Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

Multifractal analysis of diurnal temperature range over Southern Spain using validated datasets.

Multifractal properties of diurnal temperature range (DTR) have been analyzed in this work, using validated data of maximum and minimum temperature from 197 weather stations in Southern Spain (Andalusia region). DTR is a crucial factor to characterize the regional climate, providing more information than the average daily temperature. Apart from climate change studies, one of the most important applications of DTR in Agrometeorology is as an input variable in the solar radiation or reference evapotranspiration estimation models based on the temperature. With the aim of obtaining a detailed information for different time scales, different multifractal approaches have been applied. Different quality control methods such as range/limits or persistence tests were previously applied in order to detect incorrect and anomalous values, being discarded in the subsequent analysis. The DTR scaling of moments has been analyzed and the moment scaling exponent function K(q) has been obtained, finding some differences between weather stations. In addition, multifractal dimension (D1) and multifractal degree (MD) were also estimated, revealing differences at coastal and inland locations that show heterogeneity across the region, including its multifractal nature and its invariance for a range of scales. The nonlinear characterization carried out in this work improves the understanding of DTR as an indicator of climate changes, and it can have a very positive impact on the calibration of regional models for estimating solar radiation or reference evapotranspiration based on the temperature. This multifractal characterization can be used to group stations with similar nonlinear dynamics, regardless of their geographical features, in such a way that more accurate coefficients than conventional ones are used.

Multifractal analysis to study break points in temperature data sets.

Since the last century, the air surface temperature has increased at a global scale, showing trends and inhomogeneities that vary from place to place. Many statistical methods can be used to analyze whether or not an inhomogeneity or break point exists in a meteorological data series, and even to detect the time of the break. Sometimes, there is no agreement in the year at which the inhomogeneity occurs detected by different tests. The scale invariance of a process can be studied through its multifractal properties that can be related to the existence of break points in it. In this work, the multifractal properties of monthly temperature data series are used to test what is the right break point year in those situations at which different dates are found by two different tests: the Pettitt and the Standard Normal Homogeneity tests. The comparison of the fractal dimension function Dq and the multifractal spectrum obtained by the box counting method for both the original data sets and for those obtained by splitting the original into two considering the break point years was made. When different multifractal functions and parameters were obtained, a break point was confirmed. Whereas, if equal values appeared, the break point year was discarded. These results let to select the most suitable test to be applied to detect inhomogeneities in a certain data set that will be very useful for climate change studies.

Differential effects of exposure to parasites and bacteria on stress response in turbot Scophthalmus maximus simultaneously stressed by low water depth.

The stress response of turbot Scophthalmus maximus was evaluated in fish maintained 8 days under different water depths, normal (NWD, 30 cm depth, total water volume 40 l) or low (LWD, 5 cm depth, total water volume 10 l), in the additional presence of infection-infestation of two pathogens of this species. This was caused by intraperitoneal injection of sublethal doses of the bacterium Aeromonas salmonicida subsp. salmonicida or the parasite Philasterides dicentrarchi (Ciliophora:Scuticociliatida). The LWD conditions were stressful for fish, causing increased levels of cortisol in plasma, decreased levels of glycogen in liver and nicotinamide adenine dinucleotide phosphate (NADP) and increased activities of G6Pase and GSase. The presence of bacteria or parasites in fish under NWD resulted in increased cortisol levels in plasma whereas in liver, changes were of minor importance including decreased levels of lactate and GSase activity. The simultaneous presence of bacteria and parasites in fish under NWD resulted a sharp increase in the levels of cortisol in plasma and decreased levels of glucose. Decreased levels of glycogen and lactate and activities of GSase and glutathione reductase (GR), as well as increased activities of glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH) and levels of nicotinamide adenine dinucleotide phosphate (NADPH) occurred in the same fish in liver. Finally, the presence of pathogens in S. maximus under stressful conditions elicited by LWD resulted in synergistic actions of both type of stressors in cortisol levels. In liver, the presence of bacteria or parasites induced a synergistic action on several variables such as decreased activities of G6Pase and GSase as well as increased levels of NADP and NADPH and increased activities of GPase, G6PDH and 6PGDH.

Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women.

OBJECTIVES: To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 µg/g (T1) and 50 µg/g (T2)) compared to Ovestinon® (estriol 500 µg/0.5 g (R)) and placebo in postmenopausal women. METHODS: Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated. RESULTS: Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUCss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good. CONCLUSIONS: Estriol 20 and 50 µg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®.

Resolving pathways of interaction of mipafox and a sarin analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches.

The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here, our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF/TOF. The ACP was detected with a diethyl-phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl-phosphonylated and a methyl-phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diisopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However, with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand calculated in modeling was lower and, consequently, aging appeared as a more likely reaction. We document here direct evidence for a phosphorylated hAChE refractory to oxime reactivation, although we observed no aging.

Encystment/excystment response and serotypic variation in the gastropod parasite Tetrahymena rostrata (Ciliophora, Tetrahymenidae).

Tetrahymena rostrata, which is characterized by a particular encystment-excystment cycle involving autogamy, has been recently found infecting the kidney of edible Helix aspersa snails under farming conditions. In this work, the effects of several factors on its encystment/excystment behaviour and the occurrence of different serotypes were investigated. The encystment/excystment response under starvation conditions was seriously affected by temperature. While a peak of encystment at 48 h followed by a progressive spontaneous excystment was observed at 18 and 25 °C, the encystment response was practically inhibited at 5 °C and clearly slowed down at 10 °C. At 30 °C, most of surviving ciliates remained encysted throughout the experiment, with spontaneous excystment being detected only after switching the temperature to 18 °C. Soil components also affected the encystment/excystment behaviour at 18 °C, with spontaneous excystment occurring in the presence of a sterile-filtered soil extract or mineral water but being strongly minimized with a non-filtered soil extract. Resting cysts formed in the latter extract exhibited a 3­4 times thicker and ultrastructurally more complex wall than that formed in mineral water and retained the excystment ability for about 4 weeks. Incomplete desiccation did not affect significantly the encystment response, while the mucus and kidney extracts from snails as well as a ciliate extract strongly stimulated a rapid excystment. Finally, two different serotypes infecting H. aspersa in heliciculture farms of Galicia (NW Spain) were identified, but no differences were observed between the encystment/excystment responses exhibited by two isolates belonging to each serotype.

Chirped dual periodic structures for photonic Bloch oscillations and Zener tunneling.

Experimental evidence of photon Wannier-stark ladders (WSLs) and Zener tunneling (ZT) in one dimensional dual-periodical (DP) optical superlattices based on Porous Silicon (PSi), is presented. An introduction of linear gradient in physical thickness of the layers, composed of five stacks of two different periodic substructures, resulted in the appearance of four WSLs resonances and resonant Zener tunneling of nearest resonances of two consecutive WSLs. Theoretical analysis of time-resolved reflection spectra as a function of gradient reveals the presence of photonic Bloch oscillations (BOs) and an eventual tunneling at a specific value of linear gradient (20%), has been demonstrated through scattering maps. Measured reflection from different DP photonic structures confirm the presence of minibands, WSLs and ZT in the near infrared region.

High NaCl concentrations induce the nod genes of Rhizobium tropici CIAT899 in the absence of flavonoid inducers.

