Anal cancer risk and HPV infection knowledge and awareness among Hispanic persons living with HIV in Puerto Rico.

Background: Persons living with HIV (PLWH) have a higher risk of persistent infection with human papillomavirus (HPV) and anal cancer. We evaluated knowledge and awareness of HPV infection and risk factors for anal cancer among PLWH in Puerto Rico (PR). Methods: Data from a cross-sectional study (2020-2021) were analyzed (n=212). Inclusion criteria included PLWH, aged ≥ 26 years, and living in PR. Telephone interviews collected information on sociodemographic, lifestyle and clinical characteristics. Two 13-item scales were used to assess knowledge of HPV and anal cancer risk factors; adequate knowledge for both scales were defined as scoring >70%. Logistic regression models using generalized linear models were used to determine the association between 1) HPV infection awareness, 2) HPV infection knowledge, and 3) Anal cancer risk factors knowledge. Results: The median age was 54 years (IQR: 46,58), 67.5% were male, 71.7% reported having an income <$20,000, and 54.3% had an education level of more than high school. HPV awareness was high (82.1%), but only 40.2% and 3.8% had adequate knowledge of HPV and anal cancer risk factors, respectively. In adjusted logistic regression models, men who have sex with men (OR: 1.26, 95%CI: 1.07-1.47) and women (OR: 1.35, 95%CI: 1.15-1.59) aged ≥50 years had higher odds of HPV awareness than heterosexual men in that age group. Moreover, those with history of anal Pap test aged <50 years had more HPV awareness (OR 1.34, 95%CI: 1.08-1.66) than their counterparts. Adequate HPV knowledge was higher among participants with an education level of more than high-school (OR:1.28, 95%CI: 1.10-1.50) and with a history of HPV diagnosis (OR:1.33, 95%CI: 1.08-1.65) than their counterparts. In addition, people with good/very good/excellent health perception had higher odds of HPV knowledge (OR:1.23, 95%CI: 1.03-1.47) than those who reported poor/regular health perception. For anal cancer risk factors, PLWH for ≥15 years had increased odds of having adequate knowledge (OR:1.07, 95%CI: 1.02-1.14) than their counterparts. Conclusions: Despite high awareness of HPV, limited knowledge about HPV and anal cancer risk factors was observed among PLWH. Results from our study highlight the need for educational efforts within this population as an anal cancer prevention strategy.

Heterogeneous Mechanical Stress and Interstitial Fluid Flow Predictions Derived from DCE-MRI for Rat U251N Orthotopic Gliomas.

Mechanical stress and fluid flow influence glioma cell phenotype in vitro, but measuring these quantities in vivo continues to be challenging. The purpose of this study was to predict these quantities in vivo, thus providing insight into glioma physiology and potential mechanical biomarkers that may improve glioma detection, diagnosis, and treatment. Image-based finite element models of human U251N orthotopic glioma in athymic rats were developed to predict structural stress and interstitial flow in and around each animal's tumor. In addition to accounting for structural stress caused by tumor growth, our approach has the advantage of capturing fluid pressure-induced structural stress, which was informed by in vivo interstitial fluid pressure (IFP) measurements. Because gliomas and the brain are soft, elevated IFP contributed substantially to tumor structural stress, even inverting this stress from compressive to tensile in the most compliant cases. The combination of tumor growth and elevated IFP resulted in a concentration of structural stress near the tumor boundary where it has the greatest potential to influence cell proliferation and invasion. MRI-derived anatomical geometries and tissue property distributions resulted in heterogeneous interstitial fluid flow with local maxima near cerebrospinal fluid spaces, which may promote tumor invasion and hinder drug delivery. In addition, predicted structural stress and interstitial flow varied markedly between irradiated and radiation-naïve animals. Our modeling suggests that relative to tumors in stiffer tissues, gliomas experience unusual mechanical conditions with potentially important biological (e.g., proliferation and invasion) and clinical consequences (e.g., drug delivery and treatment monitoring).

