Aplicaciones terapéuticas del eculizumab / Therapeutic applications of eculizumab

Introducción: El eculizumab es un anticuerpo monoclonal de tipo IgG diseñado para el tratamiento de la hemoglobinuria paroxística nocturna (HPN), en el que su diana farmacológica forma parte del sistema del complemento. Su mecanismo de acción ha permitido implementarlo en el tratamiento de enfermedades huérfanas, como el síndrome urémico hemolítico atípico (SUHa), trastorno del espectro de la neuromielitis óptica (TENMO) y miastenia gravis, cuya incidencia, es baja. Asimismo, es viable en el tratamiento de Guillain Barré y el síndrome antifosfolípido catastrófico (CAPS). Objetivo: Evidenciar aplicaciones terapéuticas del eculizumab y beneficios más significativos en algunos padecimientos. Materiales y métodos: Se realizó búsqueda bibliográfica en el periodo 2010-2021, en bases de datos: Google Scholar, Science Direct, PubMed y Scielo, utilizando como palabra clave "eculizumab". Posteriormente, se afinó la búsqueda utilizando palabras claves asociadas a enfermedades tratadas con este medicamento. Resultados: Se identificó el mecanismo de acción del fármaco y su efecto sobre la patogénesis de hemoglobinuria paroxística nocturna, síndrome urémico atípico, miastenia gravis generalizada refractaria, trastorno del espectro de la neuromielitis óptica, síndromes antifosfolípidos catastrófico y Guillain-Barré. Conclusiones: El eculizumab tiene una alta seguridad y capacidad para tratar y disminuir síntomas de diversas enfermedades que involucran el sistema del complemento.

Introduction: Eculizumab is an IgG type monoclonal antibody designed to treat paroxysmal nocturnal hemoglobinuria (PNH) and its pharmacological target is a member of the complement system. Its mechanism of action has permitted its use in the treatment of orphan diseases such as atypical hemolytic uremic syndrome (aHUS), neuromyelitis optic spectrum disorder (NMOSD), and myasthenia gravis, all of which have a low incidence. Likewise, eculizumab is a viable treatment for Guillain Barré and catastrophic antiphospholipid syndrome (CAS). Objective: To describe the therapeutic applications of eculizumab and its most significant benefits in some illnesses. Materials and methods: A bibliographic search was carried out during the 2010-2021 period in Google Scholar, Science Direct, PubMed and Scielo databases using the keyword eculizumab. Then, the search was refined by using keywords associated with diseases treated with this medication. Results: The mechanism of action of the antibody and its effect on the pathogenesis of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis, neuromyelitis optic spectrum disorder, catastrophic antiphospholipid syndrome, and Guillain Barré were identified. Conclusions: Eculizumab has high safety and capacity in treating and diminishing symptoms of diverse illnesses, which involve the complement system.

CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma.

Biomarkers which can identify Diffuse Large B-Cell Lymphoma (DLBCL) likely to be refractory to first-line therapy are essential for selecting this population prior to therapy initiation to offer alternate therapeutic options that can improve prognosis. We tested the ability of a CT-based radiomics approach with machine learning to predict Primary Treatment Failure (PTF)-DLBCL from initial imaging evaluation. Twenty-six refractory patients were matched to 26 non-refractory patients, yielding 180 lymph nodes for analysis. Manual 3D delineation of the total node volume was performed by two independent readers to test the reproducibility. Then, 1218 hand-crafted radiomic features were extracted. The Random Forests machine learning approach was used as a classifier for constructing the prediction models. Seventy percent of the nodes were randomly assigned to a training set and the remaining 30% were assigned to an independent test set. The final model was tested on the dataset from the 2 readers, showing a mean accuracy, sensitivity and specificity of 73%, 62% and 82%, respectively, for distinguishing between refractory and non-refractory patients. The area under the receiver operating characteristic curve (AUC) was 0.83 and 0.79 for the two readers. We conclude that machine learning CT-based radiomics analysis is able to identify a priori PTF-DLBCL with a good accuracy.

Assessment of the impact of inpatient infectious events in pediatric patients with newly diagnosed acute leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican Republic.

Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital > 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures.

Evaluación de condiciones de extracción asistida por ultrasonido de compuestos bioactivos de cáscara de pitahaya amarilla / Evaluation of conditions of ultrasound assisted extraction of yellow pitahaya peel bioactive compounds / Avaliação das condições da extração com ultrassom dos compostos bioactivos da casca da pitaia amarela

Resumen Introducción: la extracción de los polifenoles ha tomado un interés debido a la relación que tiene con la prevención del estrés oxidativo y efectos benéficos sobre la salud en la prevención de enfermedades no transmisibles; estos están comúnmente en algunas frutas por lo que su extracción se ha convertido en una tendencia para obtener productos de alto valor agregado. El ultrasonido es una técnica que puede disminuir el tiempo de extracción de estos biocomponentes. Objetivo: evaluar las condiciones de la extracción asistida por ultrasonido de polifenoles con actividad antioxidantes en cáscara de pitahaya amarilla deshidratada. Materiales y métodos: Se deshidrataron las cáscaras y construyó cinéticas de secado a 60°C, con el fin de disminuir las reacciones de deterioro. Para la extracción, una solución de etanol al 96% (V/V) fue usada como disolvente, en una relación cáscara-disolvente 1:1. El proceso fue realizado a 25 °C en un sistema de ultrasonido indirecto con una frecuencia de 37 kHz. Se usó un diseño central compuesto, fueron evaluados el efecto de la potencia (40 - 80%) y tiempo de sonicación (11,90 - 33,10 minutos). Se hizo extracción con el método soxhlet (control). Los polifenoles totales y capacidad antioxidantes fue determinado por lo métodos Folin-Ciocalteau y ABTS respectivamente. Resultados: Bajos tiempos y altas potencias de sonicación fueron asociados con incremento en la extracción de polifenoles y capacidad antioxidante. En particular, la extracción asistida con ultrasonido con 60% de potencia y 11 minutos, se obtuvo un 77% más de polifenoles que 24 horas de proceso con método Soxhlet. Conclusión: El ultrasonido tiene potencial en comparación con la técnica tradicional para reducir el tiempo de procesamiento en extracción de biocomponentes, en este caso aprovechar la cáscara de pitahaya amarilla que es considerada como un residuo, se encontraron concentraciones de polifenoles de 973,10 mg/L que pueden ser extraídos por ultrasonido a 222 W de potencia nominal (60%), 35kHz de frecuencia y 22 minutos y con una capacidad antioxidante superior al 90%.

Abstract Introduction: the extraction of polyphenols has taken an interest due to the relationship it has with the prevention of oxidative stress and beneficial effects on health in the prevention of non-communicable diseases. These are commonly found in some fruits, so their extraction has become a trend to obtain products with high added value. Ultrasound is a technique that can decrease the extraction time of these biocomponents. Objective: the main objective of this work was to evaluate the conditions of the ultrasound-assisted extraction of polyphenols with antioxidant activity in dehydrated peel yellow pitahaya. Materials and methods: the kinectis drying was made at 60 °C, in order to decrease deterioration reactions. For the extraction, a solution of 96% ethanol (V / V) was used as disolvent; the ratio Peel-Disolvent was 1:1. The process was performed at 25 °C and 37 kHz frequency. A central composite design was used, in which the effect of power (40 - 80%) and ultrasonication time (11.90 -33.10 minutes) were evaluated. One control point was evaluated with Soxhlet extraction. The extracted amount of polyphenols and antioxidant capacity was determined by Folin-Ciocalteau and ABTS methods, respectively. Results: lower time exposures and higher sonication power were associated with increases in polyphenols and antioxidant capacity. In particular, ultrasound-assisted extraction in 60% power and 11 min, obtained 77% more polyphenols than 24-h standard method (Soxhlet). Conclusion: Ultrasound has potential compared to the traditional technique to reduce the processing time in biocomponent extraction, in this case taking advantage of the yellow pitahaya peel that is considered as a residue, polyphenol concentrations of 973.10 mg / L were found that They can be extracted by ultrasound at 222 W nominal power (60%), 35kHz frequency and 22 minutes and with an antioxidant capacity of over 90%.

