Effect of anaesthetic maintenance with isoflurane or propofol on ease of endoscopic duodenal intubation in dogs.

OBJECTIVE: To compare the ease of endoscopic duodenal intubation (EDI) in dogs during maintenance of general anaesthesia with isoflurane or propofol infusion. STUDY DESIGN: Prospective, randomized, partially blinded clinical trial. ANIMALS: A total of 22 dogs undergoing upper gastrointestinal tract endoscopy to include EDI were recruited. METHODS: Dogs were randomly assigned isoflurane (ISO; n = 10) or propofol (PROP; n = 11) for maintenance of general anaesthesia. Following anaesthetic premedication with intramuscular medetomidine (0.005 mg kg-1) and butorphanol (0.2 mg kg-1), general anaesthesia was induced with propofol, to effect, maintained with 1.5% (vaporizer setting) isoflurane in 100% oxygen or 0.2 mg kg-1 minute-1 propofol. The dose of both agents was adjusted to maintain general anaesthesia adequate for the procedure. Degree of sedation 20 minutes post-anaesthetic premedication, propofol induction dose, anaesthetist and endoscopist training grade, animal's response to endoscopy, presence of gastro-oesophageal and duodenal-gastric reflux, spontaneous opening of the lower oesophageal and pyloric sphincters, antral movement and time to achieve EDI were recorded. EDI was scored 1 (immediate entry with minimal manoeuvring) to 4 (no entry after 120 seconds) by the endoscopist, blinded to the agent in use. Data were tested for normality (Shapiro-Wilk test) and differences between groups analysed using independent t test, Mann-Whitney U test and Fisher's exact test as appropriate. RESULTS: There were no significant differences between groups for EDI score [median (interquartile range): 2 (3) ISO, 2 (3) PROP] or time to achieve EDI [mean ± standard deviation: 52.50 ± 107.00 seconds (ISO), 70.00 ± 196.00 seconds (PROP)]. Significantly more dogs responded to passage of the endoscope into the oesophagus in group PROP compared with group ISO (p = 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Maintenance of general anaesthesia with either isoflurane or propofol did not affect EDI score or time to achieve EDI.

Desigualdades en salud en mortalidad perinatal durante el Plan Decenal de Salud Pública 2012-2021. Cauca, Colombia

Objetivo: identificar desigualdades en salud asociadas a la mortalidad perinatal durante el Plan Decenal de Salud Pública 2012-2021 en los 42 municipios del Departamento de Cauca Colombia. Métodos: estudio ecológico que abordó el periodo 2012-2021 a partir de datos de fuentes secundarias procedentes del Departamento Administrativo Nacional de Estadística. La población de estudio fueron mujeres entre los 12 y 49 años residentes en Cauca. Se calcularon desigualdades por rangos y modelos de regresión de acuerdo con el Índice de Desigualdad de la Pendiente, el Índice de Desigualdad Relativa y el Índice de Concentración. Resultados: 42 municipios reportaron 3 110 muertes perinatales. La edad media de las mujeres afectadas fue de 25,3 años con predominio del grupo de 20 a 24 años. La región Pacifico reportó la mayor tasa de mortalidad. La pertenencia étnica, el analfabetismo y el Índice de Pobreza Multidimensional, se asociaron estadísticamente con la mortalidad. Se observó una desigualdad más pronunciada en la tasa de mortalidad perinatal en los municipios con condiciones socioeconómicas más desfavorables. Conclusiones: a pesar de la operacionalización del Plan Decenal de Salud Pública, la mortalidad perinatal en el Cauca continúa siendo un reto en el proceso salud/enfermedad. Existe disparidad en la mortalidad perinatal en relación con el nivel socioeconómico; aunque se ha observado disminución en la desigualdad en el transcurso de los años, aún persisten brechas significativas. Los hallazgos subrayan la necesidad de monitorear y dar cuenta de las desigualdades en salud al diseñar, implementar y evaluar las políticas públicas de prevención de la mortalidad perinatal.

