Use of Silver Nanoparticles as Tougheners of Alumina Ceramics

In this work, alumina/silver composites were produced through powder techniques, which involve the combination of high energy mechanical milling combined with sintering in the presence of a liquid phase and with the idea of having ceramics with good toughness values. From mechanical characterizations, it was found that increases of the silver content in the alumina origins decrease the elastic’s modulus and flexural strength of the final composite. The fracture toughness of alumina increases from 4.2 MPam−0.5 for monolithic alumina to 10 MPam−0.5 for alumina with 2 wt% silver additions. It was determined that the reinforcement mechanism of these materials is due to the deflection of cracks owing to metallic bridges formed by the silver used as toughener material

Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study

Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed

Density functional electronic spectrum of the CuO−6−10Cu O_{-6}^{-10} cluster and possible local Jahn-Teller distorsions in the La-Ba-Cu-O superconductor

We present a density functional theory (DFT) calculation in the generalized gradient approximation to study the possibility for the existence of Jahn-Teller (JT) or pseudo Jahn-Teller (PJT) type local distortions in the La-Ba-Cu-O superconducting system. We performed the calculation and correspondingly group theory classification of the electronic ground state of the CuO${_{6}}^{-10}$ elongated octahedra cluster, immersed in a background simulating the superconductor. Part of the motivation to do this study is that the origin of the apical deformation of the CuO${_{6}}^{-10}$ cluster is not due to a pure JT effect, having therefore a non {\it a priori} condition to remove the degeneracy of the electronic ground state of the parent regular octahedron. We present a comparative analysis of the symmetry classified electron spectrum with previously reported results using unrestricted Hartree-Fock calculations (UHF). Both the DFT and UHF calculations produced a non degenerate electronic ground state, not having therefore the necessary condition for a pure JT effect. However, the appearance of a degenerate E$_{g}$ state near to the highest occupied molecular orbital in the DFT calculation, suggests the possibility for a PJT effect responsible for a local distortion of the oxidized CuO$_{6}^{-9}$ cluster.Comment: 12 pages, 3 figures, submitted to International Journal of Modern Physics B (IJMPB

Recommendations for vaccination in patients with multiple sclerosis who are eligible for immunosuppressive therapies: Spanish consensus statement

Esclerosis múltiple; Vacunación; ConsensoEsclerosi múltiple; Vacunació; ConsensMultiple sclerosis; Vaccination; ConsensusAntecedentes La reciente aparición de terapias de alta efectividad para el tratamiento de la esclerosis múltiple (EM), con potencial riesgo de complicaciones infecciosas, obliga plantear estrategias de prevención y minimización de riesgos. La vacunación constituye una parte esencial del manejo de estos pacientes. Este consenso recoge una serie de pautas y escenarios prácticos de vacunación en pacientes adultos con EM candidatos a tratamiento inmunosupresor. Metodología Se llevó a cabo un consenso de tipo formal. Tras definir el alcance del documento, se realizó una búsqueda bibliográfica de vacunación en pacientes con EM, así como guías de vacunación específicas de pacientes inmunosuprimidos y en tratamiento biológico con otras enfermedades. Para la formulación de las recomendaciones se empleó la metodología de Modified Nominal Group Technique. Desarrollo La vacunación en pacientes candidatos a tratamiento inmunosupresor se debe plantear antes de iniciar un tratamiento inmunosupresor siempre que la situación clínica del paciente lo permita. Se recomendarán tanto aquellas indicadas en el calendario vacunal del adulto, como algunas específicas, en función de la inmunidad previa. Si ya está instaurado el tratamiento inmunosupresor las vacunas vivas atenuadas estarán contraindicadas. Para aquellas vacunas que dispongan de un correlato de protección se recomienda monitorizar la respuesta serológica transcurridos de uno a 2 meses de la última dosis.Background The recent development of highly effective treatments for multiple sclerosis (MS) and the potential risk of infectious complications require the development of prevention and risk minimisation strategies. Vaccination is an essential element of the management of these patients. This consensus statement includes a series of recommendations and practical scenarios for the vaccination of adult patients with MS who are eligible for highly effective immunosuppressive treatments. Methodology A formal consensus procedure was followed. Having defined the scope of the statement, we conducted a literature search on recommendations for the vaccination of patients with MS and specific vaccination guidelines for immunosuppressed patients receiving biological therapy for other conditions. The modified nominal group technique methodology was used to formulate the recommendations. Development Vaccination in patients who are candidates for immunosuppressive therapy should be considered before starting immunosuppressive treatment providing the patient's clinical situation allows. Vaccines included in the routine adult vaccination schedule, as well as some specific ones, are recommended depending on the pre-existing immunity status. If immunosuppressive treatment is already established, live attenuated vaccines are contraindicated. For vaccines with a correlate of protection, it is recommended to monitor the serological response in an optimal interval of 1-2 months from the last dose

