Autoantibodies neutralizing GM-CSF in HIV-negative Colombian patients infected with Cryptococcus gattii and C. neoformans.

Background: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Autoantibodies (auto-Abs) neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera from Colombian patients with non-HIV related cryptococcosis in a retrospective national cohort collected from 1997 to 2016. Methods: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs in 30 HIV (-) adults presenting cryptococcosis (13 by C. gattii, and 17 by C. neoformans). Results: We detected auto-Abs neutralizing GM-CSF in the plasma of 9 out of 13 (69%) patients infected with C. gattii and 1 out of 17 (6%) patients with C. neoformans. Conclusions: We report ten Colombian patients with cryptococcosis due to auto-Abs neutralizing GM-CSF. Nine of the ten patients were infected with C. gattii, and only one with C. neoformans.

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Anti-GM-CSF Neutralizing Autoantibodies in Colombian Patients with Disseminated Cryptococcosis.

BACKGROUND: Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. METHODS: We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. RESULTS: Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. CONCLUSIONS: We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.

Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria.

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rß1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.

Design and Tuning of Nanofluids Applied to Chemical Enhanced Oil Recovery Based on the Surfactant-Nanoparticle-Brine Interaction: From Laboratory Experiments to Oil Field Application.

The primary objective of this study is to develop a novel experimental nanofluid based on surfactant-nanoparticle-brine tuning, subsequently evaluate its performance in the laboratory under reservoir conditions, then upscale the design for a field trial of the nanotechnology-enhanced surfactant injection process. Two different mixtures of commercial anionic surfactants (SA and SB) were characterized by their critical micelle concentration (CMC), density, and Fourier transform infrared (FTIR) spectra. Two types of commercial nanoparticles (CNA and CNB) were utilized, and they were characterized by SBET, FTIR spectra, hydrodynamic mean sizes (dp50), isoelectric points (pHIEP), and functional groups. The evaluation of both surfactant-nanoparticle systems demonstrated that the best performance was obtained with a total dissolved solid (TDS) of 0.75% with the SA surfactant and the CNA nanoparticles. A nanofluid formulation with 100 mg·L-1 of CNA provided suitable interfacial tension (IFT) values between 0.18 and 0.15 mN·m-1 for a surfactant dosage range of 750-1000 mg·L-1. Results obtained from adsorption tests indicated that the surfactant adsorption on the rock would be reduced by at least 40% under static and dynamic conditions due to nanoparticle addition. Moreover, during core flooding tests, it was observed that the recovery factor was increased by 22% for the nanofluid usage in contrast with a 17% increase with only the use of the surfactant. These results are related to the estimated capillary number of 3 × 10-5, 3 × 10-4, and 5 × 10-4 for the brine, the surfactant, and the nanofluid, respectively, as well as to the reduction in the surfactant adsorption on the rock which enhances the efficiency of the process. The field trial application was performed with the same nanofluid formulation in the two different injection patterns of a Colombian oil field and represented the first application worldwide of nanoparticles/nanofluids in enhanced oil recovery (EOR) processes. The cumulative incremental oil production was nearly 30,035 Bbls for both injection patterns by May 19, 2020. The decline rate was estimated through an exponential model to be -0.104 month-1 before the intervention, to -0.016 month-1 after the nanofluid injection. The pilot was designed based on a production increment of 3.5%, which was successfully surpassed with this field test with an increment of 27.3%. This application is the first, worldwide, to demonstrate surfactant flooding assisted by nanotechnology in a chemical enhanced oil recovery (CEOR) process in a low interfacial tension region.

Early-Onset Invasive Infection Due to Corynespora cassiicola Associated with Compound Heterozygous CARD9 Mutations in a Colombian Patient.

PURPOSE: CARD9 deficiency is an inborn error of immunity that predisposes otherwise healthy humans to mucocutaneous and invasive fungal infections, mostly caused by Candida, but also by dermatophytes, Aspergillus, and other fungi. Phaeohyphomycosis are an emerging group of fungal infections caused by dematiaceous fungi (phaeohyphomycetes) and are being increasingly identified in patients with CARD9 deficiency. The Corynespora genus belongs to phaeohyphomycetes and only one adult patient with CARD9 deficiency has been reported to suffer from invasive disease caused by C. cassiicola. We identified a Colombian child with an early-onset, deep, and destructive mucocutaneous infection due to C. cassiicola and we searched for mutations in CARD9. METHODS: We reviewed the medical records and immunological findings in the patient. Microbiologic tests and biopsies were performed. Whole-exome sequencing (WES) was made and Sanger sequencing was used to confirm the CARD9 mutations in the patient and her family. Finally, CARD9 protein expression was evaluated in peripheral blood mononuclear cells (PBMC) by western blotting. RESULTS: The patient was affected by a large, indurated, foul-smelling, and verrucous ulcerated lesion on the left side of the face with extensive necrosis and crusting, due to a C. cassiicola infectious disease. WES led to the identification of compound heterozygous mutations in the patient consisting of the previously reported p.Q289* nonsense (c.865C > T, exon 6) mutation, and a novel deletion (c.23_29del; p.Asp8Alafs10*) leading to a frameshift and a premature stop codon in exon 2. CARD9 protein expression was absent in peripheral blood mononuclear cells from the patient. CONCLUSION: We describe here compound heterozygous loss-of-expression mutations in CARD9 leading to severe deep and destructive mucocutaneous phaeohyphomycosis due to C. cassiicola in a Colombian child.

