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The dopaminergic system influences the heart rhythm by inhibiting the rat cardiac sympathetic and parasympathetic neurotransmissions through activation of D2-like receptors (encompassing the D2, D3, and D4 subtypes). Whereas D2 receptor subtype activation results in cardiac sympatho-inhibition, the dopamine receptor subtypes involved in rat cardiac vago-inhibition remain unknown. Hence, this study investigated the specific functional role of the D2-like receptor subtypes (D2, D3, and/or D4) inhibiting the rat heart cholinergic drive. For this purpose, male Wistar rats were pithed and prepared for cardiac vagal stimulation. Bradycardic responses were obtained by electrical stimulation of vagal fibres (3, 6, 9 Hz; n = 100) or i.v. acetylcholine (ACh; 1, 5, 10 μg/kg; n = 15). Expression of D2, D3, and D4 receptors was studied in left and right atrium samples by PCR (n = 4). Intravenous injections of quinpirole (D2-like agonist; 1-30 μg/kg), but not of SFK-38393 (D1-like agonist; 1-30 μg/kg), dose-dependently inhibited the vagally induced bradycardia. The vago-inhibition induced by quinpirole (which failed to affect the bradycardia to i.v. ACh) was unchanged after i.v. injections of the antagonists L-741,626 (D2; 100 μg/kg) or SB-277011-A (D3; 100 μg/kg), but it was abolished by L-745,870 (D4; 100 μg/kg). mRNA levels of D2, D3, and D4 receptor subtype were detected in the left and right rat atria. Our results suggest that the quinpirole-induced vagolytic effect involves prejunctional D4 receptor subtypes, located in the left and right atria. This provides new evidence on the relevance of D4 receptor modulating the heart parasympathetic control.

Objectives The goal of this study is to assess, by means of pharmacokinetic/pharmacodynamic (PK/PD) analysis using the Monte Carlo simulation, the adequacy of oral cephalosporins cefuroxime axetil, cefixime and cefditoren at different dosing regimens as switch therapy after intravenous cephalosporin treatment in uncomplicated acute pyelonephritis. Methods The methodology included: (i) dosing regimen selection and acquisition of pharmacokinetic data; (ii) microbiological data acquisition; and (iii) Monte Carlo simulation to estimate the PTA (probability of PK/PD target attainment) and CFR (cumulative fraction of response), as indicators of treatment success. Results At the current susceptibility breakpoints defined by EUCAST and CLSI for either cefuroxime axetil or cefixime, the probability of bactericidal target attainment is zero for the dosage regimens simulated. Considering the bactericidal target %fT>MIC > 70%, the likelihood of the cefuroxime 500-mg q8h regimen or the cefixime 200-mg q12h regimen producing this exposure or achieving this target is only above 90% for organisms yielding MICs ≤ 0.5 mg/l and MICs ≤ 0.25 mg/l, respectively. Cefditoren pivoxil 400 mg q12h provided probabilities of bactericidal target attainment of 80% or higher for MICs ≤ 0.03 mg/l, and ≤0.25 mg/l if considering total instead of free drug concentrations. Conclusions The results of the PK/PD target attainment analysis reveal that the likelihood of treatment success based upon the current breakpoints proposed by either EUCAST or CLSI is low. Of the three cephalosporins, cefixime 400 mg q12h prove to be the best option in oral APN treatment, although this regimen is currently off label.

Antecedentes: El virus SARS-CoV-2, causante de la Enfermedad por Coronavirus de 2019 (COVID-19) emergió en Wuhan, China, en diciembre de 2019, y tiene un alcance pandémico en la actualidad. Su fisiopatología, distribución geográfica y características clínicas son objetivo de estudio y análisis continuo, con resultados prometedores e influyentes, pero difíciles de reunir y sintetizar considerando las numerosas fuentes de información y el dinamismo de la curva epidemiológica de esta pandemia. Objetivo: Esta revisión tiene como objetivo sintetizar la literatura actual sobre la pandemia del COVID-19, con el propósito de establecer de forma transparente y concisa la información de origen nacional e internacional disponible, de manera que esta sirva como una fuente confiable de la evidencia publicada. Diseño: Se utilizaron artículos científicos publicados entre diciembre de 2019 y marzo de 2020, que fueron seleccionados por su relevancia, validez y calidad de contenido, obtenidos a través de revistas científicas como New England Journal of Medicine, Journal of the American Medical Association, The Lancet y el British Medical Journal, además de la información proporcionada por instituciones reconocidas a nivel mundial, como lo son la Organización Mundial de la Salud y el Centro para el Control y la Prevención de Enfermedades. Conclusiones: La información actual sobre la pandemia del SARS-CoV-2 está renovándose continuamente y se espera que continúe haciéndolo por los próximos meses. Se torna complicado el mantenerse a la vanguardia, por lo cual confiamos en que esta revisión será útil para distintos estudiantes y profesionales de la salud.

We analysed the changes in the susceptibility of Pseudomonas aeruginosa to antimicrobials over an 18-year period (2000-2017) in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital (excluding the intensive care unit). In addition, the antimicrobial activity was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) criteria as a microbiological surveillance tool.Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR.In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses.Analysis of susceptibility and PK/PD modelling, should be considered together to select the most appropriate antimicrobial drug and dosage regimen. Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered. In this study, the PK/PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates, such as carbapenems, and the selection of the most effective antimicrobials among those with high rates of susceptibility.

Ibrutinib demonstrated robust efficacy, regardless of high-risk features, in previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). The IBRORS-CLL study supports the effectiveness and the manageable safety profile of single-agent ibrutinib, which was not adversely affected by high-risk characteristics in real-world CLL patients in Spain. We also found a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status. Background: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain.Patients: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. Results: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade >= 3 adverse events were infections (122%) and bleeding (3%). Grade >= 3 AF occurred in 1.5% of patients. Conclusion: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations. (C) 2021 The Author(s). Published by Elsevier Inc.

Introduction: Synovial fluid (SF) analysis is an important tool for the diagnosis of patients with juvenile idiopathic arthritis (JIA). Patients and methods: A retrospective analysis was carried out of cytological features of SF samples obtained from patients with JIA during the period 2008–2016. Results: A total of 102 SF samples from 59 patients were analysed. JIA was more common in females (66%). The most frequent form was persistent oligoarticular JIA (52.5%). The median age at onset was 5 years (IQR 2.4–11.8). SF usually showed an inflammatory pattern (median white blood cells count 11,757/mm3; IQR 4,543–18,800), with a predominance of polymorphonuclear (PMN) cells (61%; IQR 30–75). Eight patients (14%) had white blood cells counts of less than 2000 cells/mm3, with predominance of mononuclear cells (80%), whereas 3 patients (5%) had white blood cells counts higher than 50,000 cells/mm3, with a predominance of PMN cells (90%). Synovial white blood cells count did not show significant differences among the different forms of JIA. The median synovial white blood cells count in ANA-positive patients was 20% lower than in ANA-negative (9,340 vs. 11,600/mm3; P = .23). The proportion of PMN increased with increasing levels of ESR (P