The nodulation (nod) genes of Rhizobium tropici CIAT899 can be induced by very low concentrations (micromolar to nanomolar range) of several flavonoid molecules secreted by the roots of leguminous plants under a number of different conditions. Some of these conditions have been investigated and appear to have a great influence on the concentration and the number of different Nod factors, which can induce root nodule primordia and pseudonodules in several leguminous plant roots. In one such condition, we added up to 300 mM NaCl to the induction medium of R. tropici CIAT899 containing the nod gene inducer apigenin. At the higher concentrations of NaCl, larger amounts and more different Nod factors were produced than in the absence of extra NaCl. To our surprise, under control conditions (300 mM NaCl without apigenin), some Nod-factor-like spots were also observed on the thin-layer plates used to detect incorporation of radiolabeled glucosamine into newly synthesized Nod factors. This phenomenon was further investigated with thin-layer plates, fusions of nod genes to the lacZ gene, high-performance liquid chromatography, mass spectrometry, and the formation of pseudonodules on bean roots. Here, we report that, in the absence of flavonoid inducers, high concentrations of NaCl induced nod genes and the production of Nod factors.

Parasitic infections in mixed system-based heliciculture farms: dynamics and key epidemiological factors.

Heliciculture is an excellent alternative to obtain edible snails but its viability is seriously threatened by pathogens. A parasitological survey was conducted in 3 mixed system-based heliciculture farms in Galicia (NW Spain), with the species Tetrahymena rostrata, Tetrahymena limacis, Tetratrichomonas limacis, Cryptobia helicogenae, Brachylaima aspersae (metacercariae and sporocysts), Alloionema appendiculatum, Nemhelix bakeri, and Riccardoella limacum being commonly found infecting Helix aspersa aspersa (petit-gris) snails. With the exception of C. helicogenae, N. bakeri, and B. aspersae sporocysts, all species were also detected in Helix aspersa maxima (gros-gris) snails, although generally with lower parameters. Most monoxenous infections, and consequently multiple parasitism, exhibited a rising trend during the first 2 months of intensive mating, with tendencies being slowed down or even reversed during the third month as a result of accumulated mortality and a sampling-derived reduction in host density. No parasites were vertically transmitted and infections were initially acquired from invading gastropod and micromammal reservoirs during fattening. Finally, artificial hibernation reduced significantly the prevalence of most species. These results confirm the importance of parasites in heliciculture and emphasize the need to prevent the entry of wild reservoirs into the farms and to rapidly remove the carcasses of dead snails from the reproduction units and fattening pens.

Multifractal analysis of validated wind speed time series.

Multifractal properties of 30 min wind data series recorded at six locations in Cadiz (Southern Spain) have been studied in this work with the aim of obtaining detailed information for a range of time scales. Wind speed records have been validated, applying various quality control tests as a pre-requisite before their use, improving the reliability of the results due to the identification of incorrect values which have been discarded in the analysis. The scaling of the wind speed moments has been analysed and empirical moments scaling exponent functions K(q) have been obtained. Although the same critical moment (qcrit) has been obtained for all the places, some differences appear in other multifractal parameters like γmax and the value of K(0). These differences have been related to the presence of extreme events and zero data values in the data series analysed, respectively.

A strategic reflection for the management and implementation of CAR-T therapy in Spain: an expert consensus paper.

CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.

[Photodynamic therapy and prostate cancer]. / Thérapie photodynamique et cancer de la prostate.

PURPOSE: Photodynamic therapy (PDT) is an innovative therapeutic modality in urologic oncology. MATERIAL AND METHODS: We reviewed the current literature on principles and modalities of PDT in prostatic oncology. RESULTS: Focal therapy of prostate cancer is an application field of PDT. Clinical phase II studies are ongoing to determine PDT efficacy and safety in this indication. PDT as salvage treatment after prostatic radiotherapy has been tested. Carcinologic results were promising but important side effects were reported. Individual dosimetric planification is necessary to avoid this toxicity. CONCLUSION: PDT first clinical experience for prostate cancer has showed its technical feasibility. Several research ways are currently in study to improve carcinologic efficacy and to limit potential side effects.

Biometrics, testosterone, cortisol and antler growth cycle in Iberian red deer stags (Cervus elaphus hispanicus).