Findings and Challenges in Replacing Traditional Uterine Cervical Cancer Diagnosis with Molecular Tools in Private Gynecological Practice in Mexico.

We have been encouraging practicing gynecologists to adopt molecular diagnostics tests, PCR, and cancer biomarkers, as alternatives enabled by these platforms, to traditional Papanicolaou and colposcopy tests, respectively. An aliquot of liquid-based cytology was used for the molecular test [high-risk HPV types, (HR HPV)], another for the PAP test, and one more for p16/Ki67 dual-stain cytology. A total of 4499 laboratory samples were evaluated, and we found that 25.1% of low-grade samples and 47.9% of high-grade samples after PAP testing had a negative HR HPV-PCR result. In those cases, reported as Pap-negative, 22.1% had a positive HR HPV-PCR result. Dual staining with p16/Ki67 biomarkers in samples was positive for HR HPV, and 31.7% were also positive for these markers. Out of the PCR results that were positive for any of these HR HPV subtypes, n 68.3%, we did not find evidence for the presence of cancerous cells, highlighting the importance of performing dual staining with p16/Ki67 after PCR to avoid unnecessary colposcopies. The encountered challenges are a deep-rooted social reluctance in Mexico to abandon traditional Pap smears and the opinion of many specialists. Therefore, we still believe that colposcopy continues to be a preferred procedure over the dual-staining protocol.

Association of tobacco use and the presence of anal warts in people who attend the anal Neoplasia clinic in Puerto Rico.

Background: Limited research exists regarding the association between smoking and anal warts. In this study, we evaluated this association among a clinic-based Hispanic population in Puerto Rico. Methods: Cross-sectional study among eligible patients seen at the Anal Neoplasia Clinic of the University of Puerto Rico Comprehensive Cancer Center (2016-2023) (n = 920). Sociodemographic and clinical variables were collected from medical records. Patients underwent a high-resolution anoscopy (HRA) during the clinical visit; physicians assessed anal condylomas on HRA. Poisson regression models with robust standard errors were used to evaluate the association between smoking and anal warts. Demographic and clinical factors were also assessed. Results: The mean age of participants was 45.8 ± 13.1 years, 66.4 % were men, and 21.6 % were current smokers. While 10.8 % self-reported a history of anogenital condylomas, 18.9 % had anal condylomas on clinical evaluation. A higher prevalence of anal condylomas was observed among current smokers (PR = 1.28, 95 % CI: 0.94-1.75) in comparison to non-smokers in adjusted analysis, but this was not statistically significant. However, a higher prevalence of anal condylomas was observed among younger individuals (PR = 0.96, 95 % CI: 0.96-0.98) and individuals with anal high-grade squamous intraepithelial lesions (HSIL) as compared to those with benign histology (PR = 1.74. 95 % CI: 1.09-2.77). Conclusions: Although current smoking seemed to be positively associated with anal condylomas in this high-risk Hispanic population, this finding was not statistically significant as the power to detect an association was limited. However, younger age and HSIL diagnosis were associated with a higher prevalence of anal condylomas.

CONSENSO ARGENTINO SOBRE LA TRANSICIÓN DE LOS CUIDADOS PEDIÁTRICOS A LOS CUIDADOS ADULTOS EN PACIENTES CON ENFERMEDADES CONGÉNITAS DEL METABOLISMO / CONSENSUS STATEMENT ON THE TRANSITION FROM PEDIATRIC CARE TO ADULT CARE IN PATIENTS WITH INBORN ERRORS OF METABOLISM IN ARGENTINA