Objective: to identify health inequalities associated with perinatal mortality during the Ten-Year Public Health Plan 2012-2021 in the 42 municipalities of the Department of Cauca, Colombia. Methods: ecological study that addressed the period 2012 - 2021 based on data from secondary sources from the National Administrative Department of Statistics. The study population was women between 12 and 49 years of age residing in Cauca. Rank inequalities and regression models were calculated according to the Slope Inequality Index, the Relative Inequality Index and the Concentration Index. Results: 42 municipalities reported 3 110 perinatal deaths. The mean age of the affected women was 25,3 years with a predominance of the 20-24 years age group. The Pacific region reported the highest mortality rate. Ethnicity, illiteracy and the Multidimensional Poverty Index were statistically associated with mortality. There was greater inequality in perinatal mortality in municipalities with worse socioeconomic status. Conclusions: despite the operationalization of the Ten-Year Public Health Plan, perinatal mortality in Cauca continues to be a challenge in the health/disease process. There is disparity in perinatal mortality in relation to socioeconomic level, and although a decrease in inequality has been observed over the years, significant gaps still persist. The findings underscore the need to monitor and account for health inequalities in the design, implementation and evaluation of public policies to prevent perinatal mortality.

Efecto de la Rehabilitación Cardiovascular basada en Ejercicio en Fase de Mantención sobre Fitness Cardiorrespiratorio en Adultos con Enfermedad Cardiovascular. Revisión Sistemática / Effect of Exercise-based Cardiovascular Rehabilitation in the Maintenance Phase on Cardiorespiratory Fitness in Adults with Cardiovascular Disease, a Systematic Review

Introducción. La enfermedad cardiovascular constituye la primera causa de morbimortalidad a nivel mundial. La rehabilitación cardiovascular basada en ejercicio surge como herramienta eficaz para controlar factores de riesgo cardiovascular y mejorar determinantes de salud como el fitness cardiorrespiratorio, sin embargo, no existen revisiones actualizadas que indiquen el efecto de la fase de mantención de rehabilitación cardiovascular sobre esta variable. Objetivo. Determinar el efecto de la rehabilitación cardiovascular basada en ejercicio en fase de mantención sobre el fitness cardiorrespiratorio en adultos con enfermedad cardiovascular. Método. Se realizó la búsqueda de estudios a través de PubMed, Google Scholar y Web of Science desde el año 2010 hasta agosto de 2021. Se seleccionaron estudios que incluyeran individuos adultos de ambos sexos y cualquier raza con enfermedad cardiovascular, que analicen el efecto de la rehabilitación cardiovascular basada en ejercicio en fase de mantención sobre el fitness cardiorrespiratorio. La calidad metodológica se evaluó a través de la escala PEDro a través de dos revisores. Se analizaron de manera cualitativa variables secundarias como calidad de vida, antropometría y perfil lipídico y nivel de actividad física. Resultados. La búsqueda arrojó 541 resultados, de los cuales se seleccionaron 8 estudios. La edad promedio de los individuos fue 60,7±9,5 años, la mayoría de los ensayos incluyen individuos con cardiopatía coronaria. Los resultados muestran la mantención o mejora del fitness cardiorrespiratorio y la mantención de calidad de vida, antropometría y perfil lipídico y nivel de actividad física. La calidad de los estudios con escala PEDro fue en 6,18/10 en promedio de dos evaluadores. Conclusión. La rehabilitación cardiovascular basada en ejercicio en fase de mantención logra mantener o mejorar el fitness cardiorrespiratorio en adultos con enfermedad cardiovascular.

