Use of semi-synthetic data for catheter segmentation improvement.

In the era of data-driven machine learning algorithms, data is the new oil. For the most optimal results, datasets should be large, heterogeneous and, crucially, correctly labeled. However, data collection and labeling are time-consuming and labor-intensive processes. In the field of medical device segmentation, present during minimally invasive surgery, this leads to a lack of informative data. Motivated by this drawback, we developed an algorithm generating semi-synthetic images based on real ones. The concept of this algorithm is to place a randomly shaped catheter in an empty heart cavity, where the shape of the catheter is generated by forward kinematics of continuum robots. Having implemented the proposed algorithm, we generated new images of heart cavities with various artificial catheters. We compared the results of deep neural networks trained purely on real datasets with respect to networks trained on both real and semi-synthetic datasets, highlighting that semi-synthetic data improves catheter segmentation accuracy. A modified U-Net trained on combined datasets performed the segmentation with a Dice similarity coefficient of 92.6 ± 2.2%, while the same model trained only on real images achieved a Dice similarity coefficient of 86.5 ± 3.6%. Therefore, using semi-synthetic data allows for the decrease of accuracy spread, improves model generalization, reduces subjectivity, shortens the labeling routine, increases the number of samples, and improves the heterogeneity.

Atomistic mechanism of leptin and leptin-receptor association.

The leptin-leptin receptor complex is at the very core of energy homeostasis and immune system regulation, among many other functions. In this work, we built homology models of leptin and the leptin binding domain (LBD) of the receptor from humans and mice. Docking analyses were used to obtain the coordinates of the native leptin-LBD complexes and a mixed heterodimer formed by human leptin and mouse LBD. Molecular dynamics (MD) simulations were performed using all models (monomers and heterodimers) as initial coordinates and the GROMACS program. The overall structural and dynamical behaviors are similar for the three complexes. Upon MD simulations, several new interactions appear. In particular, hydrophobic interactions, with more than 90% persistence, seem to be the most relevant for the stability of the dimers, as well as the pair formed by Asp85Lep and Arg468LBD. This in silico analysis provides structural and dynamical information, at the atomistic level, about the mechanism of leptin-LBD complex formation and leptin receptor activation. This knowledge might be used in the rational drug design of therapeutics to modulate leptin signaling.Communicated by Ramaswamy H. Sarma.

Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.

Effect of the single mutation N9Y on the catalytical properties of xylanase Xyn11A from Cellulomonas uda: a biochemical and molecular dynamic simulation analysis.

Cellulomonas uda produces Xyn11A, moderately thermostable xylanase, with optimal activity at 50 °C and pH 6.5. An improvement in the biochemical properties of Xyn11A was achieved by site-directed mutagenesis approach. Wild-type xylanase, Xyn11A-WT, and its mutant Xyn11A-N9Y were expressed in Escherichia coli, and then both enzymes were purified and characterized. Xyn11A-N9Y displayed optimal activity at 60 °C and pH 7.5, an upward shift of 10 °C in the optimum temperature and an upward shift of 1 unit in optimum pH; also, it manifested an 11-fold increase in thermal stability at 60 °C, compared to that displayed by Xyn11A-WT. Molecular dynamics simulations of Xyn11A-WT and Xyn11A-N9Y suggest that the substitution N9Y leads to an array of secondary structure changes at the N-terminal end and an increase in the number of hydrogen bonds in Xyn11A-N9Y. Based on the significant improvements, Xyn11A-N9Y may be considered as a candidate for several biotechnological applications.

Physical Activity Space Methodology for Assessment and Prioritization (PASMAP): Combining systematic observations with community perceptions to identify community physical activity resource priorities.