Introduction To evaluate the changes in the susceptibility of Pseudomonas aeruginosa over time (2000–2017) against antimicrobials used in an intensive care unit of a Spanish tertiary hospital, and to compare them with the antimicrobial activity considering theoretical pharmacokinetic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolates to quantify susceptibility rates was also evaluated. Methods The susceptibility was studied considering the Clinical and Laboratory Standards Institute (CLSI) breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. Results A significant decrease in the susceptibility to gentamicin and imipenem was observed, and more recently the highest percentages of susceptible strains were found for amikacin, cephalosporins and piperacillin/tazobactam (>80%). The probability of success of an empiric treatment or CFR for most of the evaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem provided high probabilities (>90%) to achieve the PK/PD target. Cephalosporins provided moderate probabilities (>80%) although for ceftazidime, the highest dose (2 g/8 h) was required. Moreover, a significant decrease in the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed. Conclusions Both susceptibility rates and CFR values have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions. They are complementary tools and, they should be used jointly in surveillance programmes. In fact, susceptibility data are not always useful to detect changes in the CFR. No relevant differences were observed among the methods for handling repeated isolates.

Objectives The aim of this study was to compare antimicrobial susceptibility rates in a Spanish ICU before and after the introduction of selective digestive decontamination (SDD) and also to compare these with susceptibility data from other Spanish ICUs without SDD. Methods We performed a retrospective study in the ICU of the University Hospital of Alava, where SDD was implemented in 2002. The SDD protocol consisted of a 2% mixture of gentamicin, colistin and amphotericin B applied on the buccal mucosa and a suspension of the same drugs in the gastrointestinal tract; additionally, for the first 3 days, systemic ceftriaxone was administered. From 1998 to 2013 we analysed the susceptibility rates for 48 antimicrobial/organism combinations. Interrupted time series using a linear dynamic model with SDD as an intervention was used. Data from other ICUs were obtained from the ENVIN-HELICS national registry. Results Only amoxicillin/clavulanic acid against Escherichia coli and Proteus mirabilis, and a high concentration of gentamicin against Enterococcus faecalis, resulted in a significant decrease in the susceptibility rate after the implementation of SDD, with a drop of 20%, 27% and 32%, respectively. Compared with other Spanish ICUs without SDD, the susceptibility rate was higher in the ICU of our hospital in most cases. When it was lower, differences were Conclusions No relevant changes in the overall susceptibility rate after the implementation of SDD were detected. Susceptibility rates were not lower than those in the Spanish ICUs without SDD.

Purpose To assess the pharmacokinetics of linezolid in septic patients undergoing continuous renal replacement therapy (CRRT) and investigate whether residual renal function affects the probability of attaining the pharmacokinetic/pharmacodynamic (PK/PD) target. Material and methods Prospective study conducted in three Spanish hospitals. Linezolid concentrations were measured in plasma and effluent samples and pharmacokinetic parameters were calculated. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) were calculated considering AUC24/MIC>80 and %T>MIC > 85% as the PK/PD indexes related to efficacy. Results In anuric patients (CrCl 80 was achieved in >85% of the anuric patients, but in Conclusions The standard dose (600 mg q12h) ensures a moderately high probability of treatment success in anuric patients when the infection is due to microorganisms with MIC≤2 mg/L; although higher doses increase the probability of treatment success, the safety is compromised. In patients with residual renal function, the standard dose is insufficient, but 900 mg q8h provide higher probability of treatment success without compromising the safety.

Sympathetic overdrive is a key player in hypertension, where the mesenteric vasculature plays a relevant role in modulating blood pressure. Although 5-HT inhibits noradrenergic mesenteric neurotransmission in normotensive rats, its effect on the mesenteric sympathetic drive in hypertensive rats has not been studied. We investigated the influence of in vivo 5-HT by characterizing the implicated serotonergic receptors on the mesenteric sympathetic outflow in rats with N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Hypertension was induced in male Wistar rats by L-NAME administration (30 mg/kg per day; 21 days) in drinking water. The rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), prepared for the in situ autoperfused rat mesentery, and subjected for monitoring their systemic blood pressure (SBP), heart rate (HR), and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP without altering SBP or HR. The 5-HT and cisapride (5-HT4 agonist) i.a. bolus (1-25 µg/kg) inhibited vasopressor responses by electrical stimulation of the mesenteric nerves, unlike an i.a. bolus (25 µg/kg each) of the agonist 5-carboxamidotryptamine (5-HT1/7 agonist), α-methyl-5-HT (5-HT2), or 1-PBG (5-HT3). However, i.a. cisapride (25 µg/kg) did not affect the noradrenaline-induced vasoconstriction in the mesenteric vasculature. Administration of the selective 5-HT4 receptor antagonist GR 125487 (1 mg/kg, i.v.) completely abolished cisapride- and 5-HT-evoked mesenteric sympatholytic effects. Additionally, ELISA analysis demonstrated higher 5-HT4 receptor expression in mesenteric arteries from L-NAME-hypertensive compared with normotensive rats. Our findings suggest that L-NAME-induced hypertension modifies the 5-HT modulation of the rat mesenteric sympathetic drive: prejunctional 5-HT4 receptors are involved in the serotonergic sympathoinhibitory effect.

Introduction: In the 18th Century, Giovanni Battista Morgagni demonstrated that localized injuries to different organs caused a great variety of clinical symptoms and signs. Since then, medical practice has evolved considerably and maintains the correlation of pathological changes with the signs and symptoms of the disease as part of the academic activity known as "anatomic-clinical session". The evaluation of the aptitude for the anatomic-clinical correlation has not been empirically estimated in pediatric pathology. Objective: Construct and validate an evaluation instrument to quantitatively estimate the aptitude for the anatomical-clinical correlation in pediatric pathology (AA-CCPP). Method: Analytical cross-sectional study. An evaluation instrument was constructed with 90 true, false and I don't know type statements, grouped based on three indicators: I, diagnostic integration; II, identification of pathogenic mechanisms and III, identification of clinical and paraclinical data. The instrument was applied to three groups of residents. The Kruskal-Wallis test was used to compare the results between the groups. Results: The AA-CCPP grade was very low in most residents. When comparing the global scores between the different groups, the pediatric pathology group was the highest. The indicator that obtained the best results was that of Diagnostic Integration. Conclusions: The level of development of the AA-CCPP observed allows us to deduce that the learning strategy known as clinical-pathological conference should be strengthened.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) &gt, 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed., This research was funded by the Ministerio de Economía y Competitividad of Spain (SAF2010-15881 and SAF2013-45784-R to J.M.L.-N.), the Junta de Castilla y León (GR100 to J.M.L.-N.), the Fundación Renal Iñigo Álvarez de Toledo, the Kidney Research Network REDINREN (RD06/0016/0013, RD12/0021/0032, and RD016/0009/0025 to J.M.L.-N.), the Instituto de Salud Carlos III (PI16/00460 and PI19/01630 to M.P., co-funded by FEDER), and Consejo Superior de Investigaciones Científicas of Spain (CSIC, grant 201920E022 to C.B.).