Background. Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Exercise-based cardiovascular rehabilitation emerges as an effective tool to control cardiovascular risk factors and improve health determinants such as cardiorespiratory fitness, however, there are no updated reviews that indicate the effect of the maintenance phase of cardiovascular rehabilitation on this variable. Objective. To determine the effect of exercise-based cardiovascular rehabilitation in the maintenance phase on cardiorespiratory fitness in adults with cardiovascular disease. Method. The search for studies was carried out through PubMed, Google Scholar and Web of Science from 2010 to August 2021. Studies selected included adult individuals of both sexes and any race with cardiovascular disease, which analyzed the effect of cardiovascular rehabilitation based on maintenance phase exercise on cardiorespiratory fitness. The methodological quality was evaluated through the PEDro scale through two reviewers. Secondary variables such as quality of life, anthropometry and lipid profile, and level of physical activity were analyzed qualitatively. Results. The search yielded 541 results, of which 8 studies were selected. The average age of the individuals was 60.7±9.5 years, most trials include individuals with coronary heart disease. The results show the maintenance or improvement of cardiorespiratory fitness and the maintenance of quality of life, anthropometry and lipid profile and level of physical activity. The quality of the studies with the PEDro scale was 6.18/10 on average of two evaluators Conclusion. Cardiovascular rehabilitation based on exercise in the maintenance phase manages to maintain or improve cardiorespiratory fitness in adults with cardiovascular disease.

Real world comparison of spironolactone and eplerenone in patients with heart failure.

AIMS: In the absence of previous direct comparative studies, we aimed to evaluate the effectiveness of spironolactone and eplerenone in patients with heart failure and reduced ejection fraction (HFrEF) in a real-world clinical setting. METHODS: Using Fine-Gray´s competing risk regression, we compared the clinical outcomes of 293 patients with chronic HF and left ventricular ejection fraction <40% treated with eplerenone and 293 propensity-score matched individuals treated with spironolactone. Study subjects were selected from a prospective cohort of 1404 ambulatory patients with HFrEF seen since 2010 to 2019 in a single specialized HF clinic, among which 992 received a mineralocorticoid receptor antagonist at baseline. Median follow-up was 3.95 years. RESULTS: No statistically significant differences between patients treated with eplerenone versus spironolactone were observed with regard to the risk of the primary composite end-point cardiovascular death or HF hospitalization (HR 0.95; 95% CI 0.73-1.23; p= 0.677). However, eplerenone use was associated to lower cardiovascular mortality (HR 0.55; 95% CI 0.35-0.85; p= 0.008) and lower all-cause mortality (HR 0.67; 95% CI 0.47-0.95; p= 0.027). The incidence of drug suspension due to side effects (HR 0.58, 95% CI 0.40-0.85; p= 0.005) and drug suspension due to any reason (HR 0.70, 95% CI 0.51-0.97; p= 0.033) were lower among patients treated with eplerenone. CONCLUSIONS: In this observational, real-world, propensity-score matched study of patients with HFrEF, eplerenone was associated to lower cardiovascular mortality and lower all-cause mortality than spironolactone.

Rationale and design of the pragmatic clinical trial tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT).

AIMS: There is a lack of evidence regarding the benefits of ß-blocker treatment after invasively managed acute myocardial infarction (MI) without reduced left ventricular ejection fraction (LVEF). METHODS AND RESULTS: The tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT) trial is a pragmatic, controlled, prospective, randomized, open-label blinded endpoint (PROBE design) clinical trial testing the benefits of ß-blocker maintenance therapy in patients discharged after MI with or without ST-segment elevation. Patients eligible for participation are those managed invasively during index hospitalization (coronary angiography), with LVEF >40%, and no history of heart failure (HF). At discharge, patients will be randomized 1:1 to ß-blocker therapy (agent and dose according to treating physician) or no ß-blocker therapy. The primary endpoint is a composite of all-cause death, non-fatal reinfarction, or HF hospitalization over a median follow-up period of 2.75 years (minimum 2 years, maximum 3 years). Key secondary endpoints include the incidence of the individual components of the primary composite endpoint, the incidence of cardiac death, and incidence of malignant ventricular arrhythmias or resuscitated cardiac arrest. The primary endpoint will be analysed according to the intention-to-treat principle. CONCLUSION: The REBOOT trial will provide robust evidence to guide the prescription of ß-blockers to patients discharged after MI without reduced LVEF.

Differences in the Clinical Profile and Management of Atrial Fibrillation According to Gender. Results of the REgistro GallEgo Intercéntrico de Fibrilación Auricular (REGUEIFA) Trial.

