and Caspases-1 and -3 were performed, and supernatants were assayed in parallel for Caspase-1, NLRP3, HO-1, and IL-1ß levels whereas caspases were assessed intracellularly. The effect of a BCG infection in monocytes was characterized via a metabolic activity assay by LDH release profiles. RESULTS: Overall, the BCG vaccine induced significantly higher Caspase-1 and Bcl-2 mRNA levels in both the HD and UCB groups (p-value ≤0.05). In addition, a significant increase solely in Caspase-1 protein levels was also noted in both HD and UCB (p-value ≤0.05) notwithstanding the absence of any damaged cell membranes. CONCLUSIONS: Our data directly corroborate other findings showing that BCG Moreau led to an increased secretion of IL-1ß but not IL-18, two Caspase-1-activated cytokines, and are also in support of the model that the BCG Moreau infection of human mononuclear cells may induce a cell-death pattern involving Caspase-1 activation.

Advanced abdominal pregnancy in a spontaneous heterotopic pregnancy.

Spontaneous heterotopic pregnancy is a potentially life-threatening condition rarely considered when a patient with an intrauterine pregnancy is asymptomatic or presents with complaints such as abdominal pain. An advanced abdominal pregnancy as the form of the ectopic component, outside the context of assisted reproduction, is an even more unusual and perilous diagnosis with very few cases reported in the literature. We report such a case in a 34-year-old multipara, with no known risk factors for ectopic pregnancy. The pregnancy was initially misdiagnosed and managed as a dichorionic gestation, complicated with fetal demise of one of the twins. The correct diagnosis was only made after term delivery of the intrauterine pregnancy. The abdominal pregnancy was subsequently managed via laparotomy with no complications.

Impact of the complex humanitarian crisis on the epidemiology of the cardiometabolic risk factors in Venezuela / Impacto de la crisis humanitaria compleja en la epidemiología de los factores de riesgo cardiometabólico en Venezuela

BACKGROUND: The complex humanitarian crisis (CHC) in Venezuela is characterized by food insecurity, hyperinflation, insufficient basic services, and the collapse of the healthcare system. The evolution of the epidemiology of cardiometabolic risk factors in this context is unknown. AIM: To compile the last 20 years evidence on the prevalence of cardiometabolic risk factors in adults of Venezuela in the context of the CHC. METHODS: A comprehensive literature review of population-based studies of adults in Venezuela from 2000 to 2020. RESULTS: Seven studies (National EVESCAM 2014–2017, 3 regions VEMSOLS 2006–2010, Maracaibo city 2007–2010, Merida city 2015, Mucuchies city 2009, Barquisimeto city CARMELA 2003–2005, and Zulia state 1999–2001) with samples sizes ranging from 109 to 3414 subjects were included. Over time, apparent decrease was observed in smoking from 21.8% (2003–2005) to 11.7% (2014–2017) and for obesity from 33.3% (2007–2010) to 24.6% (2014–2017). In contrast, there was an apparent increase in diabetes from 6% (2003–2005) to 12.3% (2014–2017), prediabetes 14.6% (2006–2010) to 34.9% (2014–2017), and hypertension 24.7% (2003–2005) to 34.1% (2014–2017). The most prevalent dyslipidemia – a low HDL-cholesterol – remained between 65.3% (1999–2001) and 63.2% (2014–2017). From 2006–2010 to 2014–2017, the high total cholesterol (22.2% vs 19.8%, respectively) and high LDL-cholesterol (23.3% vs 20.5%, respectively) remained similar, but high triglycerides decreased (39.7% vs 22.7%, respectively). Using the same definition across all the studies, metabolic syndrome prevalence increased from 35.6% (2006–2010) to 47.6% (2014–2017). Insufficient physical activity remained steady from 2007–2010 (34.3%) to 2014–2017 (35.2%).

INTRODUCCIÓN: La crisis humanitaria compleja (CHC) en Venezuela se caracteriza por la inseguridad alimentaria, la hiperinflación, la insuficiencia de servicios básicos y el colapso del sistema de salud. Se desconoce la evolución de la epidemiología de los factores de riesgo cardiometabólico en este contexto. OBJETIVO: Recopilar evidencia de los últimos 20 años sobre la prevalencia de factores de riesgo cardiometabólico en adultos de Venezuela en el contexto del CHC. MÉTODOS: Revisión bibliográfica exhaustiva de estudios poblacionales de adultos en Venezuela desde 2000 hasta 2020. RESULTADOS: Se incluyeron 7 estudios (EVESCAM Nacional 2014-2017, 3 regiones VEMSOLS 2006-2010, ciudad de Maracaibo 2007-2010, ciudad de Mérida 2015, ciudad de Mucuchíes 2009, ciudad de Barquisimeto CARMELA 2003-2005 y estado de Zulia 1999-2001) con tamaños de muestra variables desde 109 hasta 3.414 sujetos. A lo largo del tiempo, hubo una aparente disminución del consumo de tabaco del 21,8% (2003-2005) al 11,7% (2014-2017) y de la obesidad del 33,3% (2007-2010) al 24,6% (2014-2017). Por el contrario, hubo un aparente aumento de la diabetes del 6% (2003-2005) al 12,3% (2014-2017), la prediabetes del 14,6% (2006-2010) al 34,9% (2014-2017) y la hipertensión del 24,7% (2003-2005) al 34,1% (2014-2017). La dislipidemia más prevalente, el colesterol HDL bajo, se mantuvo entre el 65,3% (1999-2001) y el 63,2% (2014-2017). Desde 2006-2010 hasta 2014-207, el colesterol total alto (22,2% versus 19,8%, respectivamente) y el colesterol LDL alto (23,3% versus 20,5%, respectivamente) permanecieron similares, pero los triglicéridos altos disminuyeron (39,7% versus 22,7%, respectivamente). Utilizando la misma definición en todos los estudios, la prevalencia de síndrome metabólico aumentó del 35,6% (2006-2010) al 47,6% (2014-2017). La actividad física insuficiente se mantuvo estable entre 2007-2010 (34,3%) y 2014-2017 (35,2%). [...]