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD, 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-&gamma, ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa, B) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). Results: HFD led to WAT hypertrophy in relation to PPAR-&gamma, downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-&kappa, B system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. Conclusion: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

16 pages, 5 figures, 4 tables, Dietary intake of eicosapentaenoic/docosahexaenoic acid (EPA/DHA) reduces insulin resistance and hepatic manifestations through the regulation of metabolism in the liver. Obese mice present insulin resistance and lipid accumulation in intracellular lipid droplets (LDs). LD-associated proteins perilipin (Plin) have an essential role in both adipogenesis and lipolysis; Plin5 regulates lipolysis and thus contributes to fat oxidation. The purpose of this study was to compare the effects of deodorized refined salmon oil (DSO) and its polyunsaturated fatty acids concentrate (CPUFA) containing EPA and DHA, obtained by complexing with urea, on obesity-induced metabolic alteration. CPUFA maximum content was determined using the Box–Behnken experimental design based on Surface Response Methodology. The optimized CPUFA was administered to high-fat diet (HFD)-fed mice (200 mg/kg/day of EPA + DHA) for 8 weeks. No significant differences (p > 0.05) in cholesterol, glycemia, LDs or transaminase content were found. Fasting insulin and hepatic Plin5 protein level increased in the group supplemented with the EPA + DHA optimized product (38.35 g/100 g total fatty acids) compared to obese mice without fish oil supplementation. The results suggest that processing salmon oil by urea concentration can generate an EPA+DHA dose useful to prevent the increase of fasting insulin and the decrease of Plin5 in the liver of insulin-resistant mice., This research was funded by “FONDECYT 1181774”.

Background. Type 1 Diabetes (T1D) is the most common chronic endocrinological disease diagnosed during childhood. It requires continuous education, monitoring and treatment. An analysis was developed to learn if there were discrepancies in the level of metabolic control and complications between private and public healthcare in Mexico, based on the data obtained in the National Registry of patients with Type 1 Diabetes (RENACED DT1). Objective: Describe the sociodemographic characteristics, metabolic control, treatment and complications in patients receiving private or public health care registered in RENACED DT1.Methodology: Sociodemographic and anthropometric variables, metabolic control, diabetes education, type of insulin and delivery method used for treatment, glucose monitoring and acute and chronic complications were compared between patients receiving private vs public health care. Results Of the 1458 patients registered, significant differences between HbA1c levels were seen (7.8% private health care vs 8.7% public healthcare, p 31.3%, p

Introduction In Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. Methods Pharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. Results Regardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL− and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR ≤ 8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. Conclusions Our study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.

Objectives: The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). Results: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations ≥2 mg/l in 70% of the ARC patients. MCS revealed that concentrations ≥2 mg/l would be reached in >90% of patients receiving 75 mg/h. Conclusions: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations ≥2 mg/ml. Keywords: Linezolid, Augmented renal clearance, Pharmacokinetic/pharmacodynamics, Critically ill patients, Continuous infusion

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560–840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.

Antecedentes: El alopurinol es un inhibidor de la xantinooxidasa usado en el tratamiento de pacientes con gota. Aproximadamente 2 % de los pacientes son afectados por reacciones adversas a dicho fármaco. La severidad varía de erupciones cutáneas leves a reacciones graves hasta en 0.4 % de los casos. La desensibilización se lleva a cabo incrementando paulatinamente la dosis del fármaco.Reporte de caso: Hombre de 30 años con diagnóstico de hipercolesterolemia e hipertrigliceridemia tratadas con bezafibrato y pravastatina, hipertensión arterial sistémica tratada con losartán e hiperuricemia con gota de 10 años de diagnóstico. Los tofos se encontraban en articulaciones metacarpofalángicas y codos. Se inició tratamiento con 300 mg diarios de alopurinol, a las dos semanas el paciente presentó eritema facial con prurito y lesiones maculopapulares en región malar una hora después de la ingesta del medicamento. Se inició protocolo ambulatorio de desensibilización a dicho fármaco comenzando con 5 mg, con incremento gradual de la dosis cada cuatro o cinco días por 59 días, hasta llegar a la dosis de mantenimiento deseada (300 mg).Conclusiones: La experiencia muestra que la desensibilización a alopurinol es una alternativa segura cuando existe hipersensibilidad y necesidad de tratamiento con este fármaco.

The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act75 ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity during ERT infusion (Act75-0 ) indicates the total drug exposure during infusion. The clinical response was evaluated based on criteria established by Pastores et al. and Gaucher Severity Score Index. Statistical analysis included ROC analysis and area under the curve test. Act75 and Act75-0 were found to be moderate predictive markers of an optimal clinical response (area under the ROC of Act75 was 0.733 and Act75-0 was 0.817). Act75-0 showed statistical significance in its discriminative capacity (p < 0.05) for obtaining an optimal response to ERT. The cut-off point was 58% (RR = 1.800; 95% CI: 1.003-3.229; p < 0.05). Moreover, Act75 showed a significant and inverse correlation with the Gaucher Severity Score Index, and Act75 and Act75-0 presented a significant correlation with residual enzyme activity at diagnosis. Markers based on glucocerebrosidase activity have a good correlation with clinical response to ERT. Therefore, it could provide supporting clinical data for dose management in GD1 patients.

Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well-studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes. A systematic review was conducted to include all the original studies that provided information on ARC in critically ill patients, and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Augmented renal clearance, defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m2, preferably measured in urine, is present in 20–65% of critically ill patients. Younger age, polytrauma and lower severity illness have been identified as risk factors. An influence of ARC on antimicrobial pharmacokinetics has been observed, with ARC consistently being associated with subtherapeutic antibiotic plasma concentrations. ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.

Alcohol binge drinking is a heavy pattern of alcohol consumption increasingly used by young people. In a previous study, we reported that young drinkers with a 2-year history of binge alcohol consumption had an overactivation of the innate immune system and peripheral inflammation when compared with controls. In the present study, we measured several biolipids that are fatty acid derivatives belonging to the acylethanolamide or 2-acylglycerol families in the plasma of the same subjects (n = 42; 20 men and 22 women). We found that during abstinence, alcohol binge drinkers had elevated plasma levels of oleoylethanolamide, palmitoleoylethanolamide, arachidonoylethanolamide, dihomo-γ-linolenoyl ethanolamide and linoleoyl ethanolamide, which positively correlated with changes in the mRNA expression of key inflammatory markers in peripheral blood mononuclear cells, such as toll-like receptors (TLR4), pro-inflammatory cytokines/chemokines interleukin-1 beta, interleukin-6 and monocyte chemoattractant protein-1, and cyclooxygenase-2. Additionally, plasma oleoylethanolamide positively correlated with plasma levels of high mobility group box-1, which is a danger-associated molecular pattern and an endogenous TLR4 agonist, specifically in female alcohol binge drinkers. No changes were observed in 2-acylglycerols in alcohol binge drinkers, although sex-related differences in these bioactive lipids as well as in palmitoleoylethanolamide and docosatetraenoylethanolamide levels were detected. These results extend the previous clinical findings observed in patients diagnosed with long-term alcohol use disorder to young users and suggest a prominent role for these lipids in the response to acute alcohol exposure.