To analyze the clinical profile and therapeutic strategy in atrial fibrillation (AF) according to gender in a contemporaneous patient cohort a prospective, multicenter observational study was performed on consecutive patients diagnosed with AF and assessed by cardiology units in the region of Galicia (Spain). A total of 1007 patients were included, of which 32.3% were women. The mean age of the women was significantly greater than that of the men (71.6 versus 65.7 years; p < 0.001), with a higher prevalence of hypertension (HTN) and valve disease. Women more often reported symptoms related to arrhythmia (28.2% in EHRA class I versus 36.4% in men), with a poorer level of symptoms (EHRA classes IIb and III). Thromboembolic risk was significantly higher among women (CHA2DS2-VASc 3 ± 1.3 versus 2 ± 1.5), in the same way as bleeding risk (HAS-BLED 0.83 ± 0.78 versus 0.64 ± 0.78) (p < 0.001), and women more often received anticoagulation therapy (94.1% versus 87.6%; p = 0.001). Rhythm control strategies proved significantly less frequent in women (55.8% versus 66.6%; p = 0.001), with a lesser electrical cardioversion (ECV) rate (18.4% versus 27.3%; p = 0.002). Perceived health status was poorer in women. Women were older and presented greater comorbidity than men, with a greater thromboembolic and bleeding risk. Likewise, rhythm control strategies were less frequent than in men, despite the fact that women had poorer perceived quality of life and were more symptomatic.

Ultrasound-guided erector spinae plane block in horses: a cadaver study.

OBJECTIVES: To describe dye distribution and spinal nerve involvement after a simulated erector spinae plane (ESP) block performed on fresh equine cadavers. STUDY DESIGN: Experimental cadaver study. ANIMALS: A group of 11 adult equine cadavers. METHODS: The spinal region surrounding the sixteenth thoracic vertebra (Th16) of one cadaver was removed and underwent magnetic resonance imaging. In 10 adult equine cadavers [body weight, 549 ± 58 kg (mean ± standard deviation)], 0.2 mL kg-1 of a 50:1 2% lidocaine/dye solution was injected bilaterally (n = 20 injections) into the fascial plane between the transverse process of Th16 and the erector spinae muscles. An in-plane ultrasound-guided technique with a convex transducer was used to guide injection. Dissection was performed immediately following injection. The craniocaudal and lateral extent of dye distribution was measured (cm) and the number of vertebral bodies involved were counted (n = 20). Abdominal and thoracic cavities as well as the epidural space were also examined for presence of dye (yes/no) (n = 20). Further dissection was performed to evaluate if staining of the dorsal and ventral rami of the spinal nerves and sympathetic chain occurred (n = 14). RESULTS: The thoracolumbar fascia was stained in 17/20 (85%) injections and three injections terminated intramuscularly. Multisegmental staining of the dorsal rami was observed in the 14 injections in which staining was evaluated. Ventral rami staining was observed in 3/14 injections where staining was evaluated. Epidural migration was observed in 4/20 (20%) injections. No evidence of dye was found in the thoracic and abdominal cavities or on the sympathetic chain. CONCLUSIONS AND CLINICAL RELEVANCE: The ESP block may prove beneficial to desensitize structures innervated by the dorsal rami of the thoracic spinal nerves. Further investigation is necessary to evaluate complications caused by epidural contamination.

Hiperplasia endometrial simple con complejo focal y sin atipia, en una paciente de 23 años de edad. A propósito de un caso y revisión de la literatura / Simple endometrial hyperplasia with focal complex without atypia, in a patient of 23 years old. A case presentation and literature review

Resumen Se presenta el caso de una paciente de 23 años de edad, previamente sana, G1P0A1, con cuadro clínico de hemorragia uterina anormal, a quien se le realizó ecografía transvaginal que reportó embarazo molar, sin embargo tras realizar la medición sérica de B-HCG, fue de 0.00 mUI/ml, por lo que requirió realización de legrado y biopsia para establecer diagnóstico histológico. El resultado evidenció hiperplasia simple, con complejo focal y sin atipia. Se destaca la importancia de la comunicación de este caso, debido a que a esta edad, la presentación de esta patología es infrecuente. Se hace una revisión de los artículos publicados en los últimos 10 años en las bases de datos Medline vía PubMed, y en LILACS en español, inglés y francés. Se tuvo como referencia además textos clásicos. La hiperplasia endometrial simple en pacientes menores de 30 años es poco frecuente, se debe tener en cuenta la presencia de atipias en la histología pues de ser positivo, es mayor el riesgo de transformación maligna.

