Adaptaciones de la dispensación hospitalaria a pacientes con hemofilia durante la pandemia COVID-19 en España y su influencia en la adherencia / Adaptations of hospital dispensing to haemophilia patients during the COVID-19 pandemic in Spain and its influence on adherence

Introducción: El estado de alarma decretado por la pandemia del virus SARS COV-2 del 14 de marzo hasta el 21 de junio, ha supuesto un desafío para el área de pacientes externos de los Servicios de Farmacia. Nos centramos en los pacientes con hemofilia que se administran factores de la coagulación de forma crónica para prevenir hemorragias.Objetivos: Analizar durante este periodo el porcentaje de pacientes que han recogido su medicación, han mantenido la adherencia al tratamiento y las barreras encontradas para ello. Cuantificar el número y gravedad de episodios hemorrágicos (EH) sufridos y su relación con la pandemia. Analizar la prevalencia y gravedad de COVID en hemofílicos.Métodos: Uno objetivo, utilizando los registros del hospital y otro subjetivo, mediante encuesta oral durante la consulta de atención farmacéutica presencial o telemática.Resultados: El 80% de los pacientes retiraron medicación durante el periodo de estudio, un 30% en domicilio. El último mes las dispensaciones a domicilio se acompañaron de consulta telemática.Un 24% de pacientes disminuyó su adherencia respecto al 2019. Las principales causas fueron dificultad para acudir al hospital, y percepción de no necesitar tratamiento ante la inactividad.No se registraron más EH o ingresos por causas imputables a la pandemia.No hubo ningún enfermo COVID-19 grave y la incidencia de pacientes con síntomas leves fue similar a la población general.Conclusión: La mayoría de los pacientes con hemofilia pudieron acceder a su medicación. La adherencia se redujo. Los EH no aumentaron por causas atribuibles a la pandemia. La incidencia de COVID-19 fue similar a la población. (AU)

Introduction: The state of alarm decreed by the SARS COV-2 virus pandemic from March 14th to June 21st, has meant a challenge for the outpatient area of the pharmacy services. We focus on hemophilia patients who are chronically administered clotting factors to prevent bleeding.Objectives: To analyse during this period the percentage of patients who have collected their medication, maintained adherence to treatment and the barriers encountered in doing so. To quantify the number and severity of haemorrhagic episodes (HD) suffered and their relationship with the pandemic. Analyse the prevalence and severity of COVID in haemophiliacs.Methods: One objective, using hospital records, and one subjective, using an oral survey during the face-to-face or telematic pharmaceutical care consultation.Results: 80% of patients withdrew medication during the study period, 30% at home. In the last month, home deliveries were accompanied by telematic consultation.24% of patients decreased their adherence with respect to 2019. The main causes were difficulty in going to hospital, and perception of not needing treatment in the face of inactivity.There were no more HD or admissions for reasons attributable to the pandemic.There were no serious COVID-19 patients and the incidence of patients with mild symptoms was similar to the general population.Conclusion: Most haemophilia patients were able to access their medication. Adherence was reduced. HD did not increase due to causes attributable to the pandemic. The incidence of COVID-19 was similar to the population. (AU)

Utilidad de mediciones objetivas para la programación en implantes cocleares / Use of objective measures for cochlear implant programming

RESUMEN Introducción: La programación adecuada de los implantes cocleares permiten lograr niveles de estimulación auditivos óptimos. Se realiza de forma individualizada, siendo la detección del umbral de confort ideal un desafío. Se ha descrito la utilidad de los potenciales auditivos del tronco encefálico eléctrico (ePEATC) y el reflejo eléctrico estapedial (eREE) para este propósito. Objetivo: Determinar la posibilidad de realizar ePEATC y eREE en pacientes adultos y pediátricos con implantes cocleares, y evaluar cambios en la programación de los implantes cocleares luego de las mediciones objetivas. Material y método: Se realizó un estudio prospectivo, descriptivo, de pacientes con implante coclear marca MED-EL®, separando los pacientes en dos grupos: el grupo adulto (n =5) y el grupo pediátrico (n =5). Todos los pacientes incluidos presentaron más de 6 meses de encendido del implante. Se evaluaron variables epidemiológicas y tiempo de encendido del implante. Se realizó una otoscopía, prueba básica de funcionamiento del implante, y las mediciones objetivas eléctricas (ePEATC, eREE). Con estos resultados se ajustó el umbral de confort. Resultados: El tiempo promedio de encendido del implante en el grupo adulto fue de 27 meses, y 30 meses en el grupo pediátrico. El ePEATC requiere más tiempo y cooperación al compararlo con eREE. Luego de estas evaluaciones objetivas, fue necesario el ajuste del umbral de confort en tres pacientes adultos, y en dos pacientes pediátricos. Fue necesario realizar una audiometría de campo libre para estimar el umbral de confort en dos pacientes pediátricos que no presentaron respuesta en eREE. Conclusión: Fue posible realizar estas mediciones objetivas en pacientes adultos y pediátricos, siendo mejor tolerado y requiriendo menos tiempo, el eREE.