Introduction. Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time. Methods. Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Results. 84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1. Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist [n=4], Apixaban [n=1] and LMWH [n=3] patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients). The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2. The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 [95% CI 0.188-4.928]; p = 0.964), del11q (HR = 0.042 [95% CI 0.000-682.736]; p=0.521), unmutated IGHV (HR = 0.391 [95% CI 0.110-1.394]; p = 0.148). The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons. Safety: 49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3. Conclusion. This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials. Disclosures Loscertales: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. Hernandez-Rivas:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.

5-hydroxytryptamine (5-HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5-HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure (SBP), heart rate (HR) and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP (9±1.6, 25.7±3.9 and 60.2±5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5-HT (1-25 μg/kg), 5-carboxamidotryptamine (5-HT1/7 agonist; 25 μg/kg) or L-694,247 (5-HT1D agonist; 1-25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8-OH-DPAT (5-HT1A ), CGS-12066B (5-HT1B ), BRL 54443 (5-HT1e/1F ), α-methyl-5-HT (5-HT2 ), 1-PBG (5-HT3 ), cisapride (5-HT4 ) or AS-19 (5-HT7 ) (25 μg/kg each). Interestingly, i.a. L-694,247 (25 μg/kg) also reduced the exogenous norepinephrine-induced vasoconstrictions. Pretreatment with selective 5-HT1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L-694,247- and 5-HT-induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5-HT1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms-induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5-HT1D receptors. This article is protected by copyright. All rights reserved.

Background aims Cell therapy with mesenchymal stromal cells (MSCs) offers new hope for patients suffering from spinal cord injury (SCI). Methods Ten patients with established incomplete SCI received four subarachnoid administrations of 30 × 10 6 autologous bone marrow MSCs, supported in autologous plasma, at months 1, 4, 7 and 10 of the study, and were followed until the month 12. Urodynamic, neurophysiological and neuroimaging studies were performed at months 6 and 12, and compared with basal studies. Results Variable improvement was found in the patients of the series. All of them showed some degree of improvement in sensitivity and motor function. Sexual function improved in two of the eight male patients. Neuropathic pain was present in four patients before treatment; it disappeared in two of them and decreased in another. Clear improvement in bladder and bowel control were found in all patients suffering previous dysfunction. Before treatment, seven patients suffered spasms, and two improved. Before cell therapy, nine patients suffered variable degree of spasticity, and 3 of them showed clear decrease at the end of follow-up. At this time, nine patients showed infra-lesional electromyographic recordings suggesting active muscle reinnervation, and eight patients showed improvement in bladder compliance. After three administrations of MSCs, mean values of brain-derived neurotrophic factor, glial-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin 3 and 4 showed slight increases compared with basal levels, but without statistically significant difference. Conclusions Administration of repeated doses of MSCs by subarachnoid route is a well-tolerated procedure that is able to achieve progressive and significant improvement in the quality of life of patients suffering incomplete SCI.

Infantile systemic juvenile xanthogranuloma (ISJXG) is an uncommon form of juvenile xanthogranuloma, a non-Langerhans cell proliferation of infancy and early childhood. In a small percentage of patients, the visceral involvement—most commonly to the central nervous system, liver, spleen, or lungs—may be associated with severe morbidity, and eventually fatal outcome. Here we describe the clinical and pathological findings of a 28-day-old girl with ISJXG who died with respiratory distress syndrome. She had few cutaneous lesions but massive liver and spleen infiltration; other affected organs were multiple lymph nodes, thoracic parasympathetic nodule, pleura, pancreas, and kidneys. Additional findings were mild pulmonary hypoplasia and bacteremia. Immunohistochemistry on fixed tissues is the standard for diagnosis. Immunophenotype cells express CD14, CD68, CD163, Factor XIIIa, Stabilin-1, and fascin; S100 was positive in less than 20% of the cases; CD1a and langerin were negative. No consistent cytogenetic or molecular genetic defect has been identified. This case demonstrates that the autopsy is a handy tool, because hepatic infiltration, which was not considered clinically, determined a restrictive respiratory impairment. In our opinion, this was the direct cause of death.

Pulmonary malformations are rare disorders, with cystic and pseudocystic pulmonary malformations (CPPM) the most frequent, and constitute the first cause of lobectomy in children1 year of age. Morphological overlap of congenital cystic pulmonary lesions might correspond to a spectrum of lesions in which bronchial atresia is a common etiopathogenetic mechanism. We aimed to report the frequency of CPPM resected in a tertiary-level hospital and to evaluate the degree of agreement between presurgical and anatomopathological diagnoses. We studied 44 surgical pieces with a diagnosis of CPPM received at the Pathology Service from 2009 to 2014, resected from 39 patients, 51.3 % males, with a median age of 16.8 months. Up to 69.2% of the patients had adenomatoid malformation of pulmonary airway (AMPA), with type 2 the most frequent (55.5%). Pulmonary sequestration was present in 15.4% of patients; in two cases the diagnosis was an incidental finding during surgery for the repair of a diaphragmatic hernia. Congenital lobar hyperinflation (CLH) occurred in 7.6% cases. Bronchogenic cyst (BC) was present in 7.6% cases. Presurgical and anatomopathological diagnoses in all patients coincided in 71.8% of cases. Kappa coefficient was 0.56 for global concordance in patients with AMPA, and 0.72, 0.64, 0.37 and 0.33 for CLH, BC, and types 1 and 2 AMPA, respectively. This relatively low interobserver agreement could reflect the low reproducibility of diagnoses used in the current nomenclature. Thus, the new nomenclature must be promoted in order to allow for better reproducibility and greater clinico-pathological concordance. The anatomopathological analysis must include the intentional search for bronchial atresia.

Resumen: Introducción: El análisis del líquido sinovial (LS) es una herramienta importante en el diagnóstico de pacientes con artritis idiopática juvenil (AIJ). Pacientes y métodos: Análisis retrospectivo de las características citológicas del LS obtenido de pacientes con AIJ en el periodo 2008-2016. Resultados: Se analizaron 102 LS de 59 pacientes. El 66% fueron mujeres y la forma clínica más frecuente fue la AIJ oligoarticular persistente (52,5%). La mediana de edad al inicio fue de 5 años (RIC 2,4-11,8). El LS generalmente era de características inflamatorias (mediana leucocitos 11.757/mm3; RIC 4.543-18.800) con predominio de polimorfonucleares (PMN, 61%; RIC 30-75). Ocho pacientes (14%) presentaron recuentos inferiores a 2.000 cél/mm3, con predominio de mononucleares (80%), mientras que 3 pacientes (5%) presentaron recuentos superiores a 50.000 cél/mm3, con predominio de PMN (90%). No se encontraron diferencias en los recuentos celulares entre las distintas formas de AIJ. La mediana del recuento de leucocitos de pacientes positivos para ANA fue un 20% inferior a la de niños negativos para ANA (9.340 vs. 11.600/mm3; p = 0,23). La proporción de PMN en LS tendía a aumentar conforme se incrementaba la VSG (p