Knee bone tumors: findings on conventional radiology.

The knee is a common site for bone tumors, whether clinically painful or not. Conventional radiology has been established as the first line of investigation in patients with knee pain and can reveal lesions that often generate questions not only for the generalist physician but also for the radiologist or general orthopedist. History, image examination, and histopathological analysis compose the essential tripod of the diagnosis of bone tumors, and conventional radiology is an essential diagnostic tool in patients with knee pain. This pictorial essay proposes to depict the main conventional radiography findings of the most common bone tumors around the knee, including benign and malignant tumors, as well as pseudo-tumors.

O joelho é sede comum de apresentação de tumores ósseos, sejam eles clinicamente dolorosos ou não. A radiologia convencional consagra-se como exame de primeira linha para investigação inicial dos doentes com dor no joelho e pode revelar lesões que muitas vezes geram dúvidas tanto para o médico generalista quanto para o radiologista ou ortopedista geral. História, exame de imagem e estudo histopatológico compõem o tripé essencial do diagnóstico dos tumores ósseos, sendo a radiografia simples o instrumento essencial de investigação diagnóstica nesses casos. Este ensaio iconográfico propõe expor os principais achados dos mais frequentes tumores ósseos, benignos, malignos e pseudotumorais do joelho.

Human neonates display altered ex vivo monokine production related to healthy adults.

The inflammatory response plays an important role during the induction of several neonatal diseases. Previous studies have shown that during newborn infections, the natural imbalance between pro- and anti-inflammatory responses shifts toward the production of pro-inflammatory cytokines. In this study, we employed an array system to detect 9 pro- and anti-inflammatory cytokines, and performed ELISA for 6 other cytokines. We then compared the immune response profiling in umbilical cord blood (UV) plasma samples with circulating levels in otherwise healthy donors (HD). Concentrations of ex vivo monokine levels, such as interleukins (IL)-18, IL-23 and IL-27, were profoundly reduced in the UV in relation to the HD group (p-values of 0.003, 0.009 and <0.0001, respectively). Conversely, UV-plasmatic TGF-ß1 levels displayed marked enhancement (p-value=0.005) in relation to HD. Several factors may be implicated in these neonatal alterations, and additional characterization of a broader cytokine panel is warranted to reveal other possible candidates.

Severe dengue in the early postoperative period after kidney transplantation: two case reports from Hospital Geral de Fortaleza.

Dengue is an arbovirosis that ranges from an asymptomatic presentation to a more severe disease, which is characterized by a vascular leakage syndrome where abdominal pain is a major symptom. Transplant recipients are immunosuppressed and are less likely to develop a severe form of the disease because of a reduction in immune-mediated responses that trigger plasma extravasation events. Herein, we report two cases of severe dengue in the early postoperative period of two kidney transplant recipients. Considering the severity of the cases, we emphasize the importance of dengue screening immediately before transplantation in areas endemic for the disease.

The role of host soluble inflammatory mediators induced by the BCG vaccine for the initiation of in vitro monocyte apoptosis in healthy Brazilian volunteers.

