Fiber-type transitions and satellite cell activation in low-frequency-stimulated muscles of young and aging rats

We examined satellite cell content and the activity of satellite cell progeny in tibialis anterior muscles of young (15 weeks) and aging (101 weeks) Brown Norway (BN) rats, after they were exposed for 50 days to a standardized and highly reproducible regime of chronic low-frequency electrical stimulation. Chronic low-frequency electrical stimulation was successful in inducing fast-to-slow fiber-type transformation, characterized by a 2.3-fold increase in the proportion of IIA fibers and fourfold and sevenfold decreases in the proportion of IID/X and IIB fibers in both young and aging BN rats. These changes were accompanied by a twofold increase in the satellite cell content in both the young and aging groups; satellite cell content reached a level that was significantly higher in the young group (p < .04). The total muscle precursor cell content (i.e., satellite cells plus progeny), however, did not differ between groups, because there was a greater number of satellite cell progeny passing through the proliferative and differentiative compartments of the aging group. The resulting 1.5-fold increase in myonuclear content was similar in the young and aging groups. We conclude that satellite cells and satellite cell progeny of aging BN rats possess an unaltered capacity to contribute to the adaptive response.

Buraco negros, correspondência AdS/BCFT e fluido/gravidade

Einstein’s equations with negative cosmological constant possess the so-called anti de Sitter space, AdSd+1, as one of its solutions. We will later refer to this space as to the "bulk". The holographic principle states that quantum gravity in the AdSd+1 space can be encoded by a d−dimensional quantum field theory on the boundary of AdSd+1 space, invariant under conformal transformations, a CFTd. In the most famous example, the precise statement is the duality of the type IIB string theory in the space AdS5 × S 5 and the 4−dimensional N = 4 supersymmetric Yang-Mills theory. Another example is provided by a relation between Einstein’s equations in the bulk and hydrodynamic equations describing the effective theory on the boundary, the so-called fluid/gravity correspondence. An extension of the "AdS/CFT duality"for the CFT’s with boundary was proposed by Takayanagi, which was dubbed the AdS/BCFT correspondence. The boundary of a CFT extends to the bulk and restricts a region of the AdSd+1. Neumann conditions imposed on the extension of the boundary yield a dynamic equation that determines the shape of the extension. From the perspective of fluid/gravity correspondence, the shape of the Neumann boundary, and the geometry of the bulk is sourced by the energy-momentum tensor Tµν of a fluid residing on this boundary. Clarifying the relation of the Takayanagi’s proposal to the fluid/gravity correspondence, we will study the consistence of the AdS/BCFT with finite temperature CFT’s, or equivalently black hole geometries in the bulk.

Genetic medicines for CF: hype versus reality

Since identification of the CFTR gene over 25 years ago, gene therapy for cystic fibrosis (CF) has been actively developed. More recently gene therapy has been joined by other forms of “genetic medicines” including mRNA delivery, as well as genome editing and mRNA repair-based strategies. Proof-of-concept that gene therapy can stabilize the progression of CF lung disease has recently been established in a Phase IIb trial. An early phase study to assess the safety and explore efficacy of CFTR mRNA repair is ongoing, while mRNA delivery and genome editing-based strategies are currently at the pre-clinical phase of development. This review has been written jointly by some of those involved in the various CF “genetic medicine” fields and will summarize the current state-of-the-art, as well as discuss future developments. Where applicable, it highlights common problems faced by each of the strategies, and also tries to highlight where a specific strategy may have an advantage on the pathway to clinical translation. We hope that this review will contribute to the ongoing discussion about the hype versus reality of genetic medicine-based treatment approaches in CF.

A randomised controlled trial of calcium channel blockade (CCB) with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT): study protocol

BACKGROUND: Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia.