Despite benefits of physical activity (PA), most Americans are not regularly active, with notable disparities for residents of low-income communities. PA is positively correlated with resource availability and quality, which can be measured and quantified by PA resource assessment tools. However, community members' perceptions are often not considered. This study incorporates community perceptions with systematic environmental observations to identify community PA resource priorities. The PA Space Methodology for Assessment and Prioritization (PASMAP) includes three phases. Phase 1: Promotora-researchers completed 57 PA Resource Assessments (PARAs) in colonias along the Texas-Mexico border assessing quantity and quality of features, amenities, and incivilities. Characteristics were ranked using average PARA scores from all PA spaces. Phase 2: community advisory board (CAB) members (n = 36 from 3 CABs) ranked the importance of each feature, amenity, and incivility respectively; rankings were averaged and ordered. Phase 3: differences between phases 1 and 2 were calculated. Large differences indicated high discordance between systematic observations and perceived importance. Phase 1: highest ranked PARA characteristics were sidewalks, non-street lighting, and noise. Phase 2: CAB members ranked trails/paths, sidewalks, play equipment, bathrooms, drinking fountains, substance abuse evidence, and litter most important. Phase 3: multiple characteristics had high discordance: trails/paths, fenced-in open fields (features), drinking fountains (amenity), and litter (incivility); low quantity/poor quality yet perceived as highly important. Discordant characteristics identified through PASMAP provide evidence-based, community-valued recommendations on PA resource priorities for planning and advocacy. Future work should incorporate perceptions from additional community members and apply PASMAP methods to other environmental assessments.

Prevention of severe respiratory syncytial virus infection in the pediatric population in Mexico: position of a group of experts.

Respiratory syncytial virus (RSV) is the agent that causes more hospitalizations and deaths due to lower acute respiratory infection. Its distribution is widespread, and almost every child has been infected by the age of two years. Different risk populations have been identified: preterm newborns (NB), children with congenital heart disease, bronchopulmonary dysplasia, Down syndrome, cystic fibrosis, asthmatics, neuromuscular diseases, among others. However, preterm NBs, children with congenital heart disease or bronchopulmonary dysplasia show higher rates of hospitalization and death from RSV. In the late 90s, monoclonal antibodies against RSV were developed, with demonstrated efficacy and safety for the prevention of RSV hospitalizations in these populations. Currently, the American Academy of Pediatrics recommends this therapy for the prevention of severe infection in the population at higher risk. Economic evaluations have been conducted to determine the effectiveness of immunization, resulting favorable for palivizumab. Immunization in Mexico has resulted cost-effective in NBs under 32 gestation weeks. Mexican authorities should discuss the inclusion of palivizumab in their clinical guidelines.

El virus sincicial respiratorio (VSR) es el agente que ocasiona más hospitalizaciones y muertes por infección aguda de vías respiratorias bajas. La mayoría de los niños ya han sido infectados a los 2 años de edad. Se han identificado diferentes poblaciones de riesgo: recién nacidos pretérmino y niños con cardiopatía congénita, displasia broncopulmonar, síndrome de Down, fibrosis quística, asma y enfermedades neuromusculares, entre otras. Sin embargo, las tasas de hospitalización y de muerte por VSR son más altas en los recién nacidos pretérmino y en los niños con cardiopatía congénita o displasia broncopulmonar. A finales de los años 90 se desarrollaron anticuerpos monoclonales contra el VSR, los cuales demostraron ser eficaces y seguros en la prevención de hospitalizaciones por VSR en estas poblaciones. Actualmente, la American Academy of Pediatrics los recomienda para la prevención de la infección grave en la población de mayor riesgo. Se ha recurrido a evaluaciones económicas para determinar la efectividad de la inmunización, las cuales han sido favorables para el palivizumab. En México se ha demostrado que la inmunización es costo-efectiva en los recién nacidos menores de 32 semanas de gestación. Las autoridades mexicanas deben discutir la inclusión del palivizumab en sus guías de práctica clínica.

Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors.

