Characterization of the Electrophysiological Characteristics of Chronic Atrial Fibrillation for Efficient Simulations.

Atrial biophysical simulations have the potential to enhance outcomes by enabling the simulation of pharmacological and ablative strategies. However, the high computational times associated with such simulations render them unsuitable for diagnostic purposes. To address this challenge, discrete models such as cellular automata (CA) have been developed, which consider a finite number of states, thus significantly reducing computational times. Yet, there is a pressing need to determine whether CA can replicate pathological simulations with accuracy. The analysis of simulations under different degrees of electrical remodeling shows an expected increase of Action Potential Duration (APD) with the previous Diastolic Interval (DI) interval, indicating short-term memory of atrial cardiomyocytes: shorter APD0 provoked shorter APD+1, and previous DI has a similar effect on APD+1. Independent prediction using both APD0 and DI was found to provide a far better estimation of APD+1 values, compared to relying on DI alone (p<<0.01). Finally, the CA models were able to replicate reentrant patterns and cycle lengths of different states of atrial remodeling with a high degree of accuracy when compared to biophysical simulations. Overall, the use of atrial CA with short-term memory allows accurate reproduction of arrhythmic behavior in pathological tissue within a clinically relevant timeframe.Clinical Relevance- Discrete electrophysiological models simulate pathological self-sustained arrhythmias in diagnostic times.

Assessment of Risk for Ventricular Tachycardia based on Extensive Electrophysiology Simulations.

Patients that have suffered a myocardial infarction are at high risk of developing ventricular tachycardia. Patient stratification is often determined by characterization of the underlying myocardial substrate by cardiac imaging methods. In this study, we show that computer modeling of cardiac electrophysiology based on personalized fast 3D simulations can help to assess patient risk to arrhythmia. We perform a large simulation study on 21 patient digital twins and reproduce successfully the clinical outcomes. In addition, we provide the sites which are prone to sustain ventricular tachycardias, i.e, onset sites around the scar region, and validate if they colocalize with exit sites from slow conduction channels.Clinical relevance- Fast electrophysiological simulations can provide advanced patient stratification indices and predict arrhythmic susceptibility to suffer from ventricular tachycardia in patients that have suffered a myocardial infarction.

Hydrolat of Helichrysum italicum promotes tissue regeneration during wound healing.

Wound healing is a dynamic process involving different cell types with distinct roles according to the stages of healing. Fibroblasts and stem cells actively participate in tissue regeneration. A proper stimulation could contribute to enhance wound healing process-es. Helichrysum italicum (H. italicum) is a medical plant well described for its pharmacological, antimicrobial, and anti-inflammatory activities. Aim of the present work was to examine the effect of the hydrolat derivate from H. italicum on stem cells isolated from skin and fibroblasts in vitro in presence or absence of tissue damage. The viability and proliferation of all cell types cultured in dif-ferent conditions were analyzed by MTT and BrdU assays. Cell proliferation after wound was analyzed with scratch test. Also, the expression of the main genes involved in tissue repair was evaluated by RT-qPCR analysis. Here we describe the capability of hy-drolat of H. italicum to promote tissue regeneration after scratch test both in stem cells and in fibroblasts. Moreover, the gene ex-pression analysis revealed that, hydrolat of H. italicum is also able to enhance stemness related. In conclusion our results are en-couraging, highlighting novel regenerative properties of hydrolat of H. italicum and paving the way for future application of this wasting product in accelerating wound healing.

Lactic acid bacteria biofilms and their ability to mitigate Escherichia coli O157:H7 surface colonization.

Lactic acid bacteria (LAB) exert antagonistic activities against diverse microorganisms, including pathogens. In this work, we aimed to investigate the ability of LAB strains isolated from food to produce biofilms and to inhibit growth and surface colonization of Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 at 10°C. The ability of 100 isolated LAB to inhibit EHEC O157:H7 NCTC12900 growth was evaluated in agar diffusion assays. Thirty-seven LAB strains showed strong growth inhibitory effect on EHEC. The highest inhibitory activities corresponded to LAB strains belonging to Lactiplantibacillus plantarum, Pediococcus acidilactici and Pediococcus pentosaceus species. Eighteen out of the 37 strains that showed growth inhibitory effects on EHEC also had the ability to form biofilms on polystyrene surfaces at 10°C and 30°C. Pre-established biofilms on polystyrene of four of these LAB strains were able to reduce significantly surface colonization by EHEC at low temperature (10°C). Among these four strains, Lact. plantarum CRL 1075 not only inhibited EHEC but also was able to grow in the presence of the enteric pathogen. Therefore, this strain proved to be a good candidate for further technological studies oriented to its application in food-processing environments to mitigate undesirable surface contaminations of E. coli.

Evolución hacia la era digital de la cirugía ortognática: experiencia en un centro universitario / Evolution towards the digital era of orthognatic surgery: experience in a university center

Resumen Introducción: La incorporación de tecnologías en la práctica quirúrgica, ha cambiado la forma de enfrentar el proceso quirúrgico. Objetivo: Describir la experiencia de los últimos 9 años, en cirugía ortognática, con la incorporación de la cefalometría 3D. Materiales y Método: Se realizó una revisión retrospectiva de pacientes operados de cirugía ortognática durante el período enero de 2011 a agosto de 2018. Se registraron datos demográficos, quirúrgicos, tipo de planificación quirúrgica, complicaciones y resultados a largo plazo. Resultados: 21 pacientes requirieron cirugías ortognáticas. Se realizaron 16 cirugías bimaxilares (76%), 3 cirugías de avance maxilar superior (14%) y 2 cirugías de osteotomía sagital de rama (10%). Las principales etiologías fueron: 67% maloclusión clase III (n = 14), 28% maloclusión clase II (n = 6) y 5% desviación mandibular (n = 1). La planificación prequirúrgica virtual fue utilizada en 11 pacientes (52%). La tasa de complicaciones Clavien-Dindo > III fue 4,8% (n = 1). Conclusiones: En nuestra experiencia, las técnicas de cirugía ortognática son seguras. Las complicaciones de la serie fueron escasas y bien toleradas por los pacientes. Durante los últimos años y, de acuerdo a los avances tecnológicos, la incorporación de la planificación quirúrgica virtual 3D favoreció el desarrollo de la cirugía ortognática en nuestro centro.

Introduction: Technological advances have been incorporated into cranio-maxillo-facial surgery changing the clinical practice of surgeons. Aim: The aim of this article is to describe our experience in orthognatic surgery in the last 9-years, with the incorporation of 3D cephalometry. Materials and Method: A retrospective chart review was performed from January 2011 to August 2018 on patients undergoing Orthognatic Surgery. Demographic and surgical data, type of surgical planning, complications and long-term results were recorded. Results: A total of 21 patients underwent orthognatic surgery. Average age was 28 years (DE 8.1), 11 men (52.3%) and 10 women (47.61%). The principal surgeries performed were: 16 (76%) bimaxillary, 3 maxillary advancement surgery 3 (14%) and bilateral sagital split osteotomy 2 (10%). Ethiologies were: 14 patients (this 67%) with malocclusion class III, 6 patients (28%) with malocussion class II, and 1 patient (5%) with mandibular deviation. Virtual 3D presurgical planning was used in 11 patients (52%). The total of complications Clavien-Dindo > III was 4.8% (n = 1). None patient required reoperation. Satisfaction rate with the procedure was high. Conclusions: Based on our experience, orthognatic surgery techniques are safe. The complication rate was lower and well tolerated by patients. The introduction of virtual planning provided a better scenario to develop maxillo-facial surgery.

Lung injury caused by occupational exposure to particles from the industrial combustion of cashew nut shells: a mice model.

Cashew nut shells (CNS) is already used in the energy matrix of some industries. However, it is necessary to know the harmful health effects generated by exposure to pollutants of its combustion, especially in the workers exposed to industrial pollutants. In addition, it is known that the incidence of asthma grows among workers in industries, and due to its previously reported biological effects of anethole, these will also be objects of the present study. We used 64 Balb/C mice, randomly divided into eight groups. Groups were sensitized and challenged with saline or ovalbumin, then subjected to intranasal instillation of 30 µg PM4.0 (occupational exposure) from the combustion of CNS or saline, and then were subsequently treated with oral anethole 300 mg/kg or 0.1% Tween 80. Our results serve as a starting point for the development of public policies for the prevention of diseases in workers that are exposed to the pollutants coming from industries.