ABSTRACT Introduction: Mapping a cochlear implant allows for adjusting ideal electrical stimulation limits. It is an individualized process and detecting the most comfortable loudness level can be challenging. The use of electrically evoked auditory brainstem response (ePEATC) and electrically evoked stapedius reflex thresholds (eREE) have been considered for this purpose. Aim: To determine the feasibility of performing ePEATC and eREE on adult and pediatric patients with a cochlear implant, and to evaluate changes in programming following these objective measures. Material and method: A prospective, descriptive study was completed, of patients with MED-EL® cochlear implants, separating patients into two groups: adults (n=5) and children (n=5). All of the patients included had their implants activated for 6 months or longer. Epidemiological variables and duration of implant activation were evaluated. Otoscopy, a basic implant functioning evaluation, and objective measures (ePEATC, eREE) were performed. With these results, comfortable loudness levels were adjusted. Results: Average duration of implant activation was 27 months and 30 months, for adults and children respectively. Performing ePEATC required more time and cooperation as compared to eREE. Following the objective measures, adjustment of the comfortable loudness levels was required for three adult and two pediatric patients. Sound field audiometry was necessary for two pediatric patients in order to estimate the comfortable loudness levels because the eREE responses were absent. Conclusions: It is feasible to perform these objective measures for both adult and pediatric patients, with eREE requiring less time and being better tolerated by patients.

Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential.

Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitochondria, inhibits mitochondrial respiration, and triggers a severe energy deficit and extensive glioblastoma cell death. However, fenofibrate does not cross the blood brain barrier and is quickly processed by blood and tissue esterases to form the PPARα agonist fenofibric acid, which is practically ineffective effective in triggering cancer cell death. To address these issues, we have made several chemical modifications in fenofibrate structure to increase its stability, water solubility, tissue penetration, and ultimately anticancer potential. Our data show that, in comparison to fenofibrate, four new compounds designated here as PP1, PP2, PP3, and PP4 have improved anticancer activity in vitro. Like fenofibrate, the compounds block mitochondrial respiration and trigger massive glioblastoma cell death in vitro. In addition, one of the lead compounds, PP1, has improved water solubility and is significantly more stable when exposed to human blood in comparison to fenofibrate. Importantly, mice bearing large intracranial glioblastoma tumors demonstrated extensive areas of tumor cell death within the tumor mass following oral administration of PP1, and the treated mice did not show any major signs of distress, and accumulated PP1 at therapeutically relevant concentrations in several tissues, including brain and intracranial tumors.

Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target.

BACKGROUND: Increasing evidence has shown the close link between energy metabolism and the differentiation, function, and longevity of immune cells. Chronic inflammatory conditions such as parasitic infections and cancer trigger a metabolic reprogramming from the preferential use of glucose to the up-regulation of fatty acid oxidation (FAO) in myeloid cells, including macrophages and granulocytic and monocytic myeloid-derived suppressor cells. Asthma is a chronic inflammatory condition where macrophages, eosinophils, and polymorphonuclear cells play an important role in its pathophysiology. OBJECTIVE: We tested whether FAO might play a role in the development of asthma-like traits and whether the inhibition of this metabolic pathway could represent a novel therapeutic approach. METHODS: OVA- and house dust mite (HDM)-induced murine asthma models were used in this study. RESULTS: Key FAO enzymes were significantly increased in the bronchial epithelium and inflammatory immune cells infiltrating the respiratory epithelium of mice exposed to OVA or HDM. Pharmacologic inhibition of FAO significantly decreased allergen-induced airway hyperresponsiveness, decreased the number of inflammatory cells, and reduced the production of cytokines and chemokines associated with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: These novel observations suggest that allergic airway inflammation increases FAO in inflammatory cells to support the production of cytokines, chemokines, and other factors important in the development of asthma. Inhibition of FAO by re-purposing existing drugs approved for the treatment of heart disease may provide a novel therapeutic approach for the treatment of asthma.

Study of the degradation performance (TOC, BOD, and toxicity) of bisphenol A by the photo-Fenton process.