METHODS/DESIGN: This is a randomised controlled trial of calcium channel blockade with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT) to test the hypothesis that treatment with amlodipine can improve outcomes for these patients in a phase IIb, multi-centre, double-blind, placebo-controlled randomised trial. The primary outcome is the change from baseline to 12 months in the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). Secondary outcomes include cognitive function, executive function, clinical global impression of change, change in blood pressure, quantitative evaluation of lesion accrual based on magnetic resonance imaging (MRI), health-related quality of life, activities of daily living, non-cognitive dementia symptoms, care-giver burden and care-giver health-related quality of life, cost-effectiveness and institutionalisation. A total of 588 patients will be randomised in a 1:1 ratio to either amlodipine or placebo, recruited from sites across the UK and enrolled in the trial for 104 weeks.

DISCUSSION: There are no treatments licensed for vascular dementia. The most common subtype is subcortical ischaemic vascular dementia (SIVD). This study is designed to investigate whether amlodipine can produce benefits compared to placebo in established SIVD. It is estimated that the numbers of people with VaD and SIVD will increase globally in the future and the results of this study should inform important treatment decisions.

Vasodilator-Stimulated Phosphoprotein (VASP)-dependent and -independent pathways regulate thrombin-induced activation of Rap1b in platelets

Background: Vasodilator-Stimulated Phosphoprotein (VASP) is involved in the inhibition of agonist-induced platelet aggregation by cyclic nucleotides and the adhesion of platelets to the vascular wall. αIIbβ3 is the main integrin responsible for platelet activation and Rap1b plays a key role in integrin signalling. We investigated whether VASP is involved in the regulation of Rap1b in platelets since VASP-null platelets exhibit augmented adhesion to endothelial cells in vivo.

Methods: Washed platelets from wild type and VASP-deficient mice were stimulated with thrombin, the purinergic receptors agonist ADP, or the thromboxane A2 receptor agonist U46619 and Rap1b activation was measured using the GST-RalGDS-RBD binding assay. Interaction of VASP and Crkl was investigated by co-immunoprecipitation, confocal microscopy, and pull-down assays using Crkl domains expressed as GST-fusion proteins.

Results: Surprisingly, we found that activation of Rap1b in response to thrombin, ADP, or U46619 was significantly reduced in platelets from VASP-null mice compared to platelets from wild type mice. However, inhibition of thrombin-induced activation of Rap1b by nitric oxide was similar in platelets from wild type and VASP-null mice indicating that the NO/cGMP/PKG pathway controls inhibition of Rap1b independently from VASP. To understand how VASP regulated Rap1b, we investigated association between VASP and the Crk-like protein (Crkl), an adapter protein which activates the Rap1b guanine nucleotide exchange factor C3G. We demonstrated the formation of a Crkl/VASP complex by showing that: 1) Crkl co-immunoprecipitated VASP from platelet lysates; 2) Crkl and VASP dynamically co-localized at actin-rich protrusions reminiscent of focal adhesions, filopodia, and lamellipodia upon platelet spreading on fibronectin; 3) recombinant VASP bound directly to the N-terminal SH3 domain of Crkl; 4) PKA-mediated VASP phosphorylation on Ser157 abrogated the binding of Crkl.

Conclusions: We identified Crkl as a novel protein interacting with VASP in platelets. We propose that the C3G/Crkl/VASP complex plays a role in the regulation of Rap1b and this explains, at least in part, the reduced agonist-induced activation of Rap1b in VASP-null platelets. In addition, the fact that PKA-dependent VASP phosphorylation abrogated its interaction with Crkl may provide, at least in part, a rationale for the PKA-dependent inhibition of Rap1b and platelet aggregation.

