Measurement of the

^{140}Ce(n,γ) is a key reaction for slow neutron-capture (s-process) nucleosynthesis due to being a bottleneck in the reaction flow. For this reason, it was measured with high accuracy (uncertainty ≈5%) at the n_TOF facility, with an unprecedented combination of a high purity sample and low neutron-sensitivity detectors. The measured Maxwellian averaged cross section is up to 40% higher than previously accepted values. Stellar model calculations indicate a reduction around 20% of the s-process contribution to the Galactic cerium abundance and smaller sizeable differences for most of the heavier elements. No variations are found in the nucleosynthesis from massive stars.

74 Ge( n , γ ) cross section below 70 keV measured at n_TOF CERN.

Neutron capture reaction cross sections on 74 Ge are of importance to determine 74 Ge production during the astrophysical slow neutron capture process. We present new resonance data on 74 Ge( n , γ ) reactions below 70 keV neutron energy. We calculate Maxwellian averaged cross sections, combining our data below 70 keV with evaluated cross sections at higher neutron energies. Our stellar cross sections are in agreement with a previous activation measurement performed at Forschungszentrum Karlsruhe by Marganiec et al., once their data has been re-normalised to account for an update in the reference cross section used in that experiment.

Neutron Capture on the s-Process Branching Point

The neutron capture cross sections of several unstable nuclides acting as branching points in the s process are crucial for stellar nucleosynthesis studies. The unstable ^{171}Tm (t_{1/2}=1.92 yr) is part of the branching around mass A∼170 but its neutron capture cross section as a function of the neutron energy is not known to date. In this work, following the production for the first time of more than 5 mg of ^{171}Tm at the high-flux reactor Institut Laue-Langevin in France, a sample was produced at the Paul Scherrer Institute in Switzerland. Two complementary experiments were carried out at the neutron time-of-flight facility (n_TOF) at CERN in Switzerland and at the SARAF liquid lithium target facility at Soreq Nuclear Research Center in Israel by time of flight and activation, respectively. The result of the time-of-flight experiment consists of the first ever set of resonance parameters and the corresponding average resonance parameters, allowing us to make an estimation of the Maxwellian-averaged cross sections (MACS) by extrapolation. The activation measurement provides a direct and more precise measurement of the MACS at 30 keV: 384(40) mb, with which the estimation from the n_TOF data agree at the limit of 1 standard deviation. This value is 2.6 times lower than the JEFF-3.3 and ENDF/B-VIII evaluations, 25% lower than that of the Bao et al. compilation, and 1.6 times larger than the value recommended in the KADoNiS (v1) database, based on the only previous experiment. Our result affects the nucleosynthesis at the A∼170 branching, namely, the ^{171}Yb abundance increases in the material lost by asymptotic giant branch stars, providing a better match to the available pre-solar SiC grain measurements compared to the calculations based on the current JEFF-3.3 model-based evaluation.

Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients.

OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.

[The Computer Book of the Internal Medicine resident: validity and reliability of a questionnaire for self-assessment of competences in internal medicine residents]. / El Libro Informático del residente de Medicina Interna: validez y fiabilidad de un cuestionario para la autoevalución de competencias en residentes de Medicina Interna.

BACKGROUND: There are no simple and validated instruments for evaluating the training of specialists. OBJECTIVES: To analyze the reliability and validity of a computerized self-assessment method to quantify the acquisition of medical competences during the Internal Medicine residency program. METHODS: All residents of our department participated in the study during a period of 28 months. Twenty-two questionnaires specific for each rotation (the Computer-Book of the Internal Medicine Resident) were constructed with items (questions) corresponding to three competence domains: clinical skills competence, communication skills and teamwork. Reliability was analyzed by measuring the internal consistency of items in each competence domain using Cronbach's alpha index. Validation was performed by comparing mean scores in each competence domain between senior and junior residents. Cut-off levels of competence scores were established in order to identify the strengths and weaknesses of our training program. Finally, self-assessment values were correlated with the evaluations of the medical staff. RESULTS: There was a high internal consistency of the items of clinical skills competences, communication skills and teamwork. Higher scores of clinical skills competence and communication skills, but not in those of teamwork were observed in senior residents than in junior residents. The Computer-Book of the Internal Medicine Resident identified the strengths and weaknesses of our training program. We did not observe any correlation between the results of the self- evaluations and the evaluations made by staff physicians. CONCLUSIONS: The items of Computer-Book of the Internal Medicine Resident showed high internal consistency and made it possible to measure the acquisition of medical competences in a team of Internal Medicine residents. This self-assessment method should be complemented with other evaluation methods in order to assess the acquisition of medical competences by an individual resident.