Epidemiology of pertussis in two Ibero-American countries with different vaccination policies: lessons derived from different surveillance systems

Background Pertussis is a re-emerging disease worldwide despite its high vaccination coverage. European and Latin-American countries have used different surveillance and vaccination policies against pertussis. We compared the epidemiology of this disease in two Ibero-American countries with different vaccination and surveillance policies. Methods We compared the epidemiology of pertussis in Spain and the Dominican Republic (DR). We present a 10-year observational study of reported pertussis based on suspected and/or probable cases of pertussis identified by the national mandatory reporting system in both countries between 2005 and 2014. Both countries have a similar case definition for pertussis surveillance, although Spain applies laboratory testing, and uses real time PCR and/or culture for case confirmation while in DR only probable and/or suspected cases are reported. We analyzed incidence, hospitalization, case-fatality rates, mortality and vaccination coverage. Results The average annual incidence in children aged <1 year was 3.40/100,000 population in Spain and 12.15/100,000 in DR (p = 0.01). While the incidence in DR was generally higher than in Spain, in 2011 it was six times higher in Spain than in DR. The highest infant mortality in Spain was 0.017/100,000 in 2011, and the highest in DR was 0.08/100,000 in 2014 (p = 0.01). The proportion of hospitalized cases per year among children <1 year varied between 22.0% and 93.7% in Spain, and between 1.1% and 29.4% in DR (p = 0.0002), while mortality varied from 0 to 0.017 and 0 to 0.08 per 100,000 population in Spain and DR, respectively (p = 0.001). Vaccination coverage was 96.5% in Spain and 82.2% in DR (p = 0.001). Conclusions Pertussis is a public health problem in both countries. Surveillance, prevention and control measures should be improved, especially in DR. Current vaccination programs are not sufficient for preventing continued pertussis transmission, even in Spain which has high vaccination coverag

Post-Translational Modifications Modulate Ligand Recognition by the Third PDZ Domain of the MAGUK Protein PSD-95

The relative promiscuity of hub proteins such as postsynaptic density protein-95 (PSD-95) can be achieved by alternative splicing, allosteric regulation, and post-translational modifications, the latter of which is the most efficient method of accelerating cellular responses to environmental changes in vivo. Here, a mutational approach was used to determine the impact of phosphorylation and succinimidation post-translational modifications on the binding affinity of the postsynaptic density protein-95/discs large/zonula occludens-1 (PDZ3) domain of PSD-95. Molecular dynamics simulations revealed that the binding affinity of this domain is influenced by an interplay between salt-bridges linking the α3 helix, the β2–β3 loop and the positively charged Lys residues in its high-affinity hexapeptide ligand KKETAV. The α3 helix is an extra structural element that is not present in other PDZ domains, which links PDZ3 with the following SH3 domain in the PSD-95 protein. This regulatory mechanism was confirmed experimentally via thermodynamic and NMR chemical shift perturbation analyses, discarding intra-domain long-range effects. Taken together, the results presented here reveal the molecular basis of the regulatory role of the α3 extra-element and the effects of post-translational modifications of PDZ3 on its binding affinity, both energetically and dynamically.This research was supported by grants CVI-05915, from the Andalusian Regional Government (http://www.juntadeandalucia.es), BIO2009-13261-C02 and BIO2012-39922-C02, from the Spanish Ministry of Science and Innovation (http://www.idi.mineco.gob.es/portal/site​/MICINN/) and FEDER. JMC received a postdoctoral contract from the Spanish Ministry of Science and Innovation. CCV was a recipient of a Formación de Personal Investigador fellowship from the Spanish Ministry of Science and Innovation

Factors related to abdominal pain in gastroparesis: contrast to patients with predominant nausea and vomiting

