Ultrasound-assisted diastereoselective green synthesis of spiro-fused-γ-lactams functionalized with an amide bond heterocyclic bioisostere via the Ugi azide/domino process coupled strategy.

A series of linked-type 1,5-disubstituted tetrazoles (1,5-DS-Ts) were synthesised via an isocyanide-based multicomponent reaction (IMCR) and used as synthetic platforms to access bound-type polyheterocycles containing an epoxyisoindol-1(6H)-one scaffold under green conditions. This rapid sonochemical synthetic strategy includes a double domino process using an orthogonal heterocyclic input in the Ugi-azide (UA) reaction. DFT calculations and NBO analysis were performed to understand the pseudopericyclic reaction involved in the 1,5-electrocyclization of the UA mechanism.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Magnetic separation and concentration of Aß 1-42 molecules dispersed at the threshold concentration for Alzheimer's disease diagnosis in clinically-relevant volumes of sample.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia and loss of autonomy in the elderly, implying a progressive cognitive decline and limitation of social activities. The progressive aging of the population is expected to exacerbate this problem in the next decades. Therefore, there is an urgent need to develop quantitative diagnostic methodologies to assess the onset the disease and its progression especially in the initial phases. RESULTS: Here we describe a novel technology to extract one of the most important molecular biomarkers of AD (Aß1-42) from a clinically-relevant volume - 100 µl - therein dispersed in a range of concentrations critical for AD early diagnosis. We demonstrate that it is possible to immunocapture Aß1-42 on 20 nm wide magnetic nanoparticles functionalized with hyperbranced KVLFF aptamers. Then, it is possible to transport them through microfluidic environments to a detection system where virtually all (~ 90%) the Aß1-42 molecules are concentrated in a dense plug of ca.50 nl. The technology is based on magnetic actuation by permanent magnets, specifically designed to generate high gradient magnetic fields. These fields, applied through submillimeter-wide channels, can concentrate, and confine magnetic nanoparticles (MNPs) into a droplet with an optimized shape that maximizes the probability of capturing highly diluted molecular biomarkers. These advancements are expected to provide efficient protocols for the concentration and manipulation of molecular biomarkers from clinical samples, enhancing the accuracy and the sensitivity of diagnostic technologies. CONCLUSIONS: This easy to automate technology allows an efficient separation of AD molecular biomarkers from volumes of biological solutions complying with the current clinical protocols and, ultimately, leads to accurate measurements of biomarkers. The technology paves a new way for a quantitative AD diagnosis at the earliest stage and it is also adaptable for the biomarker analysis of other pathologies.

Role of Dipolar Interactions on the Determination of the Effective Magnetic Anisotropy in Iron Oxide Nanoparticles.

Challenging magnetic hyperthermia (MH) applications of immobilized magnetic nanoparticles require detailed knowledge of the effective anisotropy constant (Keff ) to maximize heat release. Designing optimal MH experiments entails the precise determination of magnetic properties, which are, however, affected by the unavoidable concurrence of magnetic interactions in common experimental conditions. In this work, a mean-field energy barrier model (ΔE), accounting for anisotropy (EA ) and magnetic dipolar (ED ) energy, is proposed and used in combination with AC measurements to a specifically developed model system of spherical magnetic nanoparticles with well-controlled silica shells, acting as a spacer between the magnetic cores. This approach makes it possible to experimentally demonstrate the mean field dipolar interaction energy prediction with the interparticle distance, dij , ED ≈ 1/dij 3 and obtain the EA as the asymptotic limit for very large dij . In doing so, Keff uncoupled from interaction contributions is obtained for the model system (iron oxide cores with average sizes of 8.1, 10.2, and 15.3 nm) revealing to be 48, 23, and 11 kJ m-3 , respectively, close to bulk magnetite/maghemite values and independent from the specific spacing shell thicknesses selected for the study.

Significant Surface Spin Effects and Exchange Bias in Iron Oxide-Based Hollow Magnetic Nanoparticles.