[Practical considerations for implementing health outcomes measurement projects within a healthcare organization: Delphi Expert Consensus Study]. / Consideraciones prácticas para la implementación de proyectos de medición de resultados en salud en una organización sanitaria: Estudio Delphi de consenso de expertos.

INTRODUCTION: Measuring health outcomes and costs per patient is an essential element of value-based healthcare (VBHC). The aim of the study was to generate expert consensus on the activities required to implement it. METHODS: A two-round modified Delphi study with healthcare professionals, quality and clinical management methodologists and managers with academic and/or practical experience in outcome measurement projects. A median equal to or greater than 4 and a relative interquartile range (RIQR) equal to or greater than 25% were established as consensus criteria. RESULTS: Consensus was obtained on 91% of the items (N=74/81). In terms of feasibility, the items that received the highest score and consensus were the existence of data protection guarantees (median=5; mean=4.8; RIQR=0%), the vision and motivation of healthcare professionals (median=5; mean=4.7; RIQR=20%), the existence and availability of ICT tools (or systems) for data recording (median=5; mean=4.5; RIQR=20%), and having sufficient funding to undertake the project (median=5; mean=4.2; RIQR=20%). The most highly rated factors adding complexity were the number of units or departments involved in the care process for the clinical condition (median=5; mean=4.4; RIQR=20%), having an accepted set of monitoring indicators for the condition (median=5; mean=4.4; RIQR=20%), and the involvement of several levels of care in the project (median=5; mean=4.3; RIQR=20%). CONCLUSIONS: We describe practical aspects for the application of systematic outcomes measurement in routine clinical practice. These results can serve as a tool for prioritising, sizing, resource planning, and estimating implementation costs.

Cytogenetic analyses of human oocytes provide new data on non-disjunction mechanisms and the origin of trisomy 16.

BACKGROUND: Nowadays, oocyte donation is an extended practise in IVF programmes. However, to date, little information on aneuploidy frequency in oocytes from donors is available. Aneuploidy is one of the major causes of embryo and fetal wastage as well as of congenital mental and developmental disabilities. It is known that most aneuploidies are due to non-disjunction events occurring in the maternal germ line. Linkage studies have associated abnormal patterns of meiotic recombination to the origin of the non-disjunction event in many aneuploid conditions. METHODS AND RESULTS: In the present study, we analyse the frequency of chromosome imbalances in a series of metaphase I (MI; n = 44) and metaphase II (MII; n = 103) oocytes from 140 young donors (aged from 18 to 35 years, mean age 26.6) after hormone-induced superovulation. The aneuploidy frequency found in MII oocytes was 12.6%, and both whole-chromosome non-disjunction (1.94%) and premature separation of sister chromatids (PSSC) (12.6%) have been found. The chromosomes involved have been identified by multiplex fluorescent in situ hybridization (FISH). Achiasmate chromosomes have been identified in MI oocytes (9.1%), with most of them corresponding to chromosome 16 (6.8%). For this reason, the meiotic recombination pattern of chromosome 16 has been analysed in prophase I oocytes (n = 81) by immunofluorescence staining against MLH1 protein and subsequent FISH with specific probes. Our results show a percentage of oocytes with non-crossover bivalent 16 (2.5%) and a high percentage of bivalents 16 with a single exchange (19.8%). CONCLUSIONS: In the present study, we report the finding of a considerable frequency of aneuploidy in oocytes from young donors, with the frequency of PSSC being higher than the frequency of whole-chromosome non-disjunction. In addition, we report vulnerable patterns of meiotic recombination in chromosome 16 that may be at risk of leading to a non-disjunction event. This gives new data on the susceptibility of the control population to conceive a trisomic 16 embryo.

[Health policy strategies for Patient Blood Management implementation throughout the Spanish health systems]. / Estrategias de gestión y política sanitaria para el desarrollo del Patient Blood Management en los sistemas de salud en España.