Background Factors associated with abdominal pain in gastroparesis are incompletely evaluated and comparisons of pain vs other symptoms are limited. This study related pain to clinical factors in gastroparesis and contrasted pain/discomfort‐ with nausea/vomiting‐predominant disease. Methods Clinical and scintigraphy data were compared in 393 patients from seven centers of the NIDDK Gastroparesis Clinical Research Consortium with moderate‐severe (Patient Assessment of Upper Gastrointestinal Disorders Symptoms [ PAGI ‐ SYM ] score ≥3) vs none‐mild ( PAGI ‐ SYM  < 3) upper abdominal pain and predominant pain/discomfort vs nausea/vomiting. Key Results Upper abdominal pain was moderate‐severe in 261 (66%). Pain/discomfort was predominant in 81 (21%); nausea/vomiting was predominant in 172 (44%). Moderate‐severe pain was more prevalent with idiopathic gastroparesis and with lack of infectious prodrome (P ≤ 0.05) and correlated with scores for nausea/vomiting, bloating, lower abdominal pain/discomfort, bowel disturbances, and opiate and antiemetic use (P < 0.05), but not gastric emptying or diabetic neuropathy or control. Gastroparesis severity, quality of life, and depression and anxiety were worse with moderate‐severe pain (P ≤ 0.008). Factors associated with moderate‐severe pain were similar in diabetic and idiopathic gastroparesis. Compared to predominant nausea/vomiting, predominant pain/discomfort was associated with impaired quality of life, greater opiate, and less antiemetic use (P < 0.01), but similar severity and gastric retention. Conclusions & Inferences Moderate‐severe abdominal pain is prevalent in gastroparesis, impairs quality of life, and is associated with idiopathic etiology, lack of infectious prodrome, and opiate use. Pain is predominant in one fifth of gastroparetics. Predominant pain has at least as great an impact on disease severity and quality of life as predominant nausea/vomiting.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97520/1/nmo12091.pd

Increased Glycemic Variability Is Independently Associated With Length of Stay and Mortality in Noncritically Ill Hospitalized Patients

OBJECTIVE To investigate the association between glycemic variability (GV) and both length of stay (LOS) and 90-day mortality in noncritically ill hospitalized patients. RESEARCH DESIGN AND METHODS This study retrospectively analyzed 4,262 admissions to the general medicine or surgery services during a 2 year period. Patients with point-of-care glucose monitoring and a minimum of two glucose values per day on average were selected. GV was assessed by SD and coefficient of variation (CV). Data were analyzed with linear and logistic multivariate regression analysis in separate models for SD and CV. Analysis was performed with generalized estimating equations to adjust for correlation between multiple admissions in some individual cases. RESULTS After exclusions, 935 admissions comprised the sample. Results of adjusted analysis indicate that for every 10 mg/dL increase in SD and 10–percentage point increase in CV, LOS increased by 4.4 and 9.7%, respectively. Relative risk of death in 90 days also increased by 8% for every 10-mg/dL increase in SD. These associations were independent of age, race, service of care (medicine or surgery), previous diagnosis of diabetes, HbA1c, BMI, the use of regular insulin as a sole regimen, mean glucose, and hypoglycemia occurrence during the hospitalization. CONCLUSIONS Our results indicate that increased GV during hospitalization is independently associated with longer LOS and increased mortality in noncritically ill patients. Prospective studies with continuous glucose monitoring are necessary to investigate this association thoroughly and to generate therapeutic strategies targeted at decreasing GV. Inpatient hyperglycemia is common, and it has been associated with increased morbidity and mortality in patients with and without diabetes (1–7). In the intensive care unit (ICU) setting, hypoglycemia has also been independently associated with a significant increase in mortality (8–10). Recently, a third metric of glucose control, known as glycemic variability (GV), has been proposed to be additionally implicated in the disease-associated process of dysglycemia (11). GV refers to fluctuations of blood glucose values around the mean and has been posited as a novel marker for poor glycemic control (12,13). In vitro and human studies suggest that high GV leads to greater oxidative stress than does sustained hyperglycemia (14,15). Studies of ICU patients have consistently demonstrated that increased GV is independently associated with higher mortality (16–19). Notably, results from a large multicenter study concluded that GV was a stronger predictor of ICU mortality than was mean glucose concentrations (20). Although there is no consensus as to the best method to determine GV in hospitalized patients, the use of SD of glucose values has been well validated by previous ICU studies (16,20). Coefficient of variation (CV) has also been suggested as a strong independent index for measuring GV because it corrects for mean glucose levels (21,22). Despite substantial scientific evidence from the ICU, no previous studies have investigated the association between GV and clinical outcomes in patients admitted to the general medical and surgical wards. The purpose of this study was therefore to investigate the association between GV and length of stay (LOS) and 90-day mortality in noncritically ill hospitalized patients. We hypothesize that increased GV in this setting is associated with increased LOS and mortality