BACKGROUND: Tuberculosis (TB) is the second greatest killer worldwide that is caused by a single infectious agent. For its control, studies of TB vaccines are needed. Since Bacillus Calmette-Guerin (BCG) is the only vaccine against TB currently in use, studies addressing the protective role of BCG in the context of inducible inflammatory mediators are urgently required. METHODS: In this study, groups of HIV-negative adult healthy donors (HD; n = 42) and neonates (UV; n = 18) have been voluntarily enrolled, and BCG Moreau strain was used for the in vitro mononuclear cell infections for an initial period of 48 h. Subsequently, harvested conditioned medium (CM) was added to autologous resting cells for an additional 24, 48, and 120 h, and Annexin V, in conjunction with a vital dye, was then used for apoptosis detection. CM was also assayed for nitric oxide (NO), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), interferon (IFN)-ß, and transforming growth factor (TGF)-ß1 levels. The p values were set up for any differences between two groups of individuals using Student's t-test and considered significant when ≤ 0.05. RESULTS: At 120 h, CM induced the highest apoptosis levels in both group studied, but necrosis was high in UV group only (p-value < 0.05). NO was released equally during BCG infection in both groups, but higher levels were found in HD when compared with UV group (p-value < 0.05). Overall, BCG Moreau triggered high PGE2, LTB4 and IFN-ß productions in macrophages from the UV group (p-value ≤ 0.05), whereas the prostanoid PGE2 and TGF-ß1 had an opposite pattern in the HD group. CONCLUSIONS: This study uncovers critical roles for endogenous compounds in the instruction of host macrophage cell death patterns. Understanding the regulation of human immune responses is critical for vaccine development and the treatment of infectious diseases. These findings shed new light on the potential condition for a booster immunization in individuals already vaccinated with BCG for TB protection, and further studies are warranted.

A side-by-side comparison of T cell reactivity to fifty-nine Mycobacterium tuberculosis antigens in diverse populations from five continents.

We compared T cell recognition of 59 prevalently recognized Mycobacterium tuberculosis (MTB) antigens in individuals latently infected with MTB (LTBI), and uninfected individuals with previous BCG vaccination, from nine locations and populations with different HLA distribution, MTB exposure rates, and standards of TB care. This comparison revealed similar response magnitudes in diverse LTBI and BCG-vaccinated cohorts and significant correlation between responses in LTBIs from the USA and other locations. Many antigens were uniformly recognized, suggesting suitability for inclusion in vaccines targeting diverse populations. Several antigens were similarly immunodominant in LTBI and BCG cohorts, suggesting applicability for vaccines aimed at boosting BCG responses. The panel of MTB antigens will be valuable for characterizing MTB-specific CD4 T cell responses irrespective of ethnicity, infecting MTB strains and BCG vaccination status. Our results illustrate how a comparative analysis can provide insight into the relative immunogenicity of existing and novel vaccine candidates in LTBIs.

[Vaccination, quality control, and vaccine production in Brazil since 1960]. / Vacinação, controle de qualidade e produção de vacinas no Brazil a partir de 1960.

The article focuses on the Brazilian government's role in implementation of immunization policies and in the emergence of a government structure involving production and quality control of immunobiologics. It examines Brazil's National Immunization Program, creation of the National Institute for Quality Control in Health, and the Program for Self-Sufficiency in Immunobiologics. It also takes a general look at the political picture that influences participating actors and at changes in Brazil's demographic and epidemiological profile.

A whole blood assay as a simple, broad assessment of cytokines and chemokines to evaluate human immune responses to Mycobacterium tuberculosis antigens.

In vitro stimulation of whole blood or isolated peripheral blood cells with specific antigens is used for several purposes. We sought to identify a reliable, reproducible, fast and feasible in vitro method to assess human cellular immune responses to Mycobacterium tuberculosis. In contrast to peripheral blood mononuclear cell (PBMC) culture, a whole blood assay (WBA) provides a more physiological environment, which may provide a broader assessment of serum biomarker, biosignature profiles. Twenty-three asymptomatic individuals with M. tuberculosis infection were recruited. Total cells from the WBA (diluted 1:3 in completed RPMI) and PBMC (2×10(5)cells/ml) plus M. tuberculosis Ag85A, Ag85B, ESAT-6 and Mycobacterium bovis 65kDa were characterized by flow cytometry, then added in 96-well plates and on day 5 plasma and supernatants were harvested for detection of 17 cytokines by a Luminex array system. There was agreement between PBMC and WBA for IL-2, IL-5, IL-6, IL-7, IL-13, IFN-γ, TNF-α, MCP-1 and MIP-1ß. There was evidence toward higher IL-10 (p≤0.049) and G-CSF (p≤0.012) plasma production, and higher IL-1ß (p≤0.048), IL-4 (p≤0.044), IL-12p70 (p≤0.006), IL-17 (p≤0.002) and GM-CSF (p≤0.049) production for PBMC vs. WBA. Both methods provided virtually no reaction to the internal, negative control. Due to technical issues linked to data out of range, IL-8 data were not considered. These results suggest that, depending on the method employed, PBMC and/or WBA techniques provide fine conditions for the model proposed and thus whole blood cultures are well-suited low-cost proxy-measures during search for serum biomarkers.

Neglected and emerging fungal infections: review of hyalohyphomycosis by Paecilomyces lilacinus focusing in disease burden, in vitro antifungal susceptibility and management.

Paecilomyces lilacinus is an emerging pathogenic fungus that can cause different clinical manifestations ranging from cutaneous and sub-cutaneous infections to severe oculomycosis. This review discusses infections caused by P. lilacinus, as well as their symptoms and correlates of immune responses, morphological characteristics of the fungus, therapies, in vitro susceptibility tests, laboratory diagnosis and the experimental models available.