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Efectos del uso del factor estimulante de colonias granulocíticas en la obtención de células madre en un grupo de pacientes con enfermedad arterial oclusiva crónica / Effects of the use of granulocyte colony stimulating factor for obtaining stem cells in a group of patients with chronic occlusive arterial disease

Es importante evaluar el perfil del uso del factor estimulante de colonias granulocíticas (fec-g) en pacientes con enfermedad arterial oclusiva crónica (eaoc), mediante el análisis de aspectos como eficacia y seguridad. Se examinaron los datos obtenidos de la cohorte de pacientes con eaoc que asistían regularmente a la clínica de Cirugía Vascular del Hospital Militar Central en Bogotá. El protocolo de movilización de células CD34+ hacia sangre periférica consistió en el uso de FEC-Grh a dosis de 600 mg/día por vía subcutánea (Filgrastim fec-g 300 mg Roche®), repartido en dos dosis diarias, en forma continua durante cinco días. Al realizar la comparación de valores a partir de hemogramas realizados antes y después de la movilización, se demostró incremento significativo en el número de leucocitos así como en la proporción de neutrófilos y basófilos; mientras que las proporciones de monocitos, eosinófilos y linfocitos disminuyeron significativamente. Con respecto al comportamiento de las células CD34+, no se muestra una diferencia significativa en el comportamiento del CD34+ con la edad, así como tampoco con el índice de masa corporal (imc). En lo relacionado con el peso y los niveles de CD34+, se observó que los pacientes que lograron una buena respuesta tenían un peso de 59,7 kg, mientras que los pacientes con regular respuesta, 68,1 kg.

The analyzed aspects such as efficacy and safety are important in the use of Granulocyte Colony Stimulating Factor in patients with chronic occlusive arterial disease were analyzed data from the cohort of patients with eaoc that regularly attended the Clinic for Vascular Surgery of the Hospital Militar Central in Bogotá. The protocol for CD34+ cell mobilization into peripheral blood involved the use of FEC-Grh at a dose of 600 mg/day administered subcutaneously (Filgrastim g-csf 300 mg Roche®) divided into two daily doses, continuously for five days. By comparing the values from blood counts performed before and after mobilization showed increased significant number of leukocytes as well as proportion of neutrophils and basophiles, whereas proportions of monocytes, eosinophils and lymphocytes decreased significantly. About the CD34+ cell behavior, it’s not shown significant difference between the behaviors of CD34+ with age, neither the imc. The analyzed done on the weight and CD34+ levels was observed that patients achieved a good response with a weight of 59.7 kg while 68.1 kg patients with regular response.

The consciousness circuit - an approach to the hard problem.

This paper is the continuation of a study about Consciousness as a resulting function between attention and luminosity, presented at the Neuroscience International Congress, which was held in the city of Natal, in Brazil, in 2006. There it was described how visual Consciousness is generated by the interaction of the cortical area activity through FFS (Feedforward Sweep Processes), RP (Recurrent Processes) and WSRP (Wide Spread Recurrent Processes), and its relationship with the luminosity that hits the eyes. We have applied the reciprocal interaction model, which says that the eye reacts to luminosity through the regulation of sleep-awake states through EEG wave synchronization; this, in turn, is regulated by the thalamic cortical neural activity from the brainstem monoaminergic and cholinergic nuclei.Such an understanding has led us to construct a consciousness model which can be represented by an orthogonal graph. Through this model, we can represent all states of human consciousness (emotional consciousness, unconsciousness states, dreaming states, awareness states, pre-consciousness states and others) making it possible, in theory, to construct a Consciousness parameter which yields to the understanding of consciousness state observation without a subjective approach to experience.We have also applied on this orthogonal graph the Quantum Orch OR Model. According to it, subjective, phenomenal conscious vision depends on quantum computation in microtubules where the quantum is the smallest quantity of radiant energy, in a scale in which matter and energy interact. This model helps us to build the vertical axe of the consciousness orthogonal graph, a cholinergic-aminergic scale, in which activation triggers the quantum mechanism relevant to the consciousness phenomenon.