espanolLa fuerte relacion epidemiologica que existe entre la preeclampsia y la miocardiopatia periparto sugiere que las dos enfermedades comparten una fisiopatologia antiangiogenica y considera que ambas contribuyen a la morbilidad y mortalidad cardiovascular significativa en las pacientes embarazadas. El s-FLT1, una enzima recientemente identificada en la familia de la tirosina quinasa, parece ser un agente antiangiogenico con poder cardiotoxico, que aparece elevado tanto en la miocardiopatia periparto como en la preeclampsia. A la luz de la fuerte asociacion entre los dos procesos, parece recomendable que las mujeres con preeclampsia no sean excluidas de los estudios futuros de la miocardiopatia periparto EnglishThe strong epidemiological link between pre-eclampsia and peripartum cardiomyopathy suggests that the two diseases share an anti-angiogenic pathophysiology. Both contribute to significant cardiovascular morbidity and mortality in pregnant patients. The s-FLT1, a recently identified family of tyrosine kinase enzyme, appears to be an anti-angiogenic agent with cardiotoxic power, which appears high in both peripartum cardiomyopathy and pre-eclampsia. Considering the strong association between the two processes, it is recommended that women with pre-eclampsia are not excluded from future studies of peripartum cardiomyopathy.

Tranexamic acid (TXA) reduces bleeding in patients undergoing hip replacement surgery, but optimal doses and timing have yet to be established. Our primary objective in this study was to assess total blood loss 48 hours after surgery with different regimens.This was a multicenter, parallel-group, randomized, placebo-controlled clinical trial that included all ASA physical status I to III patients undergoing unilateral total hip replacement surgery who met the inclusion criteria. Patients were randomly allocated to 1 of 3 groups: a single-dose group (15 mg/kg TXA before the start of surgery and saline 3 hours later after the start of surgery), a 2-dose group (10 m/kg TXA before and 10 mg/kg of TXA 3 hours after the start of surgery), and a control group (saline before and 3 hours after the start of surgery). Total blood loss was calculated using a formula considering hematocrit values and blood transfusions received.We included 108 patients in the study. Total blood loss volumes up to day 2 were 1377 ± 689, 1308 ± 641, and 2215 ± 1136 mL in the single-dose, 2-dose and control groups, respectively (P0.001 between the placebo and the experimental groups). Blood transfusions were given to 22.9% of patients (n = 8) in the single-dose group, 11.1% (n = 4) in the 2-dose group, and 37.8% (n = 14) in the control group (P = 0.028).A single preoperative dose of TXA or 2 infusions of a lower dose, preoperatively and then after 3 hours after the start of surgery, resulted in lower blood loss during the first 2 days after surgery and less need for blood transfusion, with good levels of safety.

Introduction: Patients diagnosed with end-stage chronic kidney disease on a hemodialysis program (HDP) represent a risk group for COVID-19. Scientific societies have developed guidelines for the prevention of contagion, but there is no prophylactic medicine in them. Objectives: To describe the safety and efficacy of recombinant intranasal human Interferon alfa 2b as prophylaxis for COVID-19 in patients in an HDP. Patients and Methods: Intervention description through the monitoring of 15 patients in outpatient HDP. Prior to the administration of the drug, clinical, radiological evaluation and hematology and blood chemistry studies were performed. Daily contact was made with each study patient in person or by telephone, asking about the occurrence of adverse events or symptoms of disease. Results: In 47% of the patients, there was leukopenia, lymphopenia in 67% and anemia and thrombocytopenia in 33% respectively, prior to the use of the drug. There was no clinical suspicion of COVID-19 in any of them. Adverse events occurred in 3 patients (20%), all were mild and non-severe. All patients were negative for SARS-CoV-2 real-time polymerase chain reaction (rtPCR) and antibody studies 45 days after the study started. Conclusion: the use of intranasal recombinant human interferon alfa 2b as prophylaxis of COVID-19 in patients in a HDP at a dose of 1 MIU daily for ten days, as part of a prevention protocol, has an adequate safety profile. None of the patients in the series was infected with SARS-CoV-2 during the surveillance period.

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC &gt, 80 and 100% T&gt, MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC &ge, 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

Background: In February 2017, CT-P10 became the first rituximab biosimilar to be approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). More recently, CT-P10 was approved in the US for NHL. Although the recommended rituximab administration protocol is a slow initial infusion rate with gradual up-titration, rapid infusion protocols are used widely in patients with no serious complications from their first infusion. There are limited data on the safety of rapidly infused CT-P10. Aims: To evaluate the safety and effectiveness of rapidly infused CT-P10 in patients with NHL or CLL in a real world clinical setting over a 6 month follow up period. Methods: This non-interventional post-authorisation safety study is in progress in the United Kingdom (UK), Spain, France and Italy. It involves collection of data from the medical records of consenting adult patients with NHL or CLL who received rapidly-infused CT-P10 (total infusion time ≤90 minutes) during routine clinical practice. The index date (day 1) is the date of the first rapid CT-P10 infusion. Safety and effectiveness data have been collected over a 6 month observation period from the index date (or to death, if sooner). Early results from this study have been previously presented and showed the index IRR rate (the primary outcome) to be 8% (Bishton, 2019). Updated interim results with full 6 month follow-up are now available for 112 patients and are reported here, based on a data cut on 19 June 2019. Results: This interim analysis includes patients enrolled from the UK, Italy and Spain. Ninety four patients (84%) have NHL (68 [61%] diffuse large B-cell lymphoma [DLBCL], 26 [23%] follicular lymphoma [FL]) and 18 (16%) have CLL. Other patient characteristics at index date: 74 (66%) male; median age 67 years (interquartile range [IQR] 58.0-74.0); median disease duration 0.2 years (IQR 0.1-0.4); 20 (18%) patients with prior treatment recorded (n=111); Ann Arbor stage for NHL at index (n=58): I (n=7, 12%), II (n=7, 12%), III (n=8, 14%), IV (n=35, 60%) or other (n=1, 2%; recorded as '1E'); Binet stage for CLL at index (n=11): A (n=5, 45%), B (n=4, 36%) or C (n=2, 18%). Patients had between 1 and 4 CT-P10 infusions prior to the index date, with first infusions given over a median of 4 hours (IQR 3.5-4.1 hours). Median CT-P10 dose at index was 375 mg/m2 (IQR 375.0-375.0 mg/m2) and a median of 5 infusions per patient (IQR 3.8-6.0) were given over 6 months. A total of 512 CT-P10 infusions were given over the 6 month observation period across all 112 patients. Of 19 (17%) patients who experienced one or more IRRs over the observation period (including index IRRs), 9 patients had one, 5 had two and 5 had three or more IRRs. Thirty six IRRs were reported in total and are listed in Table 1 by grade. Ninety six (86%) patients experienced an adverse event (AE) and 31 (28%) experienced a serious AE (SAE) over the observation period. At 6 months post-index, 95 (85%) patients had discontinued first line CT-P10 due to planned completion of their treatment course, 7 (6%) had discontinued due to AEs, 1 (1%) due to disease progression and 5 (4%) due to other reasons (reason for discontinuation not known for 1 patient [1%]), with treatment ongoing for 3 patients (3%). Best responses to CT-P10 during the observation period (as documented by the local investigator) were complete response (n=83, 74%), partial response (n=24, 21%), stable disease (n=3, 3%) and progressive disease (n=2, 2%). Summary/conclusions: In this multi-country study of patients treated with rapidly-infused CT-P10 in a real world setting, a high proportion of patients achieved complete or partial responses over 6 months follow-up. The results also suggest that CT-P10 is generally well-tolerated, with 36 (predominantly mild) IRRs recorded over a total of 512 infusions, and the majority of patients discontinuing CT-P10 due to planned completion of treatment. Disclosures Bishton: Takeda: Other: Travel support, Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Celltrion: Employment. Nam Lee:Celltrion: Employment. OffLabel Disclosure: CT-P10 is a rituximab biosimilar, approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). In Europe, the recommended administration protocol is a slow initial infusion rate with gradual up-titration. However, rapid infusion protocols are used routinely in many countries for second and subsequent infusions in patients with no serious complications from their first infusion. There are limited data on the safety of rapid infusion of CT-P10 so this non-interventional study aims to address this gap and reflect practice in the real world. Rapid infusion is on-label in the United States.