Introducción: Los errores congénitos del metabolismo (ECM) son enfermedades producidas por trastornos genéticos que alteran la función de distintas vías metabólicas. La transición desde el sistema de atención médica pediátrica a la de adultos es un proceso clave en el desarrollo evolutivo de las personas con condiciones crónicas de salud. Los servicios de salud presentan fallas en satisfacer las necesidades de los jóvenes y sus familias. El objetivo fue definir un conjunto de herramientas y recomendaciones, adaptadas al contexto local de Argentina, para orientar al equipo de salud en el acompañamiento del proceso de transición de cuidados. Asimismo, se buscó analizar barreras y facilitadores para su implementación. Métodos: se definieron preguntas clínicas que se respondieron con la mejor evidencia científica disponible. Se elaboraron recomendaciones para jóvenes y adolescentes con diagnóstico de ECM que se encuentren en proceso de transición entre el servicio de atención pediátrico al servicio de adultos. Las recomendaciones elaboradas se consensuaron con expertos en la temática a través de un método Delphi. Resultados: se elaboraron y consensuaron 13 recomendaciones que permitirán guiar el proceso de transición de los cuidados pediátricos al de adultos en personas con ECM. Conclusiones: estas recomendaciones ayudarán al equipo de salud a mejorar la calidad de atención de estos pacientes y garantizar que ellos y sus familias tengan una experiencia adecuada durante todo el proceso de transición

Introduction: Inborn errors of metabolism (IEM) are diseases caused by genetic disorders that alter the function of different metabolic pathways. The transition from the pediatric to adult health care system is a key process in the evolutionary development of patients with chronic health conditions. Health services are failing to meet the needs of young patients and their families. The objective was to define a set of tools and recommendations, adapted to the local context of Argentina, to guide the health team in accompanying the process of transition. Likewise, it sought to analyze barriers and facilitators for its implementation. Methods: clinical questions were defined and answered with the best available scientific evidence. Recommendations were developed for young patients and adolescents diagnosed with IEM who are in the process of transitioning from the pediatric care service to the adult service. The recommendations developed were agreed with experts in the field through a Delphi method. Results: 13 recommendations were developed and agreed upon to guide the transition process from pediatric to adult care in people with IEM. Conclusions: These recommendations will help the health team improve the quality of care for these patients and ensure that they and their families have an adequate experience throughout the transition process

MT5-MMP promotes neuroinflammation, neuronal excitability and Aß production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease.

BACKGROUND: Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1ß)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1ß tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation. METHODS: To test this hypothesis, we used 11-14 day in vitro primary cortical cultures from wild type, MT5-MMP-/-, 5xFAD and 5xFAD/MT5-MMP-/- mice, and evaluated the impact of MT5-MMP deficiency and IL-1ß treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction. RESULTS: 5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1ß, as well as decreased stability of recombinant IL-1ß. The levels of amyloid beta peptide (Aß) were similar in 5xFAD and wild-type cultures, and IL-1ß treatment did not affect Aß levels. Instead, the absence of MT5-MMP significantly reduced Aß by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1ß and APP/Aß, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aß. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1ß treatment. CONCLUSIONS: Neuroinflammation and hyperexcitability precede Aß accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aß metabolism. In addition, MT5-MMP deficiency prevents IL-1ß-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.

Non-fluoroscopic catheter ablation of arrhythmias with origin at the summit of the left ventricle.

BACKGROUND: Catheter ablation of ventricular arrhythmias (VAs) arising from the left ventricular Summit (LVS) is challenging and requires high-dose fluoroscopy to limit vascular damage of the coronary arteries. Ionizing radiation can increase the incidence of malignancies to both patient and operator. This study describes outcomes of catheter ablation of LVS VAs using intracardiac echo-facilitated 3D electroanatomical mapping (ICE-3D) to avoid fluoroscopy. METHODS: Twenty-six patients (47 ± 17 years old; 52% males; median ejection fraction 55 ± 13%) with premature ventricular contractions or ventricular tachycardia underwent catheter ablation. VAs were localized using ICE-3D with arrhythmia foci being mapped at the LVS. Focal ablation was performed using a 3.5-mm open-irrigated, contact force sensing radiofrequency catheter. RESULTS: Acute success and recurrence rates were 84% and 24%, respectively. Holter burden was significantly reduced (24 ± 15% to 1.5 ± 2%; P = 0.01) after ablation. The use of zero fluoroscopy was achieved in 100% of cases. No major complications were observed. CONCLUSIONS: Zero fluoroscopy catheter ablation of LVS VAs using ICE-3D mapping is feasible and effective.

Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT4 receptors (5-HT4Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-ß peptide (Aß) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HT4R agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HT4R as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action.

Predictores de recurrencia y resultados en la ablación de la fibrilación auricular paroxística / Predictors of Recurrence and Outcomes in Catheter Ablation of Paroxysmal Atrial Fibrillation

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Fibrilación auricular paroxística: crioablación versus ablación por radiofrecuencia / Paroxysmal Atrial Fibrillation: Cryoballoon versus Radiofrequency Catheter Ablation

Introducción: En la ablación de la fibrilación auricular paroxística por radiofrecuencia o crioablación existe poca información acerca de la superioridad de una técnica sobre la otra. Objetivo: Comparar los resultados agudos y a largo plazo de las técnicas de ablación de la fibrilación auricular paroxística por catéter irrigado y mediante crioablación con balón de segunda generación. Material y métodos: Estudio retrospectivo, observacional, unicéntrico, en el que se evaluaron 159 pacientes consecutivos con fibrilación auricular paroxística, a los cuales se les realizó aislamiento de venas pulmonares mediante radiofrecuencia o crioablación. Se examinaron las características de los pacientes y del procedimiento, así como el éxito inmediato y en el seguimiento a 12 meses. Resultados: Sobre un total de 159 pacientes, 89 procedimientos se realizaron con crioablación y 70 mediante radiofrecuencia. El seguimiento promedio fue de 12 meses. No se encontraron diferencias significativas en las características de la población. La tasa de éxito inmediato fue del 97,8% con crioablación versus 97,1% con radiofrecuencia (p = 0,8). La tasa libre de fibrilación auricular a los 12 meses luego de un único procedimiento fue del 77,5% mediante crioablación versus 71,4% con radiofrecuencia (p = 0,33). La crioablación con balón se asoció con menor duración del procedimiento respecto de la radiofrecuencia (60,19 ± 15 minutos frente a 75,8 ± 31 minutos, respectivamente; p < 0,00001), con menor tiempo en la aurícula izquierda (45 ± 14 minutos frente a 58 ± 26 minutos; p < 0,00001). Los tiempos de fluoroscopia fueron significativamente mayores para el grupo crioablación (18 ± 3,76 minutos vs. 13 ± 2,23 minutos para radiofrecuencia; p < 0,0001). La tasa de complicaciones crioablación vs. radiofrecuencia fue similar (p = 0,76). Conclusión: La crioablación con balón, en comparación con radiofrecuencia mediante catéter irrigado, se asoció con menor tiempo del procedimiento, similar tasa de complicaciones y tasa libre de fibrilación auricular a los 12 meses luego de un único procedimiento.

Intracardiac echo-facilitated 3D electroanatomical mapping of ventricular arrhythmias from the papillary muscles: assessing the 'fourth dimension' during ablation.

AIMS: Ventricular arrhythmias (VA) originating from a papillary muscle (PM) have recently been described as a distinct clinical entity with peculiar features that make its treatment with catheter ablation challenging. Here, we report our experience using an intracardiac echo-facilitated 3D electroanatomical mapping approach in a case series of patients undergoing ablation for PM VA. METHODS AND RESULTS: Sixteen patients who underwent catheter ablation for ventricular tachycardia (VT) or symptomatic premature ventricular contractions originating from left ventricular PMs were included in the study. A total of 24 procedures (mean 1.5 per patient) were performed: 15 using a retrograde aortic approach and 9 using a transseptal approach. Integrated intracardiac ultrasound for 3D electroanatomical mapping was used in 15 of the 24 procedures. The posteromedial PM was the most frequent culprit for the clinical arrhythmia, and the body was the part of the PM most likely to be the successful site for ablation. The site of ablation was identified based on the best pace map matching the clinical arrhythmia and the site of earliest the activation. At a mean follow-up of 10.5 ± 7 months, only two patients had recurrent arrhythmias following a repeat ablation procedure. CONCLUSION: An echo-facilitated 3D electroanatomical mapping allows for real-time creation of precise geometries of cardiac chambers and endocavitary structures. This is useful during procedures such as catheter ablation of VAs originating from PMs, which require detailed representation of anatomical landmarks. Routine adoption of this technique should be considered to improve outcomes of PM VA ablation.