Amoebiasis is caused by the protozoan Entamoeba histolytica that affects millions of people throughout the world. The standard treatment is metronidazole, however, this drug causes several side effects, and is also mutagenic and carcinogenic. Therefore, the search for therapeutic alternatives is necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have been shown to exhibit activity against different protozoan. In the present study, the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives on E. histolytica proliferation, morphology, ultrastructure, and oxidative stress were evaluated, also their potential as E. histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. In vitro tests showed that 12 compounds from n-propyl and isopropyl series, were more active (IC50 = 0.331 to 3.56 µM) than metronidazole (IC50 = 4.5 µM). The compounds with better biological activity have a bulky, trifluoromethyl and isopropyl group at R1-, R2-, and R3-position, respectively. The main alterations found in trophozoites treated with some of these compounds included changes in chromatin, cell granularity, redistribution of vacuoles with cellular debris, and an increase in reactive oxygen species. Interestingly, docking studies suggested that 7-carboxylate QdNOs derivatives could interact with amino acid residues of the NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assays demonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductase activity, and diaphorase activity shows that these compounds could act as electron acceptor substrates for the enzyme. Taken together, these data indicate that among the mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivatives studied, is the induction of oxidative stress and the inhibition of EhTrxR activity.

Transit of Procaspase-9 towards its activation. New mechanistic insights from molecular dynamics simulations.

Caspases are cysteine proteases that perform a wide variety of roles in lethal intracellular signaling and cell-death regulation. Caspase-9, the primary initiator caspase of the intrinsic apoptotic pathway, is produced as a scarcely active zymogen (Procaspase-9). Here, we describe, for the first time, at the atomistic level, conformational changes which might be correlated to the activation of Procaspase-9. Molecular dynamics simulations performed at two temperatures (310 and 410 K) provide insights about the conformational space and the time-course evolution of the geometrical and structural characteristics of Procaspase-9. At both temperatures studied, the extremal globular domains of the protein approach each other, contracting the disordered region. In both temperatures, the compact conformations hide more than 40 nm2 (about 20% of the total solvent-accessible surface area), and their radius of gyration are reduced by about 40% from the original values. At each temperature, the pathway of contraction is different, as well as the compact structures reached. In consequence, the network of stabilizing interactions at the final conformations is dissimilar. Both final conformations were evaluated in their structural compatibility with the activation models described so far. In this work, we describe mechanistically how and why the activation of Procaspase-9 is favored by apoptosome recruitment via the Caspase Activation Recruitment Domain (CARD), as it has been proposed recently by in vitro experiments.

Exploring the Conformational Space of Bcl-2 Protein Variants: Dynamic Contributions of the Flexible Loop Domain and Transmembrane Region.

Members of the Bcl-2 protein family regulate apoptosis through interactions with several proteins. A critical intrinsically disordered region (IDR) present in some members of the Bcl-2 family is essential for their function. Also, the structural and conformational plasticity of disordered regions is essential for the regulation of the Bcl-2 protein's activity. Further, some proteins of the family contain transmembrane-helical regions, which anchor them into organelle membranes. Bcl-2, the archetypical member of the family, is characterized by an IDR labeled as a flexible loop domain (FLD) and a transmembrane domain (TMD). Another member of this family is the Bcl-2A1 protein, containing a TMD but lacking the FLD. To our knowledge, this is the first report which characterizes the individual and simultaneous dynamical contributions of FLD and TMD in Bcl-2 and Bcl-2A1 using molecular dynamics simulations (MDS). We examined the conformational spaces of Bcl-2, Bcl-2A1, and two artificial constructs lacking the TMD (Bcl-2ΔTM and Bcl-2A1ΔTM). As the results show, FLD and TMD stabilized each protein independently when they are present. When they coincided, such as in Bcl-2, an additive stabilizing effect is observed. This information is crucial for understanding the structural mechanisms of interaction in the Bcl-2 family.

Estimating Vehicle Movement Direction from Smartphone Accelerometers Using Deep Neural Networks.