With tyrosine kinase inhibitors (TKI), chronic myeloid leukemia (CML) patients are achieving similar rates of survival to the general population and some treatment aspects such as adherence and drug-to-drug interactions (DDI) are becoming increasingly important. Our aim was to investigate the frequency and real clinical consequences of DDI between TKI and concurrent medications in CML. We performed a retrospective multicenter study including 105 patients receiving 134 TKI treatments. Sixty-three patients (60%) had at least one potential DDI. The mean number of concomitant medications was 4.8 (0-19). The mean number of DDI by TKI treatment was 1.2 (0-8); it increased with the number of concomitant medications and age in a significant manner. A total of 159 DDI were detected, involving 55 different drugs. The most common drug classes involved were proton pump inhibitors, statins, and antidepressants. A DDI-related clinical effect (toxicity and/or lack of efficacy) was suspected during the common course of patient follow-up in only five patients (4.7%). This number increased to 20% when data were centrally reviewed. Most of the adverse events (AE) attributed to DDIs were mild. The most common were diarrhea, vomiting, edema, cramps, and transaminitis. Nilotinib and dasatinib showed a tendency towards a higher risk of DDI compared with imatinib. There were no significant differences in AE frequency or in treatment response between patients with or without DDI. Due to their frequency, and their potential to cause clinically relevant effects, DDI are an important aspect of CML management.

The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and suboptimal dosing are two major factors that should be considered because they lead to the emergence of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some recommendations are provided from a PK/PD point of view to enhance the efficacy of prophylaxis protocols used in surgery.

Antecedentes: la incidencia de la inmunodeficiencia común variable (IDCV) es de 1 por cada 15,000 a 117,000 casos, sin predominio de género. La incidencia de manifestaciones gastrointestinales en estos pacientes es de 20 a 60% y pueden ser la primera y única manifestación clínica de IDCV. En México existe escasa información en relación con el tipo y frecuencia de alteraciones gastrointestinales que padecen los pacientes adultos con IDCV.Objetivo: determinar la prevalencia de alteraciones gastrointestinales en pacientes adultos con inmunodeficiencia común variable.Material y método: estudio descriptivo, observacional y transversal en el que participaron pacientes con inmunodeficiencia común variable de la Clínica de Inmunodeficiencias del Servicio de Alergia e Inmunología Clínica del Hospital de Especialidades, Centro Médico Nacional Siglo XXI. A todos los pacientes se les aplicó un cuestionario de síntomas gastrointestinales y se les realizaron estudios de laboratorio, gabinete, endoscopia y prueba de aliento para determinar sobrepoblación bacteriana.Resultados: evaluamos 17 pacientes, 8 hombres y 9 mujeres, con edad promedio de 36 años y diagnóstico definitivo de inmunodeficiencia común variable de acuerdo con criterios internacionales. El 59% refirió dolor abdominal, 53% distensión abdominal y 17.6% estreñimiento. El 47% tenía diarrea crónica, en dos de ellos (11.8%) acompañada de pujo rectal. Las enfermedades gastrointestinales de esta población fueron: 18% diarrea crónica, enfermedad celiaca y sobrepoblación bacteriana, 24% trastorno funcional digestivo, 12% estreñimiento, 6% dispepsia. Sólo un paciente (6%) no tenía síntomas gastrointestinales.Conclusión: la prevalencia de las enfermedades gastrointestinales en pacientes adultos con inmunodeficiencia común variable fue de 94%, sin predominio de género. Debido a la frecuencia de manifestaciones gastrointestinales, es importante realizar protocolos de estudio al respecto para iniciar de manera temprana su diagnóstico y tratamiento.

Antecedentes: los pacientes con inmunodeficiencia común variable tienen riesgo elevado de padecer enfermedades neoplásicas, con incidencia de 11 a 13%, especialmente durante la quinta y sexta décadas de la vida. Los linfomas de tipo celular B son los más frecuentes, además del linfoma no Hodgkin y tumores epiteliales (carcinomas de estómago, mama, vejiga y cuello uterino).Objetivo: conocer el tipo de enfermedades neoplásicas en una cohorte de pacientes adultos con inmunodeficiencia común variable.Material y método: estudio observacional, transversal y descriptivo, en el que se revisaron los expedientes con diagnóstico de inmunodeficiencia común variable de la Clínica de Inmunodeficiencias Primarias del servicio de Alergia e Inmunología Clínica del Hospital de Especialidades del Centro Médico Nacional Siglo XXI del IMSS.Resultados: se incluyeron 23 pacientes con diagnóstico de inmunodeficiencia común variable; de éstos, 13 (56%) eran mujeres, el promedio de edad fue de 36.7 años. Se encontraron neoplasias en cuatro pacientes de este grupo (dos mujeres y dos hombres), la prevalencia de cáncer fue de 17.3%. Los tipos de cáncer reportados fueron: linfoma Hodgkin de células B (1/23), carcinoma neuroendocrino de la cabeza del páncreas (1/23), leucemia mieloide crónica (1/23) y cáncer papilar de tiroides (1/23). En dos de los pacientes, el diagnóstico de cáncer fue previo al diagnóstico de la inmunodeficiencia primaria. El promedio de edad al momento del diagnóstico de cáncer fue de 27 años (límites: 19-34 años).Conclusión: la frecuencia de cáncer en nuestra población fue similar a lo reportado en la bibliografía. Sin embargo, los tipos de cáncer fueron distintos a lo publicado. Consideramos que es necesario realizar un protocolo de escrutinio en estos pacientes para diagnosticar de manera oportuna cualquier tipo de neoplasia, debido al mayor riesgo que tienen estos pacientes.