Exchange bias (EB) properties have become especially important in hollow magnetic nanoparticles (MNPs) due to the versatility and reduced size of these materials. In this work, we present the synthesis and study of the EB properties of iron-oxide-based hollow MNPs and their precursors Fe/iron oxide MNPs with core/void/shell structure. The two mechanisms involved in EB generation were investigated: the frozen spins present in the nanograins that form the nanoparticles and the surface spins. The effect of external parameters on the coercivity (HC), remanence (MR), exchange bias field (HEB) and frozen spins, such as cooling field (HFC) and temperature, was investigated. Both HC and HEB present a maximum threshold above which their values begin to decrease with HFC, showing a new trend of HEB with HFC and allowing modulation on demand. The existence of surface spins, present on the outer and inner surfaces, was demonstrated, and an intrinsic EB phenomenon (HEB = 444 Oe for hollow iron oxide-based MNPs of 13.1 nm) with significant magnetization (MS~50 emu/g) was obtained. Finally, core/void/shell MNPs of 11.9 nm prior to the formation of the hollow MNPs showed a similar behavior, with non-negligible HEB, highlighting the importance of surface spins in EB generation.

Linfoma de Hodgkin anal primario y tumor neuroendocrino intestinal sincrónicos: a propósito de un caso y revisión de la literatura / Primary rectal Hodgkin's lymphoma and synchronous small bowel neuroendocrine tumor: Case report and literature review

Resumen La localización extranodal gastrointestinal del linfoma de Hodgkin comprende el 5% de todos los linfomas. Dentro de este grupo, el linfoma anal primario representa menos del 0,05%, siendo por tanto una entidad extremadamente rara. Por otro lado, los tumores neuroendocrinos son un grupo heterogéneo de neoplasias relativamente poco frecuentes, pero de localización fundamentalmente digestiva. La asociación entre un linfoma de Hodgkin de localización anal y un tumor neuroendocrino intestinal no ha sido descrita previamente en la literatura, pero no es en absoluto raro que los tumores neuroendocrinos puedan coexistir con otro tipo de neoplasias. Los autores presentan el caso infrecuente de presentación de linfoma Hodgkin de localización anal asociado a un tumor neuroendocrino intestinal en una paciente mujer de 74 años, describiéndose la clínica, resultados de pruebas complementarias y tratamiento recibido.

Abstract Extranodal gastrointestinal Hodgkin's lymphoma comprises 5% of all lymphomas. In this group, primary rectal lymphoma represents less than 0.05%; thus, it is an extremely rare entity. On the other hand, neuroendocrine tumors are a heterogeneous group of infrequent neoplasms, mainly of digestive location. The association between a rectal Hodgkin's lymphoma and an intestinal neuroendocrine tumor has not been previously described in the literature, but it is not at all uncommon for neuroendocrine tumors to coexist with other types of neoplasms. The authors present a rare case of rectal Hodgkin's lymphoma associated with an intestinal neuroendocrine tumor in a 74-year-old female patient, describing the symptoms, complementary test results, and treatment.

Protective Role of Flavonoids against Intestinal Pro-Inflammatory Effects of Silver Nanoparticles.

Silver nanoparticles (AgNP) have been increasingly incorporated into food-related and hygiene products for their unique antimicrobial and preservative properties. The consequent oral exposure may then result in unpredicted harmful effects in the gastrointestinal tract (GIT), which should be considered in the risk assessment and risk management of these materials. In the present study, the toxic effects of polyethyleneimine (PEI)-coated AgNP (4 and 19 nm) were evaluated in GIT-relevant cells (Caco-2 cell line as a model of human intestinal cells, and neutrophils as a model of the intestinal inflammatory response). This study also evaluated the putative protective action of dietary flavonoids against such harmful effects. The obtained results showed that AgNP of 4 and 19 nm effectively induced Caco-2 cell death by apoptosis with concomitant production of nitric oxide, irrespective of the size. It was also observed that AgNP induced human neutrophil oxidative burst. Interestingly, some flavonoids, namely quercetin and quercetagetin, prevented the deleterious effects of AgNP in both cell types. Overall, the data of the present study provide a first insight into the promising protective role of flavonoids against the potentially toxic effects of AgNP at the intestinal level.