Characterization of driving maneuvers or driving styles through motion sensors has become a field of great interest. Before now, this characterization used to be carried out with signals coming from extra equipment installed inside the vehicle, such as On-Board Diagnostic (OBD) devices or sensors in pedals. Nowadays, with the evolution and scope of smartphones, these have become the devices for recording mobile signals in many driving characterization applications. Normally multiple available sensors are used, such as accelerometers, gyroscopes, magnetometers or the Global Positioning System (GPS). However, using sensors such as GPS increase significantly battery consumption and, additionally, many current phones do not include gyroscopes. Therefore, we propose the characterization of driving style through only the use of smartphone accelerometers. We propose a deep neural network (DNN) architecture that combines convolutional and recurrent networks to estimate the vehicle movement direction (VMD), which is the forward movement directional vector captured in a phone's coordinates. Once VMD is obtained, multiple applications such as characterizing driving styles or detecting dangerous events can be developed. In the development of the proposed DNN architecture, two different methods are compared. The first one is based on the detection and classification of significant acceleration driving forces, while the second one relies on longitudinal and transversal signals derived from the raw accelerometers. The final success rate of VMD estimation for the best method is of 90.07%.

Remission and Low Disease Activity Status (LDAS) protect lupus patients from damage occurrence: data from a multiethnic, multinational Latin American Lupus Cohort (GLADEL).

OBJECTIVE: To evaluate disease activity statuses' (DAS') impact on systemic lupus erythematosus (SLE) outcomes. MATERIALS AND METHODS: Four DAS were defined: remission off-therapy: SLE Disease Activity Index (SLEDAI)=0, no prednisone or immunosuppressive drugs (IS); remission on-therapy: SLEDAI=0, prednisone ≤5 mg/day and/or IS (maintenance); low (L) DAS: SLEDAI ≤4, prednisone ≤7.5 mg/day and/or IS (maintenance); non-optimally controlled: SLEDAI >4 and/or prednisone >7.5 mg/day and/or IS (induction). Antimalarials were allowed in all. Predefined outcomes were mortality, new damage (increase of at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) point) and severe new damage (increase of at least 3 SDI points). Univariable and multivariable Cox regression models were performed to define the impact of DAS, as time-dependent variable, on these outcomes. RESULTS: 1350 patients were included, 79 died during follow-up, 606 presented new and 177 severe new damage. In multivariable analyses, remission (on/off-therapy) was associated with a lower risk of new (HR 0.60; 95% CI 0.43 to 0.85), and of severe new damage (HR 0.32; 95% CI 0.15 to 0.68); low disease activity status (LDAS) was associated with a lower risk of new damage (HR 0.66; 95% CI 0.48 to 0.93) compared with non-optimally controlled. No significant effect on mortality was observed. CONCLUSIONS: Remission was associated with a lower risk of new and severe new damage; LDAS with a lower risk of new damage after adjusting for other damage confounders.

Reviewing the connection between speech and obstructive sleep apnea.

BACKGROUND: Sleep apnea (OSA) is a common sleep disorder characterized by recurring breathing pauses during sleep caused by a blockage of the upper airway (UA). The altered UA structure or function in OSA speakers has led to hypothesize the automatic analysis of speech for OSA assessment. In this paper we critically review several approaches using speech analysis and machine learning techniques for OSA detection, and discuss the limitations that can arise when using machine learning techniques for diagnostic applications. METHODS: A large speech database including 426 male Spanish speakers suspected to suffer OSA and derived to a sleep disorders unit was used to study the clinical validity of several proposals using machine learning techniques to predict the apnea-hypopnea index (AHI) or classify individuals according to their OSA severity. AHI describes the severity of patients' condition. We first evaluate AHI prediction using state-of-the-art speaker recognition technologies: speech spectral information is modelled using supervectors or i-vectors techniques, and AHI is predicted through support vector regression (SVR). Using the same database we then critically review several OSA classification approaches previously proposed. The influence and possible interference of other clinical variables or characteristics available for our OSA population: age, height, weight, body mass index, and cervical perimeter, are also studied. RESULTS: The poor results obtained when estimating AHI using supervectors or i-vectors followed by SVR contrast with the positive results reported by previous research. This fact prompted us to a careful review of these approaches, also testing some reported results over our database. Several methodological limitations and deficiencies were detected that may have led to overoptimistic results. CONCLUSION: The methodological deficiencies observed after critically reviewing previous research can be relevant examples of potential pitfalls when using machine learning techniques for diagnostic applications. We have found two common limitations that can explain the likelihood of false discovery in previous research: (1) the use of prediction models derived from sources, such as speech, which are also correlated with other patient characteristics (age, height, sex,…) that act as confounding factors; and (2) overfitting of feature selection and validation methods when working with a high number of variables compared to the number of cases. We hope this study could not only be a useful example of relevant issues when using machine learning for medical diagnosis, but it will also help in guiding further research on the connection between speech and OSA.