Abstract A case of a 23-year-old patient, previously healthy, G1P0A1, with clinical symptoms of abnormal uterine bleeding. The patient was underwent transvaginal ultrasound that reported molar pregnancy, however after making the measurement of serum B-HCG was 0.00 mIU/ml. It was necessary curettage and biopsy to establish histological diagnosis. The result showed simple hyperplasia endometrial with focal complex without atypia. The importance of communication in this case, because at this age, the presentation of this disease is uncommon. The literature published in English, Spanish and French during the last 10 years in the Medline database were reviewed via Pubmed and LILACS. Besides, classical texts was referenced in this article. Simple endometrial hyperplasia in patients under 30 years old is rare. It should be taken into account the presence of atypia on histology, because the risk is greater of malignant transformation.

1,3,5-Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu2/3 Receptors.

The metabotropic glutamate subtype 2 (mGlu2 ) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2 receptor function with a negative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high-throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu2 NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu2 receptor occupancy. Finally, to obtain improved drug-like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency.

Percutaneous Isolated Hepatic Perfusion: Hemodynamic Monitoring and Goal-Directed Anesthetic Management: A Case Report.

The percutaneous isolated hepatic perfusion utilizes a venovenous bypass to administer high-dose chemotherapy exclusively in the liver, getting depurated through a hemofilter before returning to the systemic circulation. The hepatic perfusion is managed under general anesthesia and invasive monitoring as a result of very abrupt changes in venous return and vascular resistances because of the isolation of the hepatic territory and absorption of circulating catecholamines by the hemofilter. We report a case in which we describe the technique, physiologic implications, anesthetic, and goal-directed hemodynamic management for this procedure.

Factors associated with length of hospital stay in minor and moderate burns at Popayan, Colombia. Analysis of a cohort study.

OBJECTIVE: To determine the independent contribution of prognostic factors to length of hospital stay of minor and moderate burn victims at the Hospital Universitario San José (HUSJ), Popayán, Colombia, 2000-2010. METHODS: This was a retrospective cohort study of minor and moderate burn victims admitted between 2000 and 2010, at the burn unit (HUSJ). This is a further analysis of a same cohort previously published in Burns. The following variables were recorded and analyzed: age, gender, origin, depth and extent of burn, causal agent, length of hospital stay and mortality. The main outcome under study was length of stay. Survival analysis was done to explore the association of covariates and length of hospital stay and Cox regression model to adjust the effect of covariates in the outcome. RESULTS: During the study period 2000-2010, 842 of 921 (91.5%) patients treated at the Burn Unit of HUSJ that had complete data were included. There were 520 (61.8%) males and 322 (38.2%) females with a male to female ratio of 1.6:1. Their median age was 9 years (IQR 3-28). The median of percent total body surface area burned (TBSA) was 12% (IQR 7-21) and the most common degree of burn was 2nd degree with 58% (488 patients). There were 12 deaths (censored data) and 830 patients were discharged alive. After multivariate adjustment, significant associations with length of hospital stay remained for age group, burn degree and extension of the burn. The strongest relationship found was for burn degree (2nd degree superficial vs. 3rd degree hazard ratio=2.66 CI 95% [2.13-3.33]). CONCLUSIONS: In patients admitted with mild and moderate burns at HUSJ, the main predictors of length of stay were age, burn degree and extension of the burn.

Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms.

BACKGROUND: There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms. METHODS: Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water. RESULTS: PCS rats show increased IL-1ß and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1ß and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning. CONCLUSIONS: Increased IL-1ß alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.

1,4-Oxazine ß-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aß levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

A Versatile Approach to CF3 -Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors.

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent ß-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.

Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

Prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients without coronary artery disease.