Patient Blood Management (PBM) programs have proven to be successful in reducing overuse and improving patient safety, clinical outcomes and efficiency. Despite its benefits, PBM is still scarcely used in real clinical practice with a high variability among hospitals in Spain. Recent guidelines from the European Union on how to implement PBM, as well as recommendations from experts in the field, suggest that further development in PBM implementation requires not only the participation of healthcare professionals but also the commitment and support of Health Authorities and senior hospital management. This article provides some thoughts on health care management and policy strategies to help implement PBM throughout the Spanish autonomous healthcare systems.

Acyclovir delivery matrices based on poly(ethylene glycol)/chitosan semi-interpenetrating networks.

Chitosan matrix systems have been studied as potential vehicles for the prolonged release of acyclovir (ACV). The influence of chitosan concentration (from 0.83% to 1.67%) on viscoelastic properties of formulations with and without glyoxal was analyzed. For chitosan-poly(ethylene glycol) 400 formulations loss modulus (G'') are greater than storage modulus (G'). This corresponds to the characteristic behavior of nonstructured systems. When glyoxal was added to the chitosan-poly(ethylene glycol) 400 formulations, gelled matrix was obtained (i.e., G' is higher than G''), except for the lowest chitosan concentration. ACV release rates for the both types of systems, with and without glyoxal, were also determined. The ACV diffusion coefficient values from matrices are less than for the respective formulation without glyoxal and it was found to depend on the crosslink density within the matrices. Viscoelastic parameters, dynamic moduli (G', G''), and complex viscosity (eta*), were correlated with the ACV diffusion coefficients (D). The complex viscosity (eta*) could be used as a parameter of predictive value for the release rate of drugs.

Standalone ethanol micro-reformer integrated on silicon technology for onboard production of hydrogen-rich gas.

A novel design of a silicon-based micro-reformer for onboard hydrogen generation from ethanol is presented in this work. The micro-reactor is fully fabricated with mainstream MEMS technology and consists of an active low-thermal-mass structure suspended by an insulating membrane. The suspended structure includes an embedded resistive metal heater and an array of ca. 20k vertically aligned through-silicon micro-channels per square centimetre. Each micro-channel is 500 µm in length and 50 µm in diameter allowing a unique micro-reformer configuration that presents a total surface per projected area of 16 cm(2) cm(-2) and per volume of 320 cm(2) cm(-3). The walls of the micro-channels become the active surface of the micro-reformer when coated with a homogenous thin film of Rh-Pd/CeO2 catalyst. The steam reforming of ethanol under controlled temperature conditions (using the embedded heater) and using the micro-reformer as a standalone device are evaluated. Fuel conversion rates above 94% and hydrogen selectivity values of ca. 70% were obtained when using operation conditions suitable for application in micro-solid oxide fuel cells (micro-SOFCs), i.e. 750 °C and fuel flows of 0.02 mlL min(-1) (enough to feed a one watt power source).

Clinical and virological effects during two years of ongoing adefovir dipivoxil in the treatment of lamivudine-resistant chronic hepatitis B infection.

OBJECTIVE: Our aim was to evaluate the efficacy and safety of adding adefovir to lamivudine therapy for hepatitis B virus (HBV)-infected patients resistant to Ramivudine. PATIENTS AND METHODS: Among 17 studied patients, 7 had chronic active HBV infection and 10 were posttransplant with HBV infection (9 with de novo HBV). They received lamivudine plus adefovir therapy for 2 years. We assessed reductions in serum HBV-DNA and alanine aminotransferase (ALT) levels, loss of HBeAg (in HBeAg+ cases), and HBsAg clearance. RESULTS: A virological response, as defined by HBV-DNA below the cut off by hybridization, was observed in 12 (70.6%) patients and loss of HBeAg in 4 (44.4%) of the 9 initially HBeAg-positive cases. A biochemical response, defined as a decreased serum ALT to the normal range, occurred in 4 (26.7%) patients. Median serum creatinine increased in 3 of 15 (20%) patients, excluding those on hemodialysis. There were two noteworthy cases of sustained HBsAg seroconversion with adefovir (11.8%): one patient with de novo HBV infection posttransplantation and positive hepatitis C virus-RNA serology, and one patient with decompensated HBV cirrhosis in whom viral replication ceased, making him eligible for transplantation. CONCLUSIONS: Currently, adefovir is an effective rescue therapy that broadens the existing range of options for patients with lamivudine-resistant chronic hepatitis B infection, particularly those with decompensated cirrhosis awaiting a liver graft, and those with recurrent posttransplantation HBV. The relatively small biochemical response seen in these patients may be attributable to the high prevalence of concomitant hepatitis C virus infection (41%).