Formant Frequencies and Bandwidths in Relation to Clinical Variables in an Obstructive Sleep Apnea Population.

OBJECTIVES: We investigated whether differences in formants and their bandwidths, previously reported comparing small sample population of healthy individuals and patients with obstructive sleep apnea (OSA), are detected on a larger population representative of a clinical practice scenario. We examine possible indirect or mediated effects of clinical variables, which may shed some light on the connection between speech and OSA. STUDY DESIGN: In a retrospective study, 241 male subjects suspected to suffer from OSA were examined. The apnea-hypopnea index (AHI) was obtained for every subject using overnight polysomnography. Furthermore, the clinical variables usually reported as predictors of OSA, body mass index (BMI), cervical perimeter, height, weight, and age, were collected. Voice samples of sustained phonations of the vowels /a/, /e/, /i/, /o/, and /u/ were recorded. METHODS: Formant frequencies F1, F2, and F3 and bandwidths BW1, BW2, and BW3 of the sustained vowels were determined using spectrographic analysis. Correlations among AHI, clinical parameters, and formants and bandwidths were determined. RESULTS: Correlations between AHI and clinical variables were stronger than those between AHI and voice features. AHI only correlates poorly with BW2 of /a/ and BW3 of /e/. A number of further weak but significant correlations have been detected between voice and clinical variables. Most of them were for height and age, with two higher values for age and F2 of /o/ and F2 of /u/. Only few very weak correlations were detected between voice and BMI, weight and cervical perimeter, wich are the clinical variables more correlated with AHI. CONCLUSIONS: No significant correlations were detected between AHI and formant frequencies and bandwidths. Correlations between voice and other clinical factors characterizing OSA are weak but highlight the importance of considering indirect or mediated effects of such clinical variables in any research on speech and OSA.

Speech Signal and Facial Image Processing for Obstructive Sleep Apnea Assessment.

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by recurring breathing pauses during sleep caused by a blockage of the upper airway (UA). OSA is generally diagnosed through a costly procedure requiring an overnight stay of the patient at the hospital. This has led to proposing less costly procedures based on the analysis of patients' facial images and voice recordings to help in OSA detection and severity assessment. In this paper we investigate the use of both image and speech processing to estimate the apnea-hypopnea index, AHI (which describes the severity of the condition), over a population of 285 male Spanish subjects suspected to suffer from OSA and referred to a Sleep Disorders Unit. Photographs and voice recordings were collected in a supervised but not highly controlled way trying to test a scenario close to an OSA assessment application running on a mobile device (i.e., smartphones or tablets). Spectral information in speech utterances is modeled by a state-of-the-art low-dimensional acoustic representation, called i-vector. A set of local craniofacial features related to OSA are extracted from images after detecting facial landmarks using Active Appearance Models (AAMs). Support vector regression (SVR) is applied on facial features and i-vectors to estimate the AHI.

Cardiovascular risk profile in Mediterranean patients submitted to bariatric surgery and intensive lifestyle intervention: impact of both interventions after 1 year of follow-up.

BACKGROUND: The aim was to compare obesity-related cardiovascular (CV) risk factors (classic and emerging) and the estimated CV risk at 10 years (calculated by REGICOR) in obese Mediterranean patients submitted to bariatric surgery and intensive lifestyle intervention at baseline and after 1 year of follow-up. METHODS: Patients submitted to bariatric surgery (n = 108) and standardized program of therapeutic changes in lifestyle (n = 90) were retrospectively included. Clinical history, physical examination, and laboratory analysis were routinely determined before weight loss intervention and at 1 year follow-up. RESULTS: Seventy-five percent of the surgery patients had a CV risk lower than 5 % and not one patient had a 10-year CV risk higher than 15 %. The percentage of patients with comorbidities (diabetes and sleep apnea syndrome) was higher in the surgery group. Seventeen of the surgery patients had no comorbidities. The improvement in CV risk profile was significant higher in the surgery group. CV risk benefit of both intervention groups was related to baseline higher CV risk, with type 2 diabetes with poor metabolic control and high cholesterol levels being the most important predictors for surgery patients. Neither body mass index nor excess of weight loss was related to CV risk improvement. CONCLUSIONS: Mediterranean patients undergoing a weight loss intervention have a low CV risk. In comparison with lifestyle intervention, surgery induces a better improvement of CV risk. This benefit is related to estimated CV risk, presence of diabetes, and cholesterol levels at baseline. These observations should be taken into account in order to optimize health resources.

Structural and thermodynamic folding characterization of triosephosphate isomerases from Trichomonas vaginalis reveals the role of destabilizing mutations following gene duplication.

We report the structures and thermodynamic analysis of the unfolding of two triosephosphate isomerases (TvTIM1 and TvTIM2) from Trichomonas vaginalis. Both isoforms differ by the character of four amino acids: E/Q 18, I/V 24, I/V 45, and P/A 239. Despite the high sequence and structural similarities between both isoforms, they display substantial differences in their stabilities. TvTIM1 (E18, I24, I45, and P239) is more stable and less dissociable than TvTIM2 (Q18, V24, V45, and A239). We postulate that the identities of residues 24 and 45 are responsible for the differences in monomer stability and dimer dissociability, respectively. The structural difference between both amino acids is one methyl group. In TvTIMs, residue 24 is involved in packing α-helix 1 against α-helix 2 of each monomer and residue 45 is located at the center of the dimer interface forming a "ball and socket" interplay with a hydrophobic cavity. The mutation of valine at position 45 for an alanine in TvTIM2 produces a protein that migrates as a monomer by gel filtration. A comparison with known TIM structures indicates that this kind of interplay is a conserved feature that stabilizes dimeric TIM structures. In addition, TvTIMs are located in the cytoplasm and in the membrane. As TvTIM2 is an easily dissociable dimer, the dual localization of TvTIMs may be related to the acquisition of a moonlighting activity of monomeric TvTIM2. To our knowledge, this is the simplest example of how a single amino acid substitution can provide alternative function to a TIM barrel protein.

Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production?

Mitochondrial decay plays a central role in the aging process. Although certainly multifactorial in nature, defective operation of the electron transport chain (ETC) constitutes a key mechanism involved in the age-associated loss of mitochondrial energy metabolism. Primarily, mitochondrial dysfunction affects the aging animal by limiting bioenergetic reserve capacity and/or increasing oxidative stress via enhanced electron leakage from the ETC. Even though the important aging characteristics of mitochondrial decay are known, the molecular events underlying inefficient electron flux that ultimately leads to higher superoxide appearance and impaired respiration are not completely understood. This review focuses on the potential role(s) that age-associated destabilization of the macromolecular organization of the ETC (i.e. supercomplexes) may be important for development of the mitochondrial aging phenotype, particularly in post-mitotic tissues.

Acetyl-L-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the L-carnitine content in the rat heart.