INTRODUCTION AND OBJECTIVES: We sought to assess the prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients with normal resting echocardiography and absence of coronary artery disease. METHODS: From our database of patients referred for treadmill exercise echocardiography, we identified 93 hypertensive patients with preserved resting left ventricular ejection fraction (≥ 50%), no evidence of structural heart disease, and absence of coronary artery disease on angiography. Overall, 39 patients developed exercise-induced left ventricular systolic dysfunction (defined as a decrease in left ventricular ejection fraction below 50% at peak exercise) and 54 exhibited a normal left ventricular ejection fraction response to exercise. The mean follow-up was 6.1 (3.7) years. End points were all-cause mortality, cardiac death, heart failure, and the composite event of cardiac death or heart failure. RESULTS: Patients who developed exercise-induced left ventricular systolic dysfunction were at higher risk of death from any cause (hazard ratio=3.4; 95% confidence interval, 1.1-10.3), cardiac death (hazard ratio=5.6; 95%CI, 1.1-29.4), heart failure (hazard ratio=8.9; 95% confidence interval, 1.8-44.2), and the composite end point (hazard ratio=5.7; 95% confidence interval, 1.7-19.0). In the multivariate analysis, exercise-induced left ventricular systolic dysfunction remained an independent predictor of both heart failure (hazard ratio=6.9; 95% CI, 1.3-37.4) and the composite event of cardiac death or heart failure (hazard ratio=4.5; 95% confidence interval, 1.2-16.0). CONCLUSIONS: In hypertensive patients with preserved resting left ventricular ejection fraction and absence of coronary artery disease, exercise-induced left ventricular systolic dysfunction is a strong predictor of cardiac events and may represent early hypertensive heart disease.

N-Bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders.

The search for novel heterobicyclic compounds within the drug-like chemical space continues to be an area of interest in medicinal chemistry. Unsaturated N-bridgehead heterocycles are well represented in marketed drugs for a variety of therapeutic areas, and continue to play an important role in central nervous system (CNS) drug discovery programs. Examples of medicinal chemistry strategies that make use of N-bridged 5,6-bicyclic pyridines are discussed here in this Minireview, which covers the literature from 2010 up to 2014. B1-class imidazopyridines and B3-class pyrazolopyridines have proven to be at the forefront of molecular prototypes that are capable of interacting with disease relevant targets in neurodegeneration and neuropsychiatry.

Biochemical quantitation of the eIF5A hypusination in Arabidopsis thaliana uncovers ABA-dependent regulation.

The eukaryotic translation elongation factor eIF5A is the only protein known to contain the unusual amino acid hypusine which is essential for its biological activity. This post-translational modification is achieved by the sequential action of the enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The crucial molecular function of eIF5A during translation has been recently elucidated in yeast and it is expected to be fully conserved in every eukaryotic cell, however the functional description of this pathway in plants is still sparse. The genetic approaches with transgenic plants for either eIF5A overexpression or antisense have revealed some activities related to the control of cell death processes but the molecular details remain to be characterized. One important aspect of fully understanding this pathway is the biochemical description of the hypusine modification system. Here we have used recombinant eIF5A proteins either modified by hypusination or non-modified to establish a bi-dimensional electrophoresis (2D-E) profile for the three eIF5A protein isoforms and their hypusinated or unmodified proteoforms present in Arabidopsis thaliana. The combined use of the recombinant 2D-E profile together with 2D-E/western blot analysis from whole plant extracts has provided a quantitative approach to measure the hypusination status of eIF5A. We have used this information to demonstrate that treatment with the hormone abscisic acid produces an alteration of the hypusine modification system in Arabidopsis thaliana. Overall this study presents the first biochemical description of the post-translational modification of eIF5A by hypusination which will be functionally relevant for future studies related to the characterization of this pathway in Arabidopsis thaliana.

Diastereoselective synthesis of 2-phenyl-3-(trifluoromethyl)piperazines as building blocks for drug discovery.

The synthesis of enantiomerically pure cis- and trans-2-phenyl-3-(trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to α-amino sulfinylimines bearing Ellman's auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry.