Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Natural Time Analysis of Seismicity within the Mexican Flat Slab before the M7.1 Earthquake on 19 September 2017.

One of the most important subduction zones in the world is located in the Mexican Pacific Coast, where the Cocos plate inserts beneath the North American plate. One part of it is located in the Mexican Pacific Coast, where the Cocos plate inserts beneath the North American plate with different dip angles, showing important seismicity. Under the central Mexican area, such a dip angle becomes practically horizontal and such an area is known as flat slab. An earthquake of magnitude M7.1 occurred on 19 September 2017, the epicenter of which was located in this flat slab. It caused important human and material losses of urban communities including a large area of Mexico City. The seismicity recorded in the flat slab region is analyzed here in natural time from 1995 until the occurrence of this M7.1 earthquake in 2017 by studying the entropy change under time reversal and the variability ß of the order parameter of seismicity as well as characterize the risk of an impending earthquake by applying the nowcasting method. The entropy change ΔS under time reversal minimizes on 21 June 2017 that is almost one week after the observation of such a minimum in the Chiapas region where a magnitude M8.2 earthquake took place on 7 September 2017 being Mexico's largest quake in more than a century. A minimum of ß was also observed during the period February-March 2017. Moreover, we show that, after the minimum of ΔS, the order parameter of seismicity starts diminishing, thus approaching gradually the critical value 0.070 around the end of August and the beginning of September 2017, which signals that a strong earthquake is anticipated shortly in the flat slab.

Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics.

Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin-based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events. METHODS: The REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization). RESULTS: Between August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL. INTERPRETATION: The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017.

Molecular and morphometric characterization of two dental morphs of Saccodon dariensis (Parodontidae).

This study reports for the first time the roles of genetic and body phenotypic variation in two Saccodon dariensis dental morphs. Results showed a lack of ancient mitochondrial differentiation between morphs and body variations concordant with genetic polymorphism or differential plastic responses to diet quality and foraging strategies of S. dariensis.

Variations of body geometry in Brycon henni (Teleostei: Characiformes, Bryconidae) in different rivers and streams.

Landmark-based geometric morphometrics were used to evaluate the effect of flow and depth in the water column on the body size and shape of Brycon henni from river and stream populations. The dendrogram showed that stream populations clustered apart and showed significantly smaller centroid size and narrower bodies than river populations, indicating a role for flow and depth on whole body morphometric variation. The results are concordant with morphometric variation described in other fish species and provide the first insights into phenotypic variation in natural populations of B. henni.

Pax3 loss of function delays tumour progression in kRAS-induced zebrafish rhabdomyosarcoma models.

Rhabdomyosarcoma is a soft tissue cancer that arises in skeletal muscle due to mutations in myogenic progenitors that lead to ineffective differentiation and malignant transformation. The transcription factors Pax3 and Pax7 and their downstream target genes are tightly linked with the fusion positive alveolar subtype, whereas the RAS pathway is usually involved in the embryonal, fusion negative variant. Here, we analyse the role of Pax3 in a fusion negative context, by linking alterations in gene expression in pax3a/pax3b double mutant zebrafish with tumour progression in kRAS-induced rhabdomyosarcoma tumours. Several genes in the RAS/MAPK signalling pathway were significantly down-regulated in pax3a/pax3b double mutant zebrafish. Progression of rhabdomyosarcoma tumours was also delayed in the pax3a/pax3b double mutant zebrafish indicating that Pax3 transcription factors have an unappreciated role in mediating malignancy in fusion negative rhabdomyosarcoma.

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis.

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.

Epidermal growth factor receptor in corneal damage: update and new insights from recent reports.

Agonist and antagonist drugs acting on epidermal growth factor receptor (EGFR) signaling are emerging as a new possibility for pharmaceutical study and clinical manipulation of some skin and corneal disorders. EGFR activation appears to be effective in reducing the time of reepithelialization after corneal wound healing, with potential uses in penetrating keratoplasty, refractive surgery, alkali burns, diabetic keratopathy, keratopathy following chemotherapy, cornea transplantation, and dry eye. Most of the studies show therapeutic advantages of human recombinant epidermal growth factor (hrEGF) eye drops without showing adverse effects. In contrast, EGFR inhibition delays epithelial cell proliferation and stratification during corneal regeneration.The aim of this review is to summarize the most seminal discoveries and recent advances so as to clarify the role of the EGFR system in corneal physiology and pharmacology. Epidermal growth factor eye drops could be a first-choice treatment for promoting regeneration in numerous epithelial defects in the medium to long term.

QSAR and molecular docking modelling of anti-leishmanial activities of organic selenium and tellurium compounds.