The aging heart displays a loss of bioenergetic reserve capacity partially mediated through lower fatty acid utilization. We investigated whether the age-related impairment of cardiac fatty acid catabolism occurs, at least partially, through diminished levels of L-carnitine, which would adversely affect carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme for fatty acyl-CoA uptake into mitochondria for ß-oxidation. Old (24-28 mos) Fischer 344 rats were fed±acetyl-L-carnitine (ALCAR; 1.5% [w/v]) for up to four weeks prior to sacrifice and isolation of cardiac interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria. IFM displayed a 28% (p<0.05) age-related loss of CPT1 activity, which correlated with a decline (41%, p<0.05) in palmitoyl-CoA-driven state 3 respiration. Interestingly, SSM had preserved enzyme function and efficiently utilized palmitate. Analysis of IFM CPT1 kinetics showed both diminished V(max) and K(m) (60% and 49% respectively, p<0.05) when palmitoyl-CoA was the substrate. However, no age-related changes in enzyme kinetics were evident with respect to L-carnitine. ALCAR supplementation restored CPT1 activity in heart IFM, but not apparently through remediation of L-carnitine levels. Rather, ALCAR influenced enzyme activity over time, potentially by modulating conditions in the aging heart that ultimately affect palmitoyl-CoA binding and CPT1 kinetics.

El aislamiento de las venas pulmonares como tratamiento de la fibrilación auricular refractaria / Pulmonary vein isolation in patients with refractory atrial fibrillation

Introducción: La fibrilación auricular (FA) es la arritmia sostenida más común. En pacientes seleccionados, se realiza ablaci¢n por cat‚ter a nivel de las venas pulmonares, en donde se genera actividad ect¢pica que la produce. Se presenta la experiencia en el tratamiento de la FA mediante el aislamiento de venas pulmonares en 152 casos consecutivos. Materiales y m‚todos: La población estuvo constituida por 152 pacientes (122 hombres), edad promedio de 55.58 años. El 81.9 por ciento de la población no presentaba cardiopatía estructural. La forma de presentación fue paroxística en el 65.95 por ciento de los casos, con una historia de arritmia de 7 años en promedio, habiendo cumplido tratamiento con 3 fármacos antiarrítmicos diferentes. Se realizó mapeo no fluoroscópico y ablación de la porción antral de cada vena pulmonar, en forma secuencial. Resultados: La tasa de éxito durante el procedimiento fue el 97.87 por ciento. Se presentaron 12 complicaciones, 4 de ellas derrame pericárdico; ninguno requirió cirugía correctiva. El seguimiento promedio fue de 18+6 meses. En 24 horas pacientes se presentó recurrencia de la FA después del tercer mes de seguimiento; es decir, la tasa de éxito global primario a 12 meses fue 84.04 por ciento para el grupo en cardiopatía y del 64.8 para el grupo con cardiopatía. Conclusión: El aislamiento de las venas pulmonares es una modalidad de tratamiento con una aceptable tasa de éxito primario en casos seleccionados.

Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. In selected patients, catheterablation was performed at the sites of the pulmonary veins where ectopic activity triggers AF. Our experience with AFtreatment by pulmonary vein isolation in 152 consecutive cases is presented and discussed.Methods. Our population consisted mainly of men (122 of 152 patients), with an average age of 55.6 years. Paroxysmal AFwas present in 65.9% of the cases and 81.9% of the population had a structurally normal heart. AF had been present foran average of 7 years. All of the patients fulfilled a treatment period protocol in which three different antiarrhythmic drugswere used first. Nonfluoroscopic mapping and antral pulmonary vein isolation were performed sequentiallyResults. The procedural success rate was 97.9%. There were 12 complications, including 4 pericardial effusions but nonerequired surgical repair. The mean follow-up period was 18±6 months. AF recurred in 24 patients after the third monthof follow-up. There was an 84.04% success rate at 12 months: 88.3% for the group with a normal heart and 64.1% for thegroup with a cardiomyopathy.Conclusion. Isolation of the pulmonary veins can be achieved in appropriately selected cases with AF and has anacceptable rate of success.