Results of Cryoenergy and Radiofrequency-Based Catheter Ablation for Treating Ventricular Arrhythmias Arising From the Papillary Muscles of the Left Ventricle, Guided by Intracardiac Echocardiography and Image Integration.

BACKGROUND: Catheter radiofrequency ablation of ventricular arrhythmias (VAs) arising from the left ventricle's papillary muscles has been associated with inconsistent results. The use of cryoenergy versus radiofrequency has not been compared yet. This study compares outcomes and complications of catheter ablation of VA from the papillary muscles of the left ventricle with either cryoenergy or radiofrequency. METHODS AND RESULTS: Twenty-one patients (40±12 years old; 47% males; median ejection fraction 59±7.3%) with drug refractory premature ventricular contractions or ventricular tachycardia underwent catheter cryoablation or radiofrequency ablation. VAs were localized using 3-dimensional mapping, multidetector computed tomography, and intracardiac echocardiography, with arrhythmia foci being mapped at either the anterolateral papillary muscle or posteromedial papillary muscles of the left ventricle. Focal ablation was performed using an 8-mm cryoablation catheter or a 4-mm open-irrigated radiofrequency catheter, via transmitral approach. Acute success rate was 100% for cryoenergy (n=12) and 78% for radiofrequency (n=9; P=0.08). Catheter stability was achieved in all patients (100%) treated with cryoenergy, and only in 2 (25%) patients treated with radiofrequency (P=0.001). Incidence of multiple VA morphologies was observed in 7 patients treated with radiofrequency (77.7%), whereas none was observed in those treated with cryoenergy (P=0.001). VA recurrence at 6 months follow-up was 0% for cryoablation and 44% for radiofrequency (P=0.03). CONCLUSIONS: Cryoablation was associated with higher success rates and lower recurrence rates than radiofrequency catheter ablation, better catheter stability, and lesser incidence of polymorphic arrhythmias.

MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro.

We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer's disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP-/- mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aß) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein (APP), including soluble APPα (sAPPα), sAPPß and the MT5-MMP-linked fragment of 95 kDa, sAPP95. However, the lack of MT5-MMP did not affect the activity of ß- and γ-secretases. In cultured HEKswe cells, transiently expressed MT5-MMP localized to early endosomes and increased the content of APP and Aß40 in these organelles, as well as Aß levels in cell supernatants. This is the first evidence that the pro-amyloidogenic features of MT5-MMP lie, at least in part, on the ability of the proteinase to promote trafficking into one of the amyloidogenic subcellular loci. Together, our data further support the pathogenic role of MT5-MMP in AD and that its inhibition improves the functional and pathological outcomes, in this case in the frontal cortex. These data also support the idea that MT5-MMP could become a novel therapeutic target in AD.

MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.

Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimer's disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aß) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1ß (IL-1ß) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, ß- and γ-secretases. The positive impact of MT5-MMP deficiency was still noticeable at 16 months of age, as illustrated by reduced amyloid burden and gliosis, and a better preservation of the cortical neuronal network and synaptophysin levels in bigenic mice. MT5-MMP expressed in HEKswe cells colocalized and co-immunoprecipitated with APP and significantly increased the levels of Aß and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were significantly reduced in brain homogenates of 5xFAD/MT5-MMP(-/-) mice, supporting altogether the idea that MT5-MMP influences APP processing. MT5-MMP emerges as a new pro-amyloidogenic regulator of APP metabolism, whose deficiency alleviates amyloid pathology, neuroinflammation and cognitive decline.