Leishmaniasis affects mainly rural areas and the poorest people in the world. A computational study of the antileishmanial activity of organic selenium and tellurium compounds was performed. The 3D structures of the compounds were optimized at the wb97xd/lanl2dz level and used in the quantitative structure-activity relationship (QSAR) analysis. The antileishmanial activity was measured by L. donovani ß carbonic anhydrase inhibition (Ki) and the half-maximal inhibitory concentration (IC50) against L. infantum amastigotes. The dataset was divided into training (75%) and test sets (25%) by using a k-means clustering algorithm. For pKi prediction, model M3 with seven 3D topographic descriptors was characterized by the following statistical parameters: r 2 = 0.879, Q 2 LOO = 0.822, and Q 2 ext = 0.840. For pIC50 prediction, model M12 with six attributes was characterized by the following statistical parameters: r 2 = 0.907, Q 2 LOO = 0.824, and Q 2 ext = 0.795. Both models met all the requirements of Tropsha´s test, which implies predictions of pIC50 and pKi activities with high accuracy. Concomitantly, favourable interactions of the sulphonamide group with the Zn atom in the protein were revealed by the docking analysis.

Relationship between renal function and heart failure in hypertensive patients.

The HICAP (Hypertension and Heart Failure in Primary Care) study is a cross-sectional, multicentre, epidemiological study conduced in primary care centres in Spain. The results indicate that among hypertensive patients without heart failure (HF), diagnosed renal dysfunction is associated with the risk for developing HF and that the renal function evaluation using the Modification of Diet in Renal Disease Study Group formula could be useful to detect hypertensive patients at high risk of developing HF.

Amiodarone and itraconazole: a rational therapeutic approach for the treatment of chronic Chagas' disease.

In the Americas, approximately 20 million people suffer from the chronic phases of Chagas' disease, of which chagasic cardiomyopathy is the most important clinical feature. The elimination of Trypanosoma cruzi is a pivotal step in arresting the evolution of the disease. Unfortunately, currently available chemotherapy is mostly ineffective due to its limited efficacy and toxic side effects. The following case highlights the efficacy of new diagnostic and follow-up methods in the evaluation of novel trypanocidal compounds such as amiodarone and itraconazole.

Mexican oregano (Lippia graveolens) essential oil-in-water emulsions: impact of emulsifier type on the antifungal activity of Candida albicans.

This study examined the impact of emulsifier type on the physicochemical characteristics and antifungal capacity of oregano oil-in-water emulsions: Tween 80, hydroxylated soy lecithin, and gum arabic. GC/MS analysis showed that the major components of the Lippia graveolens essential oils were thymol (31.7%), p-cymene (18.7%), and carvacrol (14.6%). The oil-in-water emulsions were made using ultrasonic technology in which thymol and carvacrol quantities were 12.26-13.67 g/L and 5.6-6.2 g/L, respectively. The droplet size of the emulsions followed the next descendent order: gum arabic > lecithin > T80. The zeta potential of the emulsions favored the stability against coalescence. Finally, the antifungal activity of the emulsions was evaluated, in which, 30 µL/mL of gum arabic or hydroxylated soy lecithin emulsions inhibited the growth of Candida albicans. The result suggests that Mexican oregano essential oil emulsions can be used as an antifungal against of C. albicans.

Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and ß) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-ß-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

Effects of dorsal striatal infusions of R(-)-propylnorapomorphine on kappa-opioid-mediated locomotor activity in the young rat: possible role of the indirect pathway.

Stimulation of kappa-opioid receptors in the substantia nigra pars reticulata (SNPR) increases the locomotor activity of young rats: an effect blocked by systemic administration of a D2-like receptor agonist. Based on these initial findings, we proposed that: (a) D2-like receptors in the dorsal striatum are responsible for attenuating kappa-opioid-induced locomotor activity, and (b) the effects of D2-like receptor stimulation are mediated by the indirect pathway, which extends from the dorsal striatum to the SNPR via the globus pallidus (GP) and subthalamic nucleus (STN). To test the first hypothesis, young rats were given a systemic injection (i.p.) of saline or the kappa-opioid receptor agonist (+/-)-trans-U50,488 methanesulfonate salt (U50,488) on postnatal day (PD) 18. Later in the testing session, rats received bilateral infusions of vehicle or the D2-like receptor agonist R(-)-propylnorapomorphine (NPA) into the dorsal striatum, and the ability of NPA to block U50,488-induced locomotor activity was determined. To test the second hypothesis, rats were given sham or bilateral electrolytic lesions of the GP or STN on PD 16. Two days later, saline- and U50,488-induced locomotor activity was measured after systemic (i.p.) administration of vehicle or NPA. As predicted, dorsal striatal infusions of NPA attenuated the U50,488-induced locomotor activity of young rats. Contrary to our expectations, bilateral lesions of the GP or STN did not impair NPA's ability to block U50,488-induced locomotor activity. When considered together, these results suggest that: (a) stimulation of D2-like receptors in the dorsal striatum is sufficient to attenuate the kappa-opioid-mediated locomotor activity of young rats; and (b) the indirect pathway does not mediate the effects of D2-like receptor stimulation in this behavioral model.

[Efficacy and safety of intravitreal injection of bevacizumab in the treatment of neovascular glaucoma: systematic review]. / Eficacia y seguridad de la inyección intravítrea de bevacizumab en el tratamiento del glaucoma neovascular: revisión sistemática.

PURPOSE: Systematic review on efficacy and safety of intravitreal bevacizumab (IVB) in the treatment of neovascular glaucoma (NVG). All original papers published in Medline (prior to August 2008) were included. METHODS: Search and selection of information on the internet and in Medline, validated by Kappa Index (K). Statistical and clinical study of the results in the selected articles on a one by one basis. RESULTS: 26 original papers analyzed the efficacy and safety of the procedure in case reports and short series of cases (127 eyes). The efficacy calculated in the sample was 68.7% and the recurrence rate was 18.6% in 4.2 months of follow-up. All studies were after 2006 and none of them was a clinical randomized controlled assay. Ophthalmic complications were under 0.78% and no systemic complications were found. CONCLUSIONS: The use of bevacizumab demonstrates that intravitreal injections may be effective and useful to manipulate growth factors in the anterior chamber. IVB could serve as a first line treatment for NVG. Clinical trials are needed to confirm these results before its use is authorized.

[Surgical management and recurrence of congenital preauricular fistula]. / Manejo quirúrgico y recurrencia de la fístula preauricular congénita.

In this paper we describe the surgical management and postoperative recurrence of preauricular fistula (PAF) since the surgical treatment is characterized by high recurrence rates. All clinical, operative and postoperative data were collected from a retrospective review of patients's charts who underwent primary surgical management between January 2001 and December 2006 at five Hospitals in Guadalajara, Jalisco. Thirty-eight patients (15 male, 23 female) with PAF underwent 44 surgical procedures. Recurrent acute infection and discharge were the most common symptoms. The surgical management included 25 standard techniques (sinectomy) and 19 supra-auricular approaches. The overall rate of recurrence was 59%, it differed widely between surgical techniques employed. The 52.2% recurrence rate of standard technique was significantly higher than the 6.8% recurrence rate of the supra-auricular approach (p = 0.01). Also, the patients in whom a portion of the cartilage of the helix was not excised from the base of the tract, 84.6% recurred vs. 15.3% when cartilage was excised (p = 0.01). Our experience has shown that independently of clinical presentation of PAF, the standard technique and not to remove a portion of the cartilage at the base of the helix contributed to recurrence. We advise the supra-auricular approach particularly when there are abscess prior to surgery.

Alternative statistical methods and their application to research in intensive care setting. / Métodos estadísticos alternativos y su aplicación a la investigación en Cuidados Intensivos.

In nested case-control studies, sampling of controls is usually done by density of incidence and pairing. With regard to the classic control cases studies, nested ones are more efficient, allow the calculation of the incidence of the disease and they have more internal validity due to the lower presence of bias. Competitive risks techniques can be used if we study different types of events and focus on the time and type of the first event. Recursive partitioning is a type of multivariate analysis whose purpose is the construction of classification algorithms, and it is especially useful when there are a large number of predictive variables with complex relationships with the event.

[LASIK results of IntraLase femtosecond laser to correct myopia: efficacy, security and predictability]. / Resultados de LASIK realizado con láser de femtosegundo (IntraLase) para corrección de miopía: eficacia, predictibilidad y seguridad.

PURPOSE: To evaluate LASIK results obtained with the IntraLase femtosecond laser to correct myopia. METHODS: This was a prospective, single masked observer study. Flaps were created with the IntraLase femtosecond laser (FS). All laser procedures were performed by the same surgeon using the Technolas 217 excimer laser (Bausch & Lomb). We have analysed the uncorrected visual acuity (UCVA) at 1 day, 1 week, 1 month and 3 months after surgery and best spectacle-corrected visual acuity (BSCVA) after 3 months. RESULTS: 485 eyes with myopia were treated and their results evaluated. The mean preoperative sphere was of -3.9 D (SD 2.0) and a mean astigmatism of -0.9 D (SD 0.9) with BSCVA 1.1 (SD 0.1). The UCVA results were 0.94 (SD 0.1) at the first day postoperatively visit, 0.96 (SD 0.1) at first week, 1.00 (SD 0.1) at one month and 1.00 (SD 0.2) at 3 months. The refractive error at 3 months was -0.02 D (SD 0.3) and -0.1 D (SD 0.3) of myopia and astigmatism respectively. At 3 months 96.9% of eyes were within +/-1.00D and 93.6% of the eyes were within + 0.50 D. CONCLUSIONS: LASIK to correct myopia is a safe, effective and predictable procedure using IntraLase FS to create the flap.

Retinoschisis and neurosensory detachment in advanced focal glaucoma. / Retinosquisis y desprendimiento neurosensorial peripapilar asociado a glaucoma focal avanzado.

CLINICAL CASE: A 71-year-old woman with normotensive primary open-angle glaucoma presented with an asymptomatic temporal peripapillary retinoschisis, associated with serous retinal detachment in the eye with the more advanced glaucoma. It was located at the inferior pole of the optic disc, in the proximity of a glaucomatous focal disc defect. DISCUSSION: Although congenital optic pits are strongly related with juxta-papillary retinoschisis, retinoschisis can also arise from acquired defects in the proximity of glaucomatous optic discs. As symptoms depend on the extent of the retinoschisis, the prevalence of this complication could be greater than that reported in glaucomatous eyes.