Trends in Primary Angioplasty in Portugal From 2002 to 2013 According to the Portuguese National Registry of Interventional Cardiology

INTRODUCTION AND OBJECTIVES: The aim of the present paper was to report trends in coronary angioplasty for the treatment of ST-elevation myocardial infarction (STEMI) in Portugal. METHODS: Prospective multicenter data from the Portuguese National Registry of Interventional Cardiology (RNCI) and official data from the Directorate-General for Health (DGS) were studied to analyze percutaneous coronary intervention (PCI) procedures for STEMI from 2002 to 2013. RESULTS: In 2013, 3524 primary percutaneous coronary intervention (p-PCI) procedures were performed (25% of all procedures), an increase of 315% in comparison to 2002 (16% of all interventions). Between 2002 and 2013 the rate increased from 106 to 338 p-PCIs per million population per year. Rescue angioplasty decreased from 70.7% in 2002 to 2% in 2013. During this period, the use of drug-eluting stents grew from 9.9% to 69.5%. After 2008, the use of aspiration thrombectomy increased, reaching 46.7% in 2013. Glycoprotein IIb-IIIa inhibitor use decreased from 73.2% in 2002 to 23.6% in the last year of the study. Use of a radial approach increased steadily from 8.3% in 2008 to 54.6% in 2013. CONCLUSION: During the reporting period there was a three-fold increase in primary angioplasty rates per million population. Rescue angioplasty has been overtaken by p-PCI as the predominant procedure since 2006. New trends in the treatment of STEMI were observed, notably the use of drug-eluting stents and radial access as the predominant approach.

Near-infraread observation of supernovae with the Nordic Optical Telescope (NOT)

Supernova (SN) is an explosion of a star at the end of its lifetime. SNe are classified to two types, namely type I and II through the optical spectra. They have been categorised based on their explosion mechanism, to core collapse supernovae (CCSNe) and thermonuclear supernovae. The CCSNe group which includes types IIP, IIn, IIL, IIb, Ib, and Ic are produced when a massive star with initial mass more than 8 M⊙ explodes due to a collapse of its iron core. On the other hand, thermonuclear SNe originate from white dwarfs (WDs) made of carbon and oxygen, in a binary system. Infrared astronomy covers observations of astronomical objects in infrared radiation. The infrared sky is not completely dark and it is variable. Observations of SNe in the infrared give different information than optical observations. Data reduction is required to correct raw data from for example unusable pixels and sky background. In this project, the NOTCam package in the IRAF was used for the data reduction. For measuring magnitudes of SNe, the aperture photometry method with the Gaia program was used. In this Master’s thesis, near-infrared (NIR) observations of three supernovae of type IIn (namely LSQ13zm, SN 2009ip and SN2011jb), one type IIb (SN2012ey), in addition to one type Ic (SN2012ej) and type IIP (SN 2013gd) are studied with emphasis on luminosity and colour evolution. All observations were done with the Nordic Optical Telescope (NOT). Here, we used the classification by Mattila & Meikle (2001) [76], where the SNe are differentiated by the infrared light curves into two groups, namely ’ordinary’ and ’slowly declining’. The light curves and colour evolution of these supernovae were obtained in J, H and Ks bands. In this study, our data, combined with other observations, provide evidence to categorize LSQ13zm, SN 2012ej and SN 2012ey as being part of the ordinary type. We found interesting NIR behaviour of SN 2011jb, which lead it to be classified as a slowly declining type.

Angioplastia primária em Portugal entre 2002-2013. Atividade segundo o Registo Nacional de Cardiologia de Intervenção