The selection of multiresistant microorganisms, as a side-effect of the use of antimicrobials, together with the lack of new therapeutic drugs expected in the near future, forces to a rational use of antibiotics. The optimisation of antibacterial treatments based on pharmacokinetic/pharmacodynamic analysis (PK/PD) may contribute to prolong the life of antibiotics and to contain the bacterial resistance to them. A review is made of the importance of the appropriateness of the dose regimen selected, the application of PK/PD analysis of antimicrobials, the Monte Carlo simulation, PK/PD indices for efficacy, and PK/PD cut-off points. PK/PD analysis is also applicable to the prevention of bacterial resistance. Different methods have been used to study the factors that lead to its emergence and spread, such as in vitro and animal models, and resistance prevention studies (mutant selection window). Although the PK/PD analysis is a very useful tool for the selection of the most appropriate dose regimen of antibiotics, several problems limit its use in clinical practice.

Background aims Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Developing effective protocols for the administration of mesenchymal stromal cells (MSCs) is a promising therapeutic strategy to treat TBI. It is important to develop alternatives to direct parenchymal injection at the injury site because direct injection is an expensive and invasive technique. Subarachnoid transplantation, a minimally invasive and low-risk procedure, may be an important and clinically applicable strategy. The aim of this study was to test the therapeutic effect of subarachnoid administration of MSCs on functional outcome 2 months after an experimental TBI in rats. Methods Two months after TBI, 30 female Wistar rats were divided into 3 groups ( n = 10 in each group): sham, MSC (received 2 × 10 6 MSCs) and saline (received only saline) groups. Neurological function, brain and spinal cords samples and cerebrospinal fluid were studied. Results No significant differences were found in neurological evaluation and after histological analysis; differences in the expression of neurotrophins were present but were not statistically significant. MSCs survived in the host tissue, and some expressed neural markers. Conclusions Similar to direct parenchymal injections, transplanted MSCs survive, migrate to the injury cavity and differentiate into mature neural cell types for at least 6 months after engraftment. These results open the possibility that MSC administration through subarachnoid administration may be a treatment for the consequences of TBI. The transplantation technique and cell number should be adjusted to obtain functional outcome and neurotrophin production differences.

Background: Although pulmonary involvement is common in patients with cancer, its frequency and nature is seldom reported in the medical literature. Objective: To determine the frequency and type of lung pathological conditions revealed by autopsy in children with cancer. Methods: All reports from autopsies performed in children with cancer from 1989 to 2012 in a pediatric hospital were reviewed. Results: In the analyzed period, 118 autopsies (10.2% of all autopsies) corresponded to children who died with cancer; 76 had complete information and were included in the analysis. Children were seen in the Hematology (41 cases) or the Oncology (35 cases) services. Their median age at decease was 7 years (range, 15 days to 16.1 years) and 46.1% were females. Main diagnoses were acute lymphoblastic (31 patients) or myeloblastic (10 patients) leukemias and tumors of the central nervous system (12 patients). A pathological respiratory condition was diagnosed antemortem in 31 (40.8%) patients, and at autopsy in 62 (81.6%) cases. Omitted diagnoses occurred in 58 (76.3%) children, being pneumonia (24 cases) and pulmonary hemorrhage (23 cases) the most frequent omissions. Nine patients had clinically unsuspected tumor infiltration or metastases. Conclusions: In these children with cancer, more than 80% of autopsies revealed some lung pathology, mainly of infectious or hemorrhagic nature. Thus, pulmonary involvement should be investigated in all children with cancer in a timely and intentional manner. (Rev Inves ClIn. 2017;69:28-32)

Antecedentes: la inmunodeficiencia común variable es la inmunodeficiencia primaria sintomática más frecuente, afecta a 1 por cada 25,000 a 75,000 sujetos. Se distingue por la ausencia o disminución de anticuerpos. Su tratamiento consiste en el reemplazo de anticuerpos con inmunoglobulina humana y la vía de administración más frecuente es la intravenosa, a dosis de 400 a 800 mg/kg de peso/dosis cada tres a cuatro semanas. Los efectos adversos asociados con la administración de inmunoglobulina intravenosa (IgIV) ocurren incluso en 25% de todas las infusiones realizadas, las reacciones severas afectan a menos de 1% de los pacientes. Entre las reacciones adversas severas están la insuficiencia renal aguda, que sobreviene 1 a 10 días después del inicio de tratamiento con IgIV. En nuestro centro elaboramos e implementamos un esquema ambulatorio para la aplicación de IgIV que permite su administración en un promedio de 3 h, sin efectos adversos graves.Objetivos: describir los efectos adversos y evaluar la frecuencia de insuficiencia renal secundaria a la aplicación ambulatoria de IgIV en pacientes adultos con inmunodeficiencia común variable.Material y método: estudio descriptivo y prospectivo en el que participaron pacientes adultos con diagnóstico definitivo de inmunodeficiencia común variable, que recibían IgIV a dosis de sustitución cada tres semanas, a quienes se realizó exploración física, somatometría, determinación sérica de creatinina, albúmina y urea, depuración de creatinina en orina de 24 horas, cálculo de la tasa de filtración glomerular por la fórmula CKD-EPI y evaluación de la función renal inmediata, así como la asociada con la administración acumulada de IgIV a través del cálculo de la tasa de filtración glomerular. Los resultados se analizaron con estadística descriptiva para el reporte de los efectos en la función renal y la dosis acumulada de IgIV.Resultados: se determinó la frecuencia de reacciones adversas en 25 pacientes con diagnóstico de inmunodeficiencia común variable (15 mujeres y 10 varones, con edad promedio de 36.7 años), durante un periodo de 10 meses (enero a septiembre de 2013). En este periodo se aplicaron 284 infusiones de IgIV utilizando el esquema propuesto, la frecuencia de reacciones adversas fue de 12.9% del total de las infusiones, de las que 5.2% fueron reacciones adversas tempranas y 7.7% reacciones adversas tardías, todas fueron reacciones leves a moderadas, que ameritaron en algunos casos la administración de analgésico, antihistamínico o ambos, sin llegar a requerirse la suspensión de la infusión de IgIV. En el estudio de la función renal se incluyeron 19 pacientes (12 mujeres y 7 hombres, edad promedio 36 años, peso promedio 58.74 kg y talla promedio 1.60 m) y en el lapso estudiado (enero de 2009 a octubre de 2013) la determinación de creatinina en promedio fue de 0.76 ± 0.18 mg/dL; la urea sérica promedio del grupo fue de 28.6 ± 7.6 mg/dL, ningún paciente tuvo datos de insuficiencia renal aguda. La tasa de filtración glomerular se determinó mediante la fórmula de CKD-EPI y fue, en promedio, de 116 ± 34 mL/min/1.73 m2, se encontraron datos de deterioro renal crónico en cuatro pacientes. La determinación promedio de la depuración de creatinina en orina de 24 horas fue de 98.64 ± 22 mL/min/1.73 m2 y se encontraron datos de deterioro crónico en la función renal en seis pacientes.Conclusiones: con este esquema ambulatorio de aplicación de IgIV no hubo reacciones adversas graves (anafilaxia, broncoespasmo, insuficiencia renal aguda). En esta población de pacientes no se encontró afección renal aguda secundaria a la aplicación de IgIV, pero mediante la depuración de creatinina de 24 horas sí se encontraron datos que sugirieron daño renal crónico en seis pacientes. No se encontró relación entre la dosis acumulada de IgIV aplicada en los últimos cinco años con el hallazgo de disminución de la tasa de filtración glomerular. Otro beneficio de este método de aplicación de IgIV es la reducción en los costos para la institución de salud y para el paciente, además de permitir a éste reintegrarse a sus actividades cotidianas laborales o escolares de manera rápida.