Resumo Introdução: Muita atenção tem o efeito benéfico dos polifenóis e antioxidantes na obesidade relacionada ao estresse oxidativo. O ultra-som é uma técnica que pode diminuir o tempo de extração desses biocompostos. A extração de polifenóis interessou-se pela relação que tem com a prevenção do estresse oxidativo e efeitos benéficos à saúde na prevenção de doenças não transmissíveis; como são comumente encontradas em algumas frutas, sua extração tornou-se uma tendência para obter produtos com alto valor agregado. O ultrassom é uma técnica que pode diminuir o tempo de extração desses biocomponentes. Objetivo: foi avaliar as condições da extração assistida por ultrassom de polifenóis com atividade antioxidante em pitaia amarela desidratada. Materiais e métodos: as cascas foram desidratadas e construídas cinéticas de secagem a 60 °C, a fim de diminuir as reações de deterioração. Para extração, utilizou-se uma solução de etanol 96% (V/V) como dissolvente, numa proporção escudo-dissolvente 1:1. O processo foi feito a 25°C e uma frequência de 37 kHz. Foi utilizado μM projeto central composto, avaliando-se o efeito da potência (40-80%) e do tempo de sonificação (11,9-33,1 minutos). A extração foi feita com o método soxhlet (controle). A quantidade de polifenóis e capacidade antioxidantes extraídos foi determinada pelos métodos Folin-Ciocalteau e ABTS, respectivamente. Resultados: os tempos baixos e as altas potências de sonicação foram associados com aumento da extração de polifenóis e antioxidantes. Em particular, a extração assistida com ultra-som ao 60% de potência e 11 minutos, 77% a mais de polifenóis foram obtidos a 24 horas do método soxhlet. Conclusão: Ultra-som tem o potencial comparado à técnica tradicional de reduzir o tempo de processamento na extração de biocomponentes, neste caso, aproveitando a casca de pitaiaiás amarela que é considerada μM resíduo, foram encontradas concentrações de polifenóis de 973,10 mg / L que. Eles podem ser extraídos por ultrassom a 222 W de potência nominal (60%), frequência de 35kHz e 22 minutos e com uma capacidade antioxidante acima de 90%..

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

CAPACIDAD ANTIOXIDANTE Y ANTIMICROBIANA DE TUBÉRCULOS ANDINOS (Tropaeolum tuberosum y Ullucus tuberosus) / ANTIMICROBIAL AND ANTIOXIDANT CAPACITY OF ANDEAN TUBERS (Tropaeolum tuberosum y Ullucus tuberosus)

RESUMEN Los tubérculos andinos formaron parte de la dieta de poblaciones originarias y son considerados como alimentos de alta calidad nutricional; sin embargo, en la actualidad, su uso ha disminuido. En este estudio, se plantea, como objetivo, evaluar características funcionales (capacidad antioxidante y antimicrobiana) de dos tubérculos consumidos tradicionalmente en Colombia, cubio (Tropaeolum tuberosum) y ulluco (Ullucus tuberosus). Para esto, se recolectaron tallos, hojas y tubérculo de cubio y de ulluco, se secaron a 38°C, por 90 horas y se realizaron extractos con etanol al 50% v/v. En los extractos obtenidos, se midió la capacidad antioxidante, por las técnicas DPPH y ABTS y el efecto inhibitorio en Escherichia coli, Lactobacillus fermentum y Cándida utilis, mediante la técnica de discos. Se encontró alto porcentaje de capacidad antioxidante en todas las partes de la planta en ambos tubérculos; las que presentaron mayor actividad son hojas y tallos. En la capacidad antimicrobiana, el cubio tuvo un efecto bacteriostático sobre C. utilis, mientras que el ulluco tuvo un efecto sobre E. coli. Debido a lo anterior, estos dos tubérculos poseen potencial para la extracción de compuestos antioxidantes y antimicrobianos permitiendo, de esta manera, establecer alternativas de uso para los tubérculos y subproductos (hojas y tallos).