Synthesis of Polyheterocyclic Dimers Containing Restricted and Constrained Peptidomimetics via IMCR-Based Domino/Double CuAAC Click Strategy.

A novel strategy via the triple process (multicomponent reactions (MCR)-domino)/tandem was developed for the synthesis of restricted and constrained bis-1,2,3-triazole-linked pyrrolo[3,4-b]pyridine peptidomimetics dimers in overall yields of 20-55%. This strategy allows the construction of six heterocycles in two stages of the reaction.

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy.

6-Triazolylmethyl-pyrrolo[3,4-b]pyridin-5-one tris-heterocycles were synthesized in 43-57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1H-1,2,3-triazoles and pyrrolo[3,4-b]pyridin-5-ones.

Comparison of Clinical Outcomes in Surgical Patients Subjected to CIPA Nutrition Screening and Treatment versus Standard Care.

Malnutrition is prevalent in surgical patients and leads to comorbidities and a poorer postoperative course. There are no studies that compare the clinical outcomes of implementing a nutrition screening tool in surgical patients with standard clinical practice. An open, non-randomized, controlled study was conducted in general and digestive surgical hospitalized patients, who were either assigned to standard clinical care or to nutrition screening using the Control of Food Intake, Protein, and Anthropometry (CIPA) tool and an associated treatment protocol (n = 210 and 202, respectively). Length of stay, mortality, readmissions, in-hospital complications, transfers to critical care units, and reinterventions were evaluated. Patients in the CIPA group had a higher Charlson index on admission and underwent more oncological and hepatobiliary-pancreatic surgeries. Although not significant, a shorter mean length of stay was observed in the CIPA group (-1.48 days; p < 0.246). There were also fewer cases of exitus (seven vs. one) and fewer transfers to critical care units in this group (p = 0.068 for both). No differences were detected in other clinical variables. In conclusion, patients subjected to CIPA nutrition screening and treatment showed better clinical outcomes than those receiving usual clinical care. The results were not statistically significant, possibly due to the heterogeneity across patient groups.

An efficient Ugi-3CR/aza Diels-Alder/Pomeranz-Fritsch protocol towards novel aza-analogues of (±)-nuevamine, (±)-lennoxamine and magallanesine: a diversity oriented synthesis approach.

A rapid and efficient synthesis of a series of (±)-nuevamine, (±)-lennoxamine and magallanesine aza analogues is described. The synthetic strategy involves Ugi-3CR and two further condensation processes, aza-Diels-Alder cycloaddition and the Pomeranz-Fritsch reaction. The variation of the chain-size in aldehyde moieties provided structural diversity in only two operational reaction steps.

Rationale and design of a randomised controlled trial evaluating the effectiveness of an exercise program to improve the quality of life of patients with heart failure in primary care: The EFICAR study protocol.