Experiencia preliminar de crioablación con catéter balón en fibrilación auricular paroxística: serie de 100 casos / Preliminary Experience with Cryoballoon Ablation in Paroxysmal Atrial Fibrillation: 100-case series

Introducción: La evaluación de nuevas fuentes de energía para el tratamiento de la fibrilación auricular paroxística (FAP) es de gran interés clínico. La crioablación con catéter balón se presenta como una alternativa atractiva para los pacientes con FAP refractaria al tratamiento farmacológico. Objetivos: Describir la experiencia inicial llevada a cabo en nuestra institución desde noviembre de 2013 hasta mayo de 2015 con la utilización de la técnica de crioablación con catéter balón en pacientes con FAP y evaluar la seguridad, la eficacia y las características del procedimiento. Material y métodos: Estudio retrospectivo observacional de un solo centro en el que se examinaron los 100 primeros casos consecutivos realizados con criobalón Arctic Front® de 28 mm (Medtronic, Inc.) desde noviembre de 2013 hasta mayo de 2015. Se definió éxito inmediato al aislamiento de la totalidad de las venas pulmonares. La recurrencia de fibrilación auricular se evaluó en el grupo de 72 pacientes que tuvieron un seguimiento de más de 6 meses. Resultados: La duración del procedimiento fue de 78,03 ± 19,84 minutos con un tiempo de fluoroscopia de 20,79 ± 11,91 minutos y una dosis de radiación total de 202,93 ± 81 mGy La tasa de éxito inmediato fue del 100%. La tasa de complicaciones fue del 1% a raíz de una parálisis diafragmática transitoria. En el seguimiento de los pacientes con más de 6 meses del procedimiento, la tasa libre de fibrilación auricular fue del 81,95%. Conclusiones: Nuestra experiencia inicial con crioablación resultó segura y eficaz, con una tasa de éxito inmediato elevada y una tasa de complicaciones baja. El procedimiento resultó ser de corta duración y la tasa libre de fibrilación auricular en el seguimiento fue más que aceptable.

Background: The evaluation of novel energy sources for the treatment of paroxysmal atrial fibrillation (PAF) is of great clinical interest. Cryoballoon ablation appears as an attractive alternative for patients with PAF refractory to pharmacological therapy Objectives: The purpose of this study was to describe the initial cryoballoon ablation experience performed at our institution from November 2013 to May 2015 in patients with PAF, evaluating the safety, efficacy and characteristics of the procedure. Methods: This was a retrospective, observational study analyzing the first 100 consecutive cases performed with 28-mm Arctic Front™ cryoballoon (Medtronic, Inc.) from November 2013 to May 2015. Immediate success was defined as isolation of all pulmonary veins. Atrial fibrillation recurrence was assessed in 72 patients with more than 6 months follow-up. Results: The procedure lasted 78.03±19.84 min with fluoroscopy duration of 20.79±11.91 min and a total radiation dose of 202.93±81 mGy The rate of acute success was 100%. The complication rate was 1% due to transient diaphragmatic paralysis. The AF-free rate was 81.95% in patients with over 6-months follow-up. Conclusions: Our initial experience with cryoballoon ablation was safe and effective with a high rate of acute success and low rate of complications. The procedure was short and the AF-free rate was more than acceptable.

Solution structure of the reduced form of human peroxiredoxin-6 elucidated using zero-length chemical cross-linking and homology modelling.

Peroxiredoxin-6 (PRDX6) is an unusual member of the peroxiredoxin family of antioxidant enzymes that has only one evolutionarily conserved cysteine. It reduces oxidized lipids and reactive oxygen species (ROS) by oxidation of the active-site cysteine (Cys(47)) to a sulfenic acid, but the mechanism for conversion back to a thiol is not completely understood. Moreover, it has phospholipase A2 (PLA2) activity in addition to its peroxidase activity. Interestingly, some biochemical data are inconsistent with a known high-resolution crystal structure of the catalytic intermediate of the protein, and biophysical data indicate that the protein undergoes conformational changes that affect enzyme activity. In order to further elucidate the solution structure of this important enzyme, we used chemical cross-linking coupled with high-resolution MS (CX-MS), with an emphasis on zero-length cross-links. Distance constraints from high confidence cross-links were used in homology modelling experiments to determine a solution structure of the reduced form of the protein. This structure was further evaluated using chemical cross-links produced by several homo-bifunctional amine-reactive cross-linking reagents, which helped to confirm the solution structure. The results show that several regions of the reduced version of human PRDX6 are in a substantially different conformation from that shown for the crystal structure of the peroxidase catalytic intermediate. The differences between these two structures are likely to reflect catalysis-related conformational changes. These studies also demonstrate that CX-MS using zero-length cross-linking is a powerful strategy for probing protein conformational changes that is complementary to alternative methods such as crystallographic, NMR and biophysical studies.

Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the extracellular matrix turnover by inhibiting the proteolytic activity of matrix metalloproteinases (MMPs). TIMP-1 also displays MMP-independent activities that influence the behavior of various cell types including neuronal plasticity, but the underlying molecular mechanisms remain mostly unknown. The trans-membrane receptor low-density lipoprotein receptor-related protein-1 (LRP-1) consists of a large extracellular chain with distinct ligand-binding domains that interact with numerous ligands including TIMP-2 and TIMP-3 and a short transmembrane chain with intracellular motifs that allow endocytosis and confer signaling properties to LRP-1. We addressed TIMP-1 interaction with recombinant ligand-binding domains of LRP-1 expressed by CHO cells for endocytosis study, or linked onto sensor chips for surface plasmon resonance analysis. Primary cortical neurons bound and internalized endogenous TIMP-1 through a mechanism mediated by LRP-1. This resulted in inhibition of neurite outgrowth and increased growth cone volume. Using a mutated inactive TIMP-1 variant we showed that TIMP-1 effect on neurone morphology was independent of its MMP inhibitory activity. We conclude that TIMP-1 is a new ligand of LRP-1 and we highlight a new example of its MMP-independent, cytokine-like functions.

Cry1Ac protoxin from Bacillus thuringiensis promotes macrophage activation by upregulating CD80 and CD86 and by inducing IL-6, MCP-1 and TNF-α cytokines.

Bacillus thuringiensis Cry1Ac protoxin (pCry1Ac) is a promising mucosal adjuvant, but its action mechanism is unknown. We examined in vivo whether pCry1Ac promotes the activation of macrophages in the peritoneum, spleen and mesenteric lymph nodes or in the lungs and bronchoalveolar lavage after intraperitoneal or intranasal pCry1Ac administration, respectively, in BALB/c mice. pCry1Ac upregulated the costimulatory molecules CD80 and CD86 in these macrophages, but with distinct kinetics. In vitro stimulation of resident macrophages with pCry1Ac upregulated CD80 and CD86 and enhanced the production of the pro-inflammatory cytokines TNF-α, IL-6 and MCP-1. To investigate whether the pCry1Ac-induced activation was mediated through MAPK pathways, we pretreated RAW 264.7 cells with signaling inhibitors of MEK, JNK and p38 MAPKs (PD98059, SP600125 and SB203580, respectively). pCry1Ac-induced upregulation of CD86 and CD80 was partially inhibited by the MEK inhibitor. While LPS-induced upregulation mechanisms of CD80 and CD86 appear to be different; as these were particularly inhibited by MEK and JNK inhibitors, respectively. pCry1Ac-induced IL-6 and MCP-1 production was especially inhibited with the p38 MAPK inhibitor, whereas TNF-α was only slightly inhibited upon treatment with JNK and p38 MAPK inhibitors. Therefore macrophage stimulation with pCry1Ac induced the upregulation of CD80 and CD86, and the production of IL-6, TNF-α and MCP-1, possibly, through the MEK and p38 MAPK pathways. It also promoted the nuclear translocation of NF-κB p50 and p65, the upregulation of MHC-II, and the activation of T CD4+ cells. These results suggest that pCry1Ac induced macrophage activation through mechanisms which differ partially from the LPS-induced.