In this article, we aimed to describe the changes related to mating season in red deer, especially those related to antler growth, body condition score, testosterone and cortisol. Antler growth was studied in 17 Iberian red deer males, including body weight, antler length, biometric measures and testosterone and cortisol determination during 15 months. Body weight, body condition score, thoracic perimeter (TP), neck perimeter (NL) and testicular diameter (TD) showed the highest values immediately before mating season (autumn), decreased during it and remained constant at winter. Antler growth lasted 158 days and produced antlers with a final length of 80.8 +/- 2.0 cm. Testosterone and cortisol showed seasonal changes with maximum values at September and May, respectively. Final antler size was related positively to cranial longitude, TP, NL, TD and body weight at casting time. No relationship between weight loss during precedent mating season and current antler size was found, but spring recovery weight was positively related to final antler size. Final length was related to the descent in testosterone values during previous mating season and to body weight before it. Spring recovery weight was related to relative weight loss during previous mating season. These results suggest that there is no relationship between the reproductive effort performed during one season and the next year size of the antler. In contrast, antler size was positively related to spring recovery weight, in the sense that those deer that recover a higher percentage of body weight at the early stages of antler growth develop higher antlers.

[Esmolol to control hemodynamic response during removal of a bilateral pheochromocytoma from a 10-year-old girl]. / Manejo hemodinámico intraoperatorio con esmolol durante la extirpación de un feocromocitoma bilateral en una paciente de 10 años.

Pheochromocytomas, which derive from chromaffin cells, can secrete catecholamines in large amounts. The incidence of these tumors is low at 2 to 8 cases per million population and only 10% of cases occur in children. A thorough understanding of the pathophysiology of these tumors and the consequent effect of drugs will be necessary for treating these patients during the perioperative period. A great deal has been published on drugs that can be used in this setting, but only a small portion of the information is relevant to children. Esmolol, a short-action beta-blocker, figures among the drugs that have been developed in recent years. We report a case in which esmolol was used during surgery in a 10-year-old girl undergoing scheduled removal of a bilateral pheochromocytoma.

Fabrication of a multifunctional magnetic-fluorescent material for medical applications.

Multifunctional biocompatible materials have evoked considerable interest in the field of medical applications. Here we report the thermal decomposition preparation of homogeneous fluorescent-magnetic particles with a composite structure containing CoFe2O4 nanoparticles as nucleation seeds for fluorescent Gd2-xO3:Eux. The composite exhibited a wide range of fluorescence transitions in the whole visible spectrum, displaying 18 different emission peaks when excited at a 250 nm wavelength. Moreover, at low temperature the peaks of the composite were wider than the peaks of the fluorescent material, which may be attributed to a set of new energy levels due to a combination of Stark splitting with the magnetic field of CoFe2O4. Because this material is intended to be used for biomedical applications, the potential toxicity of the composite was tested using an invertebrate hemocyte cell model. The cells showed slight morphological and biochemical changes upon exposure to the composite; however, there was no increase in cell death at concentrations of up to 40 ppm. In addition, the material could be tracked by its fluorescence inside the cells, when excited at a more bio-friendly and less energetic wavelength of 405 nm. Furthermore, MRI showed T1 and T2 dual contrast with relaxivity values in the range of most reported materials.

Effect of milk minerals on calf gains and sex differences in mineral composition of milk from Iberian red deer (Cervus elaphus hispanicus).

Milk mineral content has received little attention in studies focusing on milk nutrient effects on offspring growth. This study examines calf growth in Iberian deer and compares the influence of milk minerals, other nutrients, and lactation variables relevant for growth to discern the relative weight of each factor. In addition, because Iberian deer hinds are the first mammal found to produce different milk for sons and daughters, the present study examines whether there are also sex differences in milk mineral composition. Concentrations and yields of Ca, P, Mg, Na, K, Fe, and Zn in milk of 46 red deer hinds were monitored through 18 weeks of lactation. Calf growth was influenced by Ca and P percent, and total Fe production. Milk for males had a lower content in Ca and P, a greater content of K, and Mg, whereas no sex effects were found in Na, Fe, or Zn percentages. Higher percentages in Ca and P for daughters might constitute a compensatory response, as daily production was not biased towards females in Ca or P, whereas in the latter and all the other minerals daily production was greater for heavier calves, which are usually males. In conclusion, milk mineral content and production influence calf growth even after controlling for other important lactation variables and nutrients, and they show effects and interactions more complicated than expected.