Introdução e objectivos: Foi nosso objectivo reportar a evolução da angioplastia coronária no tratamento do enfarte agudo do miocárdio com supradesnivelamento do segmento ST (EAMCST), entre 2002-2013. Métodos: Os dados prospectivos multicêntricos do Registo Nacional de Cardiologia de Intervenção (RNCI) e os dados oficiais da Direção Geral de Saúde (DGS) foram conjugados para estudar os procedimentos no EAMCST entre 2002 e 2013. Resultados: Em 2013 realizaram-se 3524 angioplastias primárias (ICP-P), representando um crescimento de 315% relativamente ao ano 2002. Em 2002 a ICP-P representava 16% do total de angioplastias coronárias, passando a representar 25% nos anos de 2012-2013. Entre 2002-2013 o número de procedimentos por milhão de habitantes aumentou de 106 de 338 e a angioplastia de recurso decresceu de 70,7 para 2%. Durante o período em análise, a utilização de stents eluidores de fármaco cresceu de 9,9 para 69,5%. Após 2008, observou-se uma utilização crescente de trombectomia de aspiração, atingindo 46,7% em 2013. Os inibidores das glicoproteínas IIb/IIIa registaram um decréscimo no seu uso, sendo de 73,2% em 2002 e de 23,6% em 2013. O acesso radial cresceu de 8,3% em 2008 até 54,6% em 2013. Conclusões: Durante o período em análise, a taxa de angioplastia coronária por milhão de habitantes triplicou. A angioplastia de recurso foi ultrapassada pela angioplastia primária a partir de 2006. Observaram-se novas tendências no tratamento do enfarte agudo do miocárdio com supradesnivelamento do segmento ST, salientando-se a utilização de stents eluidores de fármacos e o acesso radial.

Caracterización clínico epidemiológica del cáncer de mama en el Hospital Nacional Rosales

El cáncer de mama es el más frecuente en mujeres con 1.38 millones de casos nuevos para el 2008 (23%) y el segundo más frecuente en general (10.9%). Es el más frecuente tanto en países desarrollados como en desarrollo (690 000 casos nuevos). En El Salvador es la segunda causa de cáncer y la tercera causa de muerte por cáncer. El riesgo de enfermar es superior en las mujeres de países con nivel socioeconómico alto, pero el riesgo de morir es mayor entre las mujeres que habitan países pobres. Se realiza este estudio para conocer el comportamiento de esta patología en nuestra población. Materiales y métodos: Se realizó un estudio descriptivo de seguimiento de una cohorte con cáncer de mama, tratados en el Hospital Nacional Rosales en un periodo de tiempo. Resultados: Se encontró una muestra de 132 pacientes. La edad media fue 54.61 años (DS +13.61). 55 pacientes (41.7%) provenían del departamento de San Salvador. De 119 pacientes en que se obtuvo datos de paridad se encontró una mediana de 3 hijos. 15.52% tenían antecedentes familiares. El 91.7% consultaron por presencia de tumor, con una mediana de consulta de 6 meses. Biopsia fue el método diagnostico en 84.41% de las pacientes. El tipo Ductal invasor fue el más frecuente (78.8%) y el estadio de presentación más frecuente fue IIb y IIIa correspondiendo al 50% de la población total. 5 pacientes no fueron sometidos a ninguna terapia quirúrgica, 20% recibido neoadyuvancia, 50% adyuvancia y 35.6% tamoxifeno. Hubo una pérdida de vista al año del 31% de pacientes, y en los restantes se obtuvo una sobrevida del 97.8%.

Caracterización clínico - epidemiológicas de los pacientes con cáncer gástrico en el Instituto Salvadoreño del Seguro Social

El cáncer gástrico es una de las neoplasias malignas más frecuentes a nivel mundial, la segunda causa de muerte por cáncer a nivel mundial, y la octava causa de muerte en los Estados Unidos debido a neoplasias, es por tanto, un problema que afecta tanto a los países desarrollados como a los países en vías de desarrollo. A nivel mundial es más frecuente en la sexta década de la vida, con una incidencia mayor en el sexo femenino, además se han descrito diversos factores de riesgo asociados a la aparición de dicha neoplasia. Dentro de la presentación clínica podemos encontrar la pérdida de peso y el dolor abdominal como las presentaciones clínicas más frecuentes del cáncer gástrico. La mayoría de pacientes son diagnosticados en estadios avanzados de la enfermedad. Con el presente estudio se determinó el comportamiento de los pacientes con diagnóstico de cáncer gástrico del Hospital Oncológico del ISSS en el período enero de 2012 a diciembre de 2013, mediante un estudio observacional, descriptivo, transversal, tomando como población a todos los pacientes con cáncer gástrico del ISSS diagnosticados en dicho periodo. Con los datos obtenidos se concluyó que la edad media de los pacientes con cáncer gástrico es de 63.4 años, los síntomas más frecuentes en pacientes con cáncer gástrico en orden decreciente de frecuencia son dolor abdominal, pérdida de peso, nausea, vómito, melenas y saciedad temprana; al examen físico los hallazgos más frecuentemente reportados son palidez y presencia de masa abdominal palpable; los datos más frecuentemente observados en exámenes de laboratorio son anemia (normo-normo) y alteraciones de AST y ALT. Se diagnostican en un estadio 0= 0%, IA= 1.41%; IB= 5.63%; IIA=14.08%; IIB= 11.27%; IIIA= 18.31%; IIIB= 7.04%; IIIC= 4.23% y IV=38.03%. Además el adenocarcinoma tubular, seguido del carcinoma de células en anillo de sello son los tipos histológicos más frecuentes.