BACKGROUND: Quality of life (QoL) decreases as heart failure worsens, which is one of the greatest worries of these patients. Physical exercise has been shown to be safe for people with heart failure. Previous studies have tested heterogeneous exercise programs using different QoL instruments and reported inconsistent effects on QoL. The aim of this study is to evaluate the effectiveness of a new exercise program for people with heart failure (EFICAR), additional to the recommended optimal treatment in primary care, to improve QoL, functional capacity and control of cardiovascular risk factors. METHODS/DESIGN: Multicenter clinical trial in which 600 patients with heart failure in NYHA class II-IV will be randomized to two parallel groups: EFICAR and control. After being recruited, through the reference cardiology services, in six health centres from the Spanish Primary Care Prevention and Health Promotion Research Network (redIAPP), patients are followed for 1 year after the beginning of the intervention. Both groups receive the optimized treatment according to the European Society of Cardiology guidelines. In addition, the EFICAR group performs a 3 month supervised progressive exercise program with an aerobic (high-intensity intervals) and a strength component; and the programme continues linked with community resources for 9 months. The main outcome measure is the change in health-related QoL measured by the SF-36 and the Minnesota Living with Heart Failure Questionnaires at baseline, 3, 6 and 12 months. Secondary outcomes considered are changes in functional capacity measured by the 6-Minute Walking Test, cardiac structure (B-type natriuretic peptides), muscle strength and body composition. Both groups will be compared on an intention to treat basis, using multi-level longitudinal mixed models. Sex, age, social class, co-morbidity and cardiovascular risk factors will be considered as potential confounding and predictor variables. DISCUSSION: A key challenges of this study is to guarantee the safety of the patients; however, the current scientific evidence supports the notion of there being no increase in the risk of decompensation, cardiac events, hospitalizations and deaths associated with exercise, but rather the opposite. Safety assurance will be based on an optimized standardised pharmacological therapy and health education for all the participants. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01033591.

Brain Ag-NOR activity in cholestatic rats with hepatic encephalopathy.

The serious repercussions of cholestasis in the liver and other organic systems have led to the creation of many experimental models in efforts to understand better its pathogenesis, prophylaxis and treatment. The extrahepatic cholestasis produces an encephalopathy by the deposition of neurotoxins in the brain similar to alcoholic and other hepatic encephalopathies. This work was designed to assess the effects of cholestasis and hepatic encephalopathy on argyrophilic nucleolar organiser region (Ag-NOR) activity in the hippocampus and inferotemporal cortex (INF). Twenty-eight male Wistar rats were used and the parameters evaluated were the area of nucleus, the area of Ag-NORs, the number of Ag-NORs per cell and the ratio of the area of Ag-NORs to that of the nucleus. The results show that cholestasis decreased neuronal synthetic activity significantly and affected the nuclear cytoarchitecture in the hippocampus and the INF.

Efecto de la rehabilitación cardiaca en pacientes isquémicos no sometidos a revascularización coronaria / Cardiac rehabilitation in ischemic patients rejected for coronary by-pass surgery

Se realizó un programa de rehabilitación cardiaca (RC) en 65 pacientes con cardiopatía isquémica (CI), rechazados para tratamiento de derivación arterial coronaria (DAC) y angioplastia coronaria transluminal percutánea (ACTP) con seguimiento de 16 ñ 2 meses. Se trata de 63 varones (96.9 por ciento) y 2 mujeres (3.0 por ciento) con edad promedio de 54.5 + 8.7 años. Los factores de riesgo (FR) son: tabaquismo en 25 pacientes (38.4 por ciento), hipercolesterolemia en 47 (72.3 por ciento), hipertensión arterial en 33 (50.7 por ciento), diabetes mellitus en 30 (46.1 por ciento), infarto del miocardio en 56 (86.1 por ciento), lesiones coronarias de 1 vaso en 16 (25.5 por ciento), de 2 vasos en 25 (38.3 por ciento) y de 3 vasos en 24 (36.1 por ciento), fracción de expulsión (FE) < 50 por ciento en 26 pacientes (40 por ciento). Se evaluaron número de vasos lesionados, FE y edad. Un paciente falleció, 52 permanecieron asintomáticos (80 por ciento), 10 presentaban angina estable (15.3 por ciento) y 3 angina inestable (4.6 por ciento). El tabaquismo disminuyó un 92 por ciento, la hipertensión se controló en 42.2 por ciento, la hipercolesterolemia en 82.9 por ciento p < 0.05, la hipertrigliceridemia en 53 por ciento p < 0.05, el consumo de O2 (VO2) y el pulso de O2 (PO2) mejoraron en el 64.6 por ciento de los pacientes, p = .001 y .01 respectivamente. La RC es una buena alternativa para mejorar la calidad de vida de pacientes fuera de la posibilidad de revascularización coronaria.