The mechanical properties of red deer antler bone when used in fighting.

We assessed the hydration state of antlers and its effect on antler mechanical properties compared with wet femur. Red deer antlers were removed from the head at various times, from a few days after velvet shedding till late in the season, and weighed weekly until after casting time. Antlers cut just after losing their velvet lost weight rapidly in the first few weeks, then settled down and changed weight very little, the latter changes correlating with air relative humidity. Antlers cut later showed little weight change at any time. The water content of cortical and trabecular parts of the contralateral antler was assessed after cutting. Most of the weight loss was from the cancellous, not the cortical, part of the antler. Wet and dry specimens from the antlers, and wet specimens from deer femora, were tested mechanically. Compared with wet bone, wet antler had a much lower modulus of elasticity and bending strength, but a higher work to fracture. Compared with wet bone, dry antler showed a somewhat lower Young's modulus, but a considerably higher bending strength and a much higher work to fracture. The impact energy absorption of dry antler was much greater than that of wet bone. In red deer, the antler is effectively dry during its use in fights, at least in southern Spain. In addition, dry antler, compared with ordinary bone, shows mechanical properties that suit it admirably for its fighting function.

Coccomyxa sp. (chlorophyta: chlorococcales), a new pathogen in mussels (Mytilus galloprovincialis) of Vigo estuary (Galicia, NW Spain).

In this work, we describe the occurrence of irregular shaped green aggregations in the mantle, gill filaments, adductor muscle, visceral mass and haemolymph of wild mussels (Mytilus galloprovincialis) collected from the Vigo estuary (Galicia, NW Spain). Microscopic examination of these masses revealed that they consist of intracellular green algae which are spherical to oval in shape, 5 microm in length and 3 microm in width, without flagella and with a smooth surface. The algal cells present a small single nucleus, a mitochondrion, 1-2 parietal chloroplasts and lack pyrenoids. Reproduction is by formation of 2-4 autospores or daughter cells. Pigment analysis reveals the presence of photopigments typical of green algae in addition to alloxanthin, diadinoxanthin and diatoxanthin. These carotenoids are noted for the first time in a parasitic chlorophyte. The signs of infection, together with the morphological observations, suggest that this parasitic algae may be Coccomyxa parasitica. However, further molecular studies are required for confirmation. This is the first report of Coccomyxa algae parasitizing the species M. galloprovincialis.

Age-related body weight constraints on prenatal and milk provisioning in Iberian red deer (Cervus elaphus hispanicus) affect allocation of maternal resources.

Maternal phenotypic characteristics can influence key life history variables of their offspring through maternal effects. In this study, we examined how body size constraints on maternal weight in yearling and subadult compared to adult hinds (age class effects) affected prenatal (calf birth weight, calf to hind weight ratio) and postnatal (milk) provisioning of Iberian red deer calves. Age correlated with all prenatal and postnatal investment traits except calf gains, although correlations were weaker than those with maternal weight. Once the effect of linear increase in weight with age was removed from models, yearlings showed additional reductions in calf birth weight, calf gains, and milk provisioning. The low-calf birth weight might increase the risk of calf mortality during lactation, as this occurs primarily during the first day of life and is strongly related to birth weight. Yearlings showed a greater prenatal allocation of resources in terms of greater calf to hind weight ratio probably as an extra effort by yearling mothers to balance calf neonatal mortality. It might compensate young mothers to produce low-quality calves while still growing rather than waiting for the uncertain possibility of surviving to the next reproductive season.