Phosphate uptake and phosphate transporter expression during immune cell proliferation in in vitro and ex vivo leukemic murine models

Dissertação de Mestrado, Ciências Biomédicas, Departamento de Medicina e Ciências Biomédicas, Universidade do Algarve, 2015

Maternal creatine supplementation during pregnancy prevents long-term changes in diaphragm muscle structure and function after birth asphyxia

Using a model of birth asphyxia, we previously reported significant structural and functional deficits in the diaphragm muscle in spiny mice, deficits that are prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. The long-term effects of this exposure are unknown. Pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam until 33±2 days of age when they were euthanized to obtain the diaphragm muscle for ex-vivo study of twitch tension and muscle fatigue, and for structural and enzymatic analyses. Functional analysis of the diaphragm revealed no differences in single twitch contractile parameters between any groups. However, muscle fatigue, induced by stimulation of diaphragm strips with a train of pulses (330 ms train/sec, 40 Hz) for 300 sec, was significantly greater for asphyxia pups compared with controls (p<0.05), and this did not occur in diaphragms of creatine + asphyxia pups. Birth asphyxia resulted in a significant increase in the proportion of glycolytic, fast-twitch fibres and a reduction in oxidative capacity of Type I and IIb fibres in male offspring, as well as reduced cross-sectional area of all muscle fibre types (Type I, IIa, IIb/d) in both males and females at 33 days of age. None of these changes were observed in creatine + asphyxia animals. Thus, the changes in diaphragm fatigue and structure induced by birth asphyxia persist long-term but are prevented by maternal creatine supplementation.

Emerging drugs for partial-onset epilepsy: a review of brivaracetam

There are more than 12 new antiepileptic drugs approved in the last 2 decades. Even with these newer agents, seizure remission is still unachievable in around 30% of patients with partial-onset seizures (POS). Brivaracetam (BRV) is chemically related to levetiracetam (LEV) and possesses a strong binding affinity for the synaptic vesicle protein 2A tenfold above that of LEV, and other possible modes of antiepileptic actions. BRV is now under Phase III development for POS, but data from one Phase III trial also suggested its potential efficacy for primary generalized seizures. The purpose of this review is to provide updated information on the mechanisms of action of the available antiepileptic drugs, with a focus on BRV to assess its pharmacology, pharmacokinetics, clinical efficacy, safety, and tolerability in patients with uncontrolled POS. To date, six Phase IIb and III clinical trials have been performed to investigate the efficacy, safety, and tolerability of BRV as an adjunctive treatment for patients with POS. Generally, BRV was well tolerated and did not show significant difference in safety profile, compared to placebo. The efficacy outcomes of BRV, although not consistent across trials, did indicate that BRV was a promising add-on therapy for patients with POS. In conclusion, the many favorable attributes of BRV, like its high oral efficacy, good tolerability, dosing regimen, and minimal drug interaction, make it a promising antiepileptic therapy for patients with uncontrolled partial-onset epilepsy.

A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .