Plitidepsin as an Immunomodulator against Respiratory Viral Infections.

Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-κB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-κB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-κB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.

Isolation and Total Synthesis of PM170453, a New Cyclic Depsipeptide Isolated from Lyngbya sp.

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound was determined by spectroscopic methods including MS, 1H, 13C and 2D-NMR. To solve the supply problem for 1 and progress pharmaceutical development, the total synthesis of 1 that involves a total of 20 chemical steps in a convergent process was carried out. Its in vitro cytotoxic activity against four human tumor cell lines, as well as the inhibition of the interaction between the programmed cell death protein 1 PD-1 and its ligand PD-L1 were also evaluated.

PM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.

Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida, family Theonellidae, genus Discodermia (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin ßIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.

Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Manual sobre atención al recién nacido en la comunidad: su pertinencia para el médico general / Manual on newborn care in the community: its relevance to the general practitioner

Fundamento: la atención al recién nacido constituye un reto para el médico general, el cual debe estar capacitado para la continuidad de su cuidado en la comunidad. Objetivo: elaborar un manual instructivo para perfeccionar la capacitación del médico general en su atención al recién nacido, una vez que este se incorpora a la comunidad. Métodos: se realizó una investigación de desarrollo en la Universidad de Ciencias Médicas de Villa Clara, durante septiembre 2015-enero 2016. Se utilizaron métodos teóricos: analítico-sintético e inductivo-deductivo; y empíricos: análisis documental, la encuesta como cuestionario y la entrevista a informantes clave. El producto fue valorado por criterio de especialistas. Resultados: se diagnosticaron necesidades de aprendizaje acerca de la atención al recién nacido, por falta de experiencia profesional y pocas horas planificadas en el programa de Pediatría para su tratamiento, por lo que se omiten aspectos importantes; la mayoría de los médicos generales consideraron tener carencias sobre el manejo del recién nacido, el cuidado que conlleva el de alto riesgo y reconocimiento de los signos de alerta sugestivos de enfermedades neonatales que pueden ser diagnosticados en la comunidad; no existe ningún material que facilite la consulta de estos temas, por lo que se elaboró un manual instructivo. Conclusiones: constituye un material de apoyo para elevar el desempeño profesional en la solución de los problemas de la atención al recién nacido en la práctica médica; su consulta propicia el mejoramiento del estado de salud de esta población infantil.

Background: newborn care is a challenge for the general practitioner, who must be trained for their follow up in the community. Objective: to elaborate an instructional manual to strengthen the training of the general practitioner in the newborn care, once it is incorporated into the community. Methods: a development research was carried out at Villa Clara University of Medical Sciences, from September 2015 to January 2016. Theoretical methods were used: analytic-synthetic and inductive-deductive; and empirical: documentary analysis, the survey in questionnaire form and the interview to key informants. The product was evaluated by specialists' criteria. Results: training needs were diagnosed regarding newborn care, due to lack of professional experience and few hours planned in the pediatric program for treatment, so important aspects are omitted; the majority of general practitioners consider that they have shortcomings in the management of the newborn, the high risk care and identification of alarming signs which suggest a neonatal disease that can be diagnosed in the community; there is no postgraduate modality to supply these insufficiencies, so an instructional manual on the subject was prepared. Conclusions: this material aid contributes to elevate the professional performance in the solution of the problem of newborn care in the medical practice; its study promotes the improvement of the health status of the newborn.

Cambios antropométricos durante el primer año de vida en niños nacidos con bajo peso y peso adecuado para la edad gestacional / Anthropometric changes during the first year of life in new-borns with low weight and adequate weight for gestational age

Se presentan los resultados del seguimiento realizado a una muestra de nacidos pretérminos mediante varias mediciones antropométricas, las cuales se compararon según las características del peso al nacer. A todos se les midió peso, longitud supina, circunferencia del tercio medio del brazo y el pliegue cutáneo tricipital a ese nivel, y a partir de estas mediciones se estimaron la circunferencia y el área muscular, así como áreas grasa y total branquial, en los 4 trimestres del primer año de vida. Al ser comparados los valores de los nacidos con peso adecuado y bajo peso para la edad gestacional, la mayoría de las variables directas presentaron diferencias estadísticamente significativas en todas las ocasiones, lo que no ocurrió con las variables indirectas de composición corporal. A pesar de comprobarse como secuelas básicas del bajo peso para la edad gestacional la baja talla y la disminución del peso, se observó una recuperación favorable a expensas fundamentalmente de la masa magra, lo cual nos impide valorar el déficit de tamaño como definitivo al final del primer año de vida. Se demuestra la mayor sensibilidad de las mediciones del tercio medio del brazo para evaluar el estado nutricional

Participación del hígado en el suministro de ácidos grasos esenciales poliinsaturados de cadena larga durante el desarrollo postnatal del cerebro de rata / The liver as a cource of essential long chain polyunsatureted fatty acids for postnatal brain development in the rat

El presente trabajo tuvo por objeto estudiar el origen de los ácidos grasos poliinsaturados de cadena larga (AGPI-CL) necesarios para el desarrollo postnatal del cerebro. Ratas normales recién nacidas de 1,5,10 y 20 días de edad fueron decapitadas, inmediatamente después los hígados fueron procesados para obtener la fracción microsomal y determinar la compossición de ácidos grasos y la actividad de la enzima delta6 desaturasa. También se nalizaron: la composición de ácidos grasos en plasma, homogenizado de hemisferios cerebrales y en la leche tomada del estómago de las ratas recién nacidas. Nosotros encontramos que la actividad de la enzima delta6 desaturada en el hígado fue muy baja en comparación a la observada en ratas adultas. Durante el desarrollo postnatal se observaron cantidades apreciables de DHA y AA en la lehe, microsomas hepáticos, lípidos de plasma y hemisferios cerebrales. En conclusión proponemos que durante el desarrollo postnatal, la síntesis hepática contribuye poco en el aporte de DHA y AA para el crecimiento del cerebro, pero tiene la capacidad de concentrar estos ácidos grasos provenientes de la leche, en los microsomas hepáticos y secretarlos hacia el plasma para finalmente llegar al cerebro.

Enfermedad meningocócica: estudio de los fallecidos desde 1979 a 1984 / Meningococcal disease: study of deaths occurred from 1979 to 1984

Se realiza un estudio del total de fallecidos por enfermedad meningocócica ocurridos en la Provincia de Villa Clara durante los años 1979 a 1984. La investigación se efectuó en el Hospital pediátrico Provincial de Santa Clara, analizándose la morbilidad y mortalidad por años y municipios. Se tuvieron en cuenta algunos aspectos como primer síntoma-ingreso, estadía, signos clínicos, exámenes complementarios y hallazgos necrópsicos. Las manifestaciones hemorrágicas, la fiebre y el shock constituyeron los elementos más frecuentes encontrados en los fallecidos, donde predominó la forma séptica. Se señala que a partir del año 1982 hubo una franca tendencia a la disminución de la letalidad de la enfermedad meningocócica, gracias al adiestramiento del personal médico y técnico en la atención del paciente grave y un mejor diagnóstico y tratamiento precoz en la atención primaria y los servicios de urgencia