Combination of phenotype and polygenic risk score in breast cancer risk evaluation in the Spanish population: a case -control study.

BACKGROUND: In recent years, the identification of genetic and phenotypic biomarkers of cancer for prevention, early diagnosis and patient stratification has been a main objective of research in the field. Different multivariable models that use biomarkers have been proposed for the evaluation of individual risk of developing breast cancer. METHODS: This is a case control study based on a population-based cohort. We describe and evaluate a multivariable model that incorporates 92 Single-nucleotide polymorphisms (SNPs) (Supplementary Table S1) and five different phenotypic variables and which was employed in a Spanish population of 642 healthy women and 455 breast cancer patients. RESULTS: Our model allowed us to stratify two groups: high and low risk of developing breast cancer. The 9th decile included 1% of controls vs 9% of cases, with an odds ratio (OR) of 12.9 and a p-value of 3.43E-07. The first decile presented an inverse proportion: 1% of cases and 9% of controls, with an OR of 0.097 and a p-value of 1.86E-08. CONCLUSIONS: These results indicate the capacity of our multivariable model to stratify women according to their risk of developing breast cancer. The major limitation of our analysis is the small cohort size. However, despite the limitations, the results of our analysis provide proof of concept in a poorly studied population, and opens up the possibility of using this method in the routine screening of the Spanish population.

Measurement of Jupiter's asymmetric gravity field.

The gravity harmonics of a fluid, rotating planet can be decomposed into static components arising from solid-body rotation and dynamic components arising from flows. In the absence of internal dynamics, the gravity field is axially and hemispherically symmetric and is dominated by even zonal gravity harmonics J2n that are approximately proportional to qn, where q is the ratio between centrifugal acceleration and gravity at the planet's equator. Any asymmetry in the gravity field is attributed to differential rotation and deep atmospheric flows. The odd harmonics, J3, J5, J7, J9 and higher, are a measure of the depth of the winds in the different zones of the atmosphere. Here we report measurements of Jupiter's gravity harmonics (both even and odd) through precise Doppler tracking of the Juno spacecraft in its polar orbit around Jupiter. We find a north-south asymmetry, which is a signature of atmospheric and interior flows. Analysis of the harmonics, described in two accompanying papers, provides the vertical profile of the winds and precise constraints for the depth of Jupiter's dynamical atmosphere.

Upper Body Lift: serie de casos en un hospital clínico universitario entre los años 2013-2016: descripción de la técnica quirúrgica / Upper Body Lift: cases series from a clinical hospital between years 2013-2016, and description of the surgical technique

Introducción: En pacientes obesos la pérdida masiva de peso presenta efectos beneficiosos para la salud, sin embargo, suelen cursar con un excedente cutáneo que genera problemas físicos, afectando la calidad de vida. En casos severos las técnicas convencionales de contorno corporal, no permiten dar solución a grandes alteraciones, siendo necesario utilizar procedimientos más extensos. El Upper Body Lift es una técnica que ofrece un manejo integral del tronco superior. Objetivos: Describir una serie de casos de pacientes sometidos a Upper Body Lift y presentar la técnica quirúrgica. Material y Método: Serie de casos prospectiva entre enero del 2013 y junio de 2016, en un hospital clínico universitario. Se excluyó a pacientes con información incompleta u operados en otro centro. Se utilizó estadística descriptiva. Resultados: 8 pacientes manejados mediante Upper Body Lift, con edad 39,75 ± 9,37 años, 6 (75%) mujeres. Con pérdida de peso de 36,75 ± 9,11 Kg, alcanzando un IMC de 25,97 ± 2,35 Kg/m2. En hombres la región pectoral se manejó con liposucción y posterior injerto de pezón, en mujeres se realizó mastopexia sin implantes en 5 (83,33%). No se observó complicación mayor y en 4 casos (50%) se presentó complicación menor durante posoperatorio. Discusión: Esta serie presenta resultados similares a lo descrito por otros autores. Conclusiones: El Upper Body Lift es un procedimiento que ofrece un manejo integral y con buenos resultados, en pacientes con gran excedente cutáneo en tronco superior.

Introduction: Obese patients gets beneficial health effects with the massive weight