Background : Oral allergy syndrome (OAS) is the mildest form of an allergic reaction to foods. It is characterized by the presence of IgE mediated symptoms restricted to oral mucosa after intake of fresh fruits and vegetables. OAS diagnosis is based on suggestive clinical manifestations and can be con rmed with tests such as prick-to-prick skin test with the food implicated, which have a sensitivity > 90%, speci city 30-60%, positive predictive value (PPV) of 40% and negative predictive value (NPV) > 95%. Objective : To know the prevalence of OAS in adult patients attending a third level hospital in southern Mexico City, and also describe the demo graphics of these patients and comorbidities more frequently associated. Patients and method : We studied 44 patients (40 women and 4 men), with an average age of 33.4 years, with suggestive clinical features of OAS, evaluated with prick-by-prick skin tests with fresh food. Results : There was a predominance of OAS in woman (91%) and a pre valence of asthma and allergic rhinitis of 54% among this population. We found that 60.4% of these patients had positive prick-by-prick skin tests, being the most frequently involved families of foods: rosaceae (60%), crustaceans (25%), musaceae (23%), actinidacea (21%), laura - ceae (16%) and cucurbitaceae (16%). Only 5 patients presented adverse reactions with prick-by-prick skin tests, in 4 of the cases with grade 3 and grade 4 anaphylaxis, while testing with banana-watermelon, peach, papaya and peanut, respectively. Conclusions : Oral allegy syndrome affects more women than men, the most frequent comorbidities in patients with oral allergy syndrome are allergic rhinitis and asthma, thus, in patients with asthma and allergic rhinitis, sensitized to pollens we have to ask about symptoms suggestive of oral allergy syndrome.

La hipersensibilidad a corticoesteroides es un fenómeno complejo en el que interactúan múltiples factores como idiosincrasia, intolerancia o alergia. La prevalencia de las reacciones de hipersensibilidad inmediata a corticoesteroides es de 0.2 a 0.5%. Debido a la relevancia terapéutica de los esteroides, es importante confirmar el diagnóstico de hipersensibilidad con pruebas in vivo, in vitro, o ambas, el patrón de referencia es la prueba de reto con el fármaco implicado. Una vez realizado el diagnóstico y en caso de que se requiera continuar con el tratamiento con esteroides, deberá considerarse la reactividad cruzada entre los diferentes grupos propuestos en la clasificación de Coopman, en la que los corticoesteroides pertenecientes a los grupos A, B y D2 tienen una elevada reactividad cruzada entre sí; sin embargo, hacen falta más estudios para determinar el grado de reactividad cruzada entre estos fármacos. Comunicamos el caso de una paciente en la que se confirmó el diagnóstico de hipersensibilidad a succinato de hidrocortisona con la prueba de reto.

El síndrome DRESS (exantema inducido por fármacos con eosinofilia y síntomas sistémicos) es una reacción idiosincrática (tipo B), que se distingue por eosinofilia periférica y síntomas sistémicos, como fiebre, exantema, linfadenopatía, hepatitis, linfocitos atípicos y elevación de enzimas hepáticas al menos dos veces su valor normal o incremento de la alanina aminotransferasa (ALT) >100 U/L. La incidencia es de 1 por cada 1,000 a 10,000 exposiciones y su mortalidad es de 10 a 20%. El tratamiento se basa en esteroides y en la suspensión del fármaco sospechoso. Se comunican los casos de seis pacientes con síndrome DRESS atendidos en el Centro Médico Nacional Siglo XXI, de septiembre de 2012 a septiembre de 2013, que correspondieron a 12.5% de los pacientes atendidos con reacciones adversas a fármacos.

5-HT₂ receptor activation induces vasoconstriction, hypertension and platelet aggregation; therefore, its blocking may be useful in cardiovascular diseases, probably due to alterations in the modulation of serotonergic system. The aim of this study was to evaluate whether 5-HT₂ receptor blockade changes serotonergic modulation of sympathetic neurotransmission in pithed rats. Serotonergic modulation of sympathetic neurotransmission was investigated in Wistar rats treated with sarpogrelate, a 5-HT₂ receptor antagonist, during 14 days (30 mg/kg/day). After central nervous system destruction, we conducted electrical stimulation throughout the spinal cord flow to study the 5-HT-related products action on adrenergic system. 5-Hydroxytryptamine exerted inhibition of sympathetic outflow in sarpogrelate-treated pithed rats. This effect was mimicked and enhanced by 5-CT (5-HT₁/₇ receptor agonist). L-694,247 and AS-19, 5-HT₁D and 5-HT₇ receptor agonists respectively, reproduced this action. Pretreatment with LY310762+SB258719 (5-HT₁D and 5-HT₇ receptor antagonists, respectively) completely abolished 5-CT inhibitory action. The nature of this action was prejunctional since these agonists did not modify the pressor responses induced by exogenous noradrenaline. Western Blot analysis confirmed a higher expression of 5-HT₁D receptors in sarpogrelate-treated rats. Experimental 5-HT₂ receptor blockade induces changes in the 5-HT receptors involved in the serotonergic inhibition of sympathetic-induced pressor responses. Prejunctional activation of 5-HT₁D and 5-HT₇ receptors induces a significantly higher serotonergic inhibition on adrenergic neurotransmission in sarpogrelate-treated pithed rats. The antagonism of 5-HT₂ receptors produces an enhancement of serotonergic sympathoinhibitory effect, which may explain the beneficial effects of this blockade in cardiovascular disorders where 5-hydroxytryptamine plays a crucial role.

At present, cell therapy with adult stem cells offers hope for treating neurological diseases considered incurable. In this paper, we review our current experience with delayed intracerebral transplantation of bone marrow stromal cells (BMSC) as a potential treatment of established neurological deficits occurring after intracerebral hemorrhage (ICH). The injection of collagenase IV into basal ganglia of adult Wistar rats causes intracerebral hemorrhage and subsequent neurological deficits that can be quantified by means of functional assessment tests. When the neurological deficit is stabilized, the intracerebral administration of BMSC is followed by a clear functional recovery of the treated animals compared to controls. Furthermore, histological studies show that transplanted stem cells can survive long-term in the injured brain, acquiring a phenotype of neurons and glial cells. These findings suggest that stem cell therapy represents an important field of research, with potential clinical application to treatment of established neurological deficits after brain hemorrhage.