ABSTRACT Andean tubers formed part of the diet of native populations and are considered as foods of high nutritional quality, however today its use has waned. This study proposes to evaluate functional characteristics (antioxidant and antimicrobial capacity) of two tubers traditionally consumed in Colombia, cubio (Tropaeolum tuberosum) and ulluco (Ullucus tuberosus). For this were collected stems, leaves and tuber of cubio and ulluco, were dried up to 38°C for 90 hours, and extracts were made with ethanol 50% v/v. In the extracts was measured the antioxidant capacity by DPPH and ABTS techniques and the inhibitory effect on Escherichia coli, Lactobacillus fermentum, and Candida utilis, using the technique of discs. Found higher antioxidant capacity in all parts of the plant in both tubers, however, which showed greater activity are leaves and stems. The antimicrobial capacity, the cubio had a bacteriostatic effect on C. utilis, while the ulluco had an effect on E. coli. Due to the above, these two tubers have potential for the extraction of antioxidant compounds, antibiotics, thus allowing establish alternatives of use for tubers and by products (leaves and stems).

Steroidal C-21 heteroaryl thioethers (Part 2): discovery of orally bioavailable selective glucocorticoid receptor modulators (dissociated steroids).

The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.

Estenosis del canal auditivo interno (CAI): hallazgos por imagen / Internal auditory canal (IAC) stenosis: imaging findings

Objetivos: Describir los hallazgos por imagen en tomografía computarizada (TAC ) y resonancia magnética (RM) en una paciente con estenosis del CAI. Describir el desarrollo embriológico de las estructuras del CAI y la historia natural de la estenosis del CAI . Métodos: Se presenta el caso de una paciente de 4 años de edad con diagnóstico de cardiopatía congénita, hipoacusia neurosensorial (HNS ) y otitis media recurrente bilateral, y a quien se realizó TAC del hueso temporal con imágenes axiales y reconstrucciones coronales, en las cuales se observa disminución del diámetro de la luz del CAI izquierdo (menor de 2 mm), ausencia del CAI derecho y estructuras del oído interno de características normales, compatibles con estenosis del CAI izquierdo. Las imágenes de RM demuestran la estenosis del CAI izquierdo, sin observarse las estructuras nerviosas dentro de éste, compatible con hipoplasia/aplasia del nervio vestibulococlear. Resultados: Se describen brevemente la patología, el origen embriológico y la importancia de la asociación de la estenosis delCAI a hipoplasia/aplasia del nervio vestibulococlear en el diagnóstico diferencial de las causas de HNS , que contraindican la realización de implante coclear. Conclusiones: La estenosis del CAI e hipoplasia/aplasia del nervio vestibulococlear es un diagnóstico para tener en cuenta dentro de las causas de HNS , y su diagnóstico puede realizarse a través de TAC y de RM.

Objectives: To describe the computed tomography (CT) and magnetic resonance (MR) findings in a patient with a diagnosis of internal auditory canal (IAC) stenosis. To describe the embryological development of the IAC structures and the natural history of IAC stenosis. Methods: A 4 year old girl presents with sensorineural hearing loss and bilateral recurrent otitis media. The temporal bone CT shows diminished left IAC diameter (less than 2 mm),right IAC absence and normal inner ear structures. These findings are pathognomonic for left IAC stenosis. The MR findings include left IAC stenosis and IAC neural structures absence secondary to aplasia of the vestibulocochlear nerve on each IAC . Results: Hypoplasia/aplasia of the vestibulocochlear nerve in association with IAC stenosis is an important consideration in the differential diagnosis of sensorineural hearing loss, as it is a relative contraindication for cochlear implant placement. Conclusions: IAC stenosis and vestibulocochlear nerve hypoplasia/aplasia must be excluded as an etiology of sensorineural hearing loss. The diagnosis can be made by CT and MR.

Concomitant activity of histamine and cysteinyl leukotrienes on porcine nasal mucosal vessels and nasal inflammation in the rat.

BACKGROUND: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. METHODS: For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. RESULTS: Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). CONCLUSION: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.