Three-dimensional esophagus reconstruction and monitoring during ablation of atrial fibrillation: combination of two imaging techniques.

OBJECTIVE: The purpose of the study was to determine the accuracy of a novel three-dimensional (3D) imaging integration technique of the esophagus combining multislice computed tomography (CT) scan of the esophagus into the three-dimensional (3D) electroanatomic map just before pulmonary vein (PV) isolation. METHODS: We included 94 consecutive patients with symptomatic atrial fibrillation (AF) who underwent ablation. All patients had a CT performed prior procedure that was integrated to the 3D reconstruction electromechanical map of the atrium and the esophagus (Verismo(TM), EnSite® NavX version 7.0 J, St. Jude Medical Inc.). During the procedure, a quadripolar electrophysiology catheter placed in the esophagus was used for mapping and to monitor esophagus position. Integrated (fusion) images were used to determinate the esophagus position compared to the left atrium posterior wall and its relationship with PV ostiums. We compared esophagus position by CT and fusion images. RESULTS: Procedural success was 97.9% with no fatal complications. Esophagus locations were as follows: left 57%, right 7%, oblique course 11% and central 25%. Agreements in esophageal position between CT and fusion imaging techniques were 83.3% and 64% for patients with a recent (≤48 h) and non-recent CT assessment (>48 h), respectively. Throughout the procedure, esophagus stability was 88.8% (lateral displacement<15 mm). Ablative strategy was modified in 51% of the cases due to awareness of esophagus location. CONCLUSION: Guidance of AF ablation with 3D fusion images was safe and effective. CT images of the esophagus, especially if acquired within 48 h before ablation, ensure appropriate intraprocedural localization of the esophagus.

Role of matrix metalloproteinases in migration and neurotrophic properties of nasal olfactory stem and ensheathing cells.

Adult olfactory ectomesenchymal stem cells (OE-MSCs) and olfactory ensheathing cells (OECs), both from the nasal olfactory lamina propria, display robust regenerative properties when transplanted into the nervous system, but the mechanisms supporting such therapeutic effects remain unknown. Matrix metalloproteinases (MMPs) are an important family of proteinases contributing to cell motility and axonal outgrowth across the extracellular matrix (ECM) in physiological and pathological conditions. In this study, we have characterized for the first time in nasal human OE-MSCs the expression profile of some MMPs currently associated with cell migration and invasiveness. We demonstrate different patterns of expression for MMP-1, MMP-2, MMP-9, and MT1-MMP upon cell migration when compared with nonmigrating cells. Our results establish a correspondence between the localization of these proteinases in the migration front with the ability of cells to migrate. Using various modulators of MMP activity, we also show that at least MMP-2, MMP-9, and MT1-MMP contribute to OE-MSC migration in an in vitro 3D test. Furthermore, we demonstrate under the same conditions of culture used for in vivo transplantation that OE-MSCs and OECs secrete neurotrophic factors that promote neurite outgrowth of cortical and dorsal root ganglia (DRG) neurons, as well as axo-dendritic differentiation of cortical neurons. These effects were abolished by the depletion of MMP-2 and MMP-9 from the culture conditioned media. Altogether, our results provide the first evidence that MMPs may contribute to the therapeutic features of OE-MSCs and OECs through the control of their motility and/or their neurotrophic properties. Our data provide new insight into the mechanisms of neuroregeneration and will contribute to optimization of cell therapy strategies.