Degradation of bisphenol A (BPA, 0.5 L, 30 mg L-1) was studied by photo-Fenton treatment, while Fenton reagents were variables. The efficiency of the degradation process was evaluated by the reduction of total organic carbon (TOC), the biochemical oxygen demand (BOD), and toxicity. For toxicity analysis, bacterial methods were found infeasible, but the in vitro assay of VERO cells culture was successfully applied. Experiments according to a 22 design of experiments (DOE) with star points and three center points for statistical validity allowed selecting those process conditions (Fe(II) and H2O2 load) that maximized the process performance. Photo-Fenton process effectively eliminated BPA and partly degraded its by-products (residual TOC <15 %) under substoichiometric H2O2 dose (100.62 mg L-1) and at least 4 mg L-1 Fe(II), after a 90-min treatment. All treated samples were at least partially biodegradable. The cytotoxic concentration (LD50) of BPA for VERO cells was 7 mg L-1. With small H2O2 amount (15.24 mg L-1), only low BPA mineralization (TOC = 92 %) was attained. Toxicity was also detected to 50 % of cellular mortality even at long reaction times. However, 40.25 mg L-1 of H2O2 decreased residual TOC to 70 % while cell mortality decreased down to 25 %. With more H2O2, the residual TOC decreased down to 15 % but cell mortality remained within the 20-25 % level. Photo-Fenton increased the biodegradability and reduced the toxicity of the studied sample.

A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma.

Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-κB, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-κB activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-κB activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.

Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines ßlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.

Biocompatibility and drug release behavior of scaffolds prepared by coaxial electrospinning of poly(butylene succinate) and polyethylene glycol.

Scaffolds constituted by electrospun microfibers of poly(ethylene glycol) (PEG) and poly(butylene succinate) (PBS) were studied. Specifically, coaxial microfibers having different core-shell distributions and compositions were considered as well as uniaxial micro/nanofibers prepared from mixtures of both polymers. Processing conditions were optimized for all geometries and compositions and resulting morphologies (i.e. diameter and surface texture) characterized by scanning electron microscopy. Chemical composition, molecular interactions and thermal properties were evaluated by FTIR, NMR, XPS and differential scanning calorimetry. The PEG component of electrospun fibers could be solubilized by immersion of scaffolds in aqueous medium, giving rise to high porosity and hydrophobic samples. Nevertheless, a small amount of PEG was retained in the PBS matrix, suggesting some degree of mixing. Solubilization was slightly dependent on fiber structure; specifically, the distribution of PEG in the core or shell of coaxial fibers led to higher or lower retention levels, respectively. Scaffolds could be effectively loaded with hydrophobic drugs having antibacterial and anticarcinogenic activities like triclosan and curcumin, respectively. Their release was highly dependent on their chemical structure and medium composition. Thus, low and high release rates were observed in phosphate buffer saline (SS) and SS/ethanol (30:70 v/v), respectively. Slight differences in the release of triclosan were found depending on fiber distribution and composition. Antibacterial activity and biocompatibility were evaluated for both loaded and unloaded scaffolds.

Anhydric maleic functionalization and polyethylene glycol grafting of lactide-co-trimethylene carbonate copolymers.

Lactide and trimethylene carbonate copolymers were successfully grafted with polyethylene glycol via previous functionalization with maleic anhydride and using N,N'-diisopropylcarbodiimide as condensing agent. Maleinization led to moderate polymer degradation. Specifically, the weight average molecular weight decreased from 36,200 to 30,200 g/mol for the copolymer having 20 mol% of trimethylene carbonate units. Copolymers were characterized by differential scanning calorimetry, thermogravimetry and X-ray diffraction. Morphology of spherulites and lamellar crystals was evaluated with optical and atomic force microscopies, respectively. The studied copolymers were able to crystallize despite the randomness caused by the trimethylene carbonate units and the lateral groups. Contact angle measurements indicated that PEG grafted copolymers were more hydrophilic than parent copolymers. This feature justified that enzymatic degradation in lipase medium and proliferation of both epithelial-like and fibroblast-like cells were enhanced. Grafted copolymers were appropriate to prepare regular drug loaded microspheres by the oil-in-water emulsion method. Triclosan release from loaded microspheres was evaluated in two media.

Restricted puckering of mineralized RNA-like riboses.

The pseudorotational motions of highly hydroxylated pentafuranose sugars in the free state and tethered to hydroxyapatite have been compared. The conformation pentafuranose ring remains restricted at the North region of the pseudorotational wheel, which is the one typically observed for nucleosides and nucleotides in the double helix A-RNA, when the phosphate-bearing sugar is anchored to the mineral surface. Results indicate that the severe restrictions imposed by the mineral are responsible of the double helix preservation when DNA and RNA are encapsulated in crystalline nanorods.