Manejo endovascular en pacientes con síndrome de compresión iliocava: experiencia en 17 casos / Endovascular treatment in patients with iliocaval compression syndrome: experience in 17 cases

Objetivo: reportar la experiencia del manejo endovascular en pacientes con síndrome de compresión iliocava.Materiales y métodos: durante tres años se evaluaron 84 pacientes con sospecha de compresión iliocava, cuyo diagnóstico se confirmó mediante flebografía ascendente e Iliocavografía.Se trataron 17 pacientes por vía endovascular, terapia de anticoagulación y seguimiento radiológico seriado.Resultados: en un total de 17 pacientes con edad promedio de 43 años, se observó mejoría clínica completa en 88 porciento, parcial en 6 porciento y ninguna en 6 porciento. Permeabilidad del stent en 94,12 porciento a 36 meses.Conclusión: la terapia endovascular muestra excelente permeabilidad y baja morbilidad en el tratamiento de pacientes con síndrome de compresión iliocava.

Objective: to report our experience in the intravascular management in patients with iliocaval compression syndrome. Material and methods: 84 patients with suspicion of iliocaval compression were evaluated during a three years period. This diagnosis was confirmed by ascendant phlebography and iliocavography. 17 patients received endovascular treatment, anticoagulants and serial radiological follow-up. Results: from 17 patients with mean age of 43 years, 88% had a complete clinical recovery; it was partial in 6% and absent in 6%. Stent’s patency was 94.12% after 36 months. Conclusion: endovascular therapy shows excellent patency and low morbidity in the treatment of patients with iliocaval compression syndrome.

Prevalencia del síndrome metabólico entre los pacientes que asisten al servicio clínica de hipertensión de la Fundación Santa Fe de Bogotá / Metabolic syndrome prevalence in patients attending the hypertension clinic at the Fundación Santa Fe de Bogotá

Antecedentes: en los últimos cinco años han surgido diferentes definiciones para síndrome metabólico, lo cual ha llevado a confusiones. En octubre de 2005, la American Heart Association (AHA) propuso algunas recomendaciones y modificaciones para optimizar el uso de los criterios del National Cholesterol Education Program´s Adult Treatment Panel III Report (ATP III).Objetivo: determinar la prevalencia del síndrome metabólico como lo define el ATP III comparado con la definición de la AHA 2005, en los pacientes de la Clínica de Hipertensión de la Fundación Santa Fe de Bogotá.Materiales y métodos: estudio retrospectivo de corte transversal. Se revisaron 550 historias clínicas entre enero de 2004 y septiembre de 2005. Se describió la población a estudio y se estimó la prevalencia de síndrome metabólico según los criterios del ATP III y de la AHA.Resultados: de acuerdo con los criterios del ATP III, la prevalencia del síndrome fue del 27,3 porciento (hombres 19,29 porciento, mujeres 30,05 porciento), mientras que según los criterios de la AHA fue del 75,9 porciento (hombres 77,9 porciento y mujeres 75,25 porciento).Conclusiones: la población a estudio presenta una alta prevalencia de síndrome metabólico de acuerdo con los criterios del ATP III y de la AHA. Los criterios de la AHA identifican una proporción mayor de pacientes con esta patología, y es de mayor utilidad para diagnosticar personas en riesgo e implementar estrategias terapéuticas, cambios de estilo de vida y modificación de factores de riesgo de forma más temprana.

Physico-chemical treatment of Merida landfill leachate for chemical oxygen demand reduction by coagulation.

In order to determine the optimal dosage and type of coagulant for the physico-chemical treatment of leachate from the sanitary landfill of Merida, Mexico, a total of 864 jar tests were performed. Four metallic coagulants (ferric chloride, ferric sulphate, aluminium polychloride and aluminium sulphate) with doses ranging between 50 and 300 mg L(-1) and two polyelectrolytes (high-density anionic and cationic reagents) with doses from 2 to 12 mg L(-1) were tested. Neither an adequate type of coagulant nor an optimal dose could be found. The removal of contaminants was measured as total and dissolved chemical oxygen demand (COD). Soluble COD removal efficiencies were low, from 0 to 47%, with a 4% average value only. These low values of organic material removal were attributed to the particular characteristics of the Merida landfill leachate (low suspended solids concentration), so even with sweep-floc coagulation (300 mg L(-1) dose) only low COD removal efficiencies were obtained. A study of the suspended particle size distribution of the leachate was conducted in order to explain the poor performance. The particle size distribution ranged from 0.375 to 948.2 microm, with an average value of 22.97 microm. In a second step the optimal pH for physico-chemical treatment of these leachates was determined. Finally a greater than 90% removal of organic material, measured as suspended COD, was obtained at pH 2, which was considered as the optimal value.