Adverse effects of a SOD1-peptide immunotherapy on SOD1 G93A mouse slow model of amyotrophic lateral sclerosis.

Previous reports from our lab had shown that some anti-purinergic receptor P2X4 antibodies cross-reacted with misfolded forms of mutant Cu/Zn superoxide dismutase 1 (SOD1), linked to amyotrophic lateral sclerosis (ALS). Cross-reactivity could be caused by the abnormal exposure of an epitope located in the inner hydrophobic region of SOD1 that shared structural homology with the P2X4-immunizing peptide. We had previously raised antibodies against human SOD1 epitope mimicked by the P2X4 immunizing peptide. One of these antibodies, called AJ10, was able to recognize mutant/misfolded forms of ALS-linked mutant SOD1. Here, we used the AJ10 antigen as a vaccine to target neurotoxic species of mutant SOD1 in a slow mouse model of ALS. However, the obtained results showed no improvement in life span, disease onset or weight loss in treated animals; we observed an increased microglial neuroinflammatory response and high amounts of misfolded SOD1 accumulated within spinal cord neurons after AJ10 immunization. An increase of immunoglobulin G deposits was also found due to the treatment. Finally, a significantly worse clinical evolution was displayed by an impairment on motor function as a consequence of AJ10 peptide immunization.

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients.

OBJECTIVE: To describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score. PATIENTS AND METHODS: By December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (<20mg/day), high dose GCS (>20mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]). RESULTS: There were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses >20mg/day in 255-23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34-0.95). We classified 16 (7%) of the 255 patients treated with >20mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity. CONCLUSION: The management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.

Calcitonin gene-related peptide in rat spinal cord motoneurons: subcellular distribution and changes induced by axotomy.

Using light and electron microscopy, a study has been made of the changes of calcitonin gene-related peptide-like immunoreactivity in rat lumbar spinal cord motoneurons during cell body response to sciatic nerve injury. At light microscopy level, calcitonin gene-related peptide-like immunoreactivity was evaluated using an indirect immunofluorescence technique combined with Fast Blue retrograde tracing and a peroxidase-antiperoxidase procedure. The calcitonin gene-related peptide changes to sciatic nerve transection and crushing were compared. Calcitonin gene-related peptide-like immunoreactivity was transiently increased after the peripheral nerve lesion, but the response was sustained for a longer period when the peripheral nerve was transected and nerve regeneration prevented. The first changes in calcitonin gene-related peptide-like immunoreactivity were detected four days after nerve crush or transection. In animal spinal cords to which nerve crush had been applied, the maximal enhancement of immunoreactivity was found 11 days after lesion. This was followed by a gradual decline, normal levels being attained 45 days after nerve crushing. When the nerve was transected, the response was similar, but the maximal calcitonin gene-related peptide-like immunoreactivity was maintained over a period of between 11 and 30 days. As with crushing, an important decrease was observed after 45 days. The ultrastructural compartmentation of calcitonin gene-related peptide-like immunoreactivity was studied using either peroxidase-antiperoxidase method or immunogold labelling. Calcitonin gene-related peptide-like immuno-reactivity was located in restricted sacs of the Golgi complex, multivesicular bodies, small vesicles and tubulo-vesicular structures. Large, strongly labelled vesicles resembling secretory granules were also observed in neuronal bodies. Our results reveal that the increase of calcitonin gene-related peptide in motoneurons is a relevant change the cell body undergoes in response to peripheral injury. The ultrastructural location of the peptide distribution suggests specific compartmentation on tubulo-vesicular structures connected with the Golgi complex which form a network in the neuronal cytoplasm. The distribution pattern observed may be related to the sorting and delivery of calcitonin gene-related peptide to secretory vesicles.

Prevention by lamotrigine, MK-801 and N omega-nitro-L-arginine methyl ester of motoneuron cell death after neonatal axotomy.

Motoneuron cell death was analysed in the rat facial motor nucleus after neonatal facial nerve transection. In situ DNA fragmentation labelling showed that axotomized motoneurons die by an apoptotic mechanism. In order to investigate the existence of excitotoxic mechanisms in this type of neuronal death, rats were treated with several agents known to possess neuroprotective action through a variety of mechanisms. The Na+ channel inhibitor lamotrigine and the antagonist for the N-methyl-D-aspartate-type glutamate receptor, dizocilpine maleate (MK-801) were found to be able to rescue motoneurons from cell death induced by axotomy. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester was also able to protect motoneurons from death, but to a lesser extent. The distribution of constitutive and inducible isoforms of nitric oxide synthase was investigated by immunocytochemistry in the facial motor nucleus. No changes were detected in constitutive nitric oxide synthase immunoreactivity in the facial motor nucleus after axotomy. However, in the axotomized facial motor nucleus, inducible nitric oxide synthase showed a positive immunolabelling specifically located in activated astrocytes, but not in microglia. Nitric oxide derived from activated astrocytes may have a role in promoting excitotoxic mechanisms in axotomized motoneurons. We conclude that excitotoxic mechanisms involving apoptotic cell death are present when immature motoneurons die as a consequence of target disconnection.

Induction of reactive astrocytosis and prevention of motoneuron cell death by the I(2)-imidazoline receptor ligand LSL 60101.

I(2)-imidazoline receptors are mainly expressed on glial cells in the rat brain. This study was designed to test the effect of treatment with the I(2)-imidazoline selective receptor ligand LSL 60101 [2-(2-benzofuranyl)imidazole] on the morphology of astrocytes in the neonate and adult rat brain, and to explore the putative neuroprotective effects of this glial response. Short-term (3 days) or chronic (7-10 days) treatment with LSL 60101 (1 mg kg(-1), i.p. every 12 h) enhanced the area covered by astroglial cells in sections of facial motor nucleus from neonate rats processed for glial fibrillary acidic protein (GFAP) immunostaining. Facial motoneurons surrounded by positive glial cell processes were frequently observed in sections of LSL 60101-treated rats. A similar glial response was observed in the parietal cortex of adult rats after chronic (10 days) treatment with LSL 60101 (10 mg kg(-1), i.p. every 12 h). Western-blot detection of the specific astroglial glutamate transporter GLT-1, indicated increased immunoreactivity after LSL 60101 treatment in the pons of neonate and in the parietoccipital cortex of adult rats. In the facial motor nucleus of neonate rats, the glial response after LSL 60101 treatment was associated to a redistribution of the immunofluorescence of the basic fibroblast growth factor (FGF-2) from the perinuclear area of motoneurons to cover most of their cytoplasm, suggesting a translocation of this mitogenic and neurotrophic factor towards secretion pathways. The neuroprotective potential of the above effects of LSL 60101 treatment was tested after neonatal axotomy of facial motor nucleus. Treatment with LSL 60101 (1 mg kg(-1), i.p. every 12 h from day 0 to day 10 after birth) significantly reduced (38%) motoneuron death rate 7 days after facial nerve axotomy performed on day 3 after birth. It is concluded that treatment with the I(2)-imidazoline selective receptor ligand LSL 60101 provokes morphological/biochemical changes in astroglia that are neuroprotective after neonatal axotomy.

Interaction of local anaesthetics with cytochrome oxidase studied with fluorescence quenching.

The interaction of a series of eight local anaesthetics with cytochrome oxidase chosen as a membrane model protein has been studied with fluorescence technique using quinacrine as a fluorescent probe. The existence of hydrophobic interactions with a non polar region of cytochrome oxidase complex has been shown. The ability of the drug molecules to displace quinacrine bound to cytochrome oxidase correlate as closely with their anaesthetic potency as with their octanol-water partition coefficient. Our results are in good agreement with a recent model of local anaesthetic action on nerve membranes presenting a site of anaesthesia including both lipid binding and protein binding environments.

Inhibition of cytochrome oxidase activity by local anaesthetics.

Using a polarographic method, we studied the inhibition of mitochondrial electron transport at the cytochrome c oxidase site caused by eight local anaesthetics. The diversity of the types of inhibition observed indicate the importance of electrostatic interactions between the anaesthetic molecules and the membrane protein. A linear relationship was recognized between the anaesthetic activity of infiltration and the affinity for the enzyme. We also observed a significant relationship between this affinity and the octanol-water partition coefficient. This result suggests that lipophilic interactions are involved in cytochrome oxidase-anaesthetic binding. We tried to establish a parallel between this binding and the mechanism of anaesthesia involving the nerve membrane proteins.