Analysis of quinolone-resistance in commensal and diarrheagenic Escherichia coli isolates from infants in Lima, Peru.

BACKGROUND: Antibiotic resistance is an increasing problem, particularly in countries where antibiotic use is frequently not controlled. The aim of this study was to analyse the prevalence of the molecular mechanisms of quinolone-resistance in E. coli isolated from faeces of healthy Peruvian children or those presenting diarrhoea. METHODS: The presence of target mutations, transferable quinolone-resistance mechanisms and the role of Phe-Arg-ß-Naphtylamyde inhibitible efflux pumps were studied in 96 Escherichia coli (46 diarrheogenic and 50 non-diarrheogenic) isolates exhibiting resistance or diminished susceptibility to quinolones. RESULTS: The most resistant phenotype, Nal(R) and Cip(R), was most frequently present in isolates of healthy children. The distribution of quinolone resistance mechanisms between diarrheogenic (DEC) and commensal (non DEC) isolates was equitable, although the aac(6')Ib-cr gene was mainly detected in DEC isolates: 17 (34%) vs non DEC isolates nine (20%). QnrB was present in five (10%) DEC vs three (6%) non DEC isolates. CONCLUSIONS: Point mutations in gyrA and parC genes play a relevant role in quinolone resistance acquisition and highlight the role of efflux pumps also. This study provides knowledge about the molecular mechanisms involved in quinolone resistance in isolates in a non exposed population under high community antibiotic pressure.

Temporal and geographic clustering of polyomavirus-associated olfactory tumors in 10 free-ranging raccoons (Procyon lotor).

Reports of primary nervous system tumors in wild raccoons are extremely rare. Olfactory tumors were diagnosed postmortem in 9 free-ranging raccoons from 4 contiguous counties in California and 1 raccoon from Oregon within a 26-month period between 2010 and 2012. We describe the geographic and temporal features of these 10 cases, including the laboratory diagnostic investigations and the neuropathologic, immunohistochemical, and ultrastructural characteristics of these tumors in the affected animals. All 9 raccoons from California were found within a localized geographic region of the San Francisco Bay Area (within a 44.13-km radius). The tight temporal and geographic clustering and consistent anatomic location in the olfactory system of tumor types not previously described in raccoons (malignant peripheral nerve sheath tumors and undifferentiated sarcomas) strongly suggest either a common cause or a precipitating factor leading to induction or potentiation of neuro-oncogenesis and so prompted an extensive diagnostic investigation to explore possible oncogenic infectious and/or toxic causes. By a consensus polymerase chain reaction strategy, a novel, recently reported polyomavirus called raccoon polyomavirus was identified in all 10 tumors but not in the normal brain tissue from the affected animals, suggesting that the virus might play a role in neuro-oncogenesis. In addition, expression of the viral protein T antigen was detected in all tumors containing the viral sequences. We discuss the potential role of raccoon polyomavirus as an oncogenic virus.

Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia.

New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic-translation-initiation factor 2 alpha (eIF2α). Inhibition of eIF2α phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2α form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2α by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2α signaling further increased the anti-leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2α in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target.

IGF-IR-dependent expression of Survivin is required for T-antigen-mediated protection from apoptosis and proliferation of neural progenitors.

The insulin-like growth factor-1 receptor (IGF-IR) and the human polyomavirus JCV protein, T-antigen cooperate in the transformation of neuronal precursors in the cerebellum, which may be a contributing factor in the development of brain tumors. Because it is not clear why T-antigen requires IGF-IR for transformation, we investigated this process in neural progenitors from IGF-IR knockout embryos (ko-IGF-IR) and from their wild-type nontransgenic littermates (wt-IGF-IR). In contrast to wt-IGF-IR, the brain and dorsal root ganglia of ko-IGF-IR embryos showed low levels of the antiapoptotic protein Survivin, accompanied by elevated numbers of apoptotic neurons and an earlier differentiation phenotype. In wt-IGF-IR neural progenitors in vitro, induction of T-antigen expression tripled the expression of Survivin and accelerated cell proliferation. In ko-IGF-IR progenitors induction of T-antigen failed to increase Survivin, resulting in massive apoptosis. Importantly, ectopic expression of Survivin protected ko-IGF-IR progenitor cells from apoptosis and siRNA inhibition of Survivin activated apoptosis in wt-IGF-IR progenitors expressing T-antigen. Our results indicate that reactivation of the antiapoptotic Survivin may be a critical step in JCV T-antigen-induced transformation, which in neural progenitors requires IGF-IR.

Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment.

OBJECTIVE: Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. METHODS: OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. RESULTS: CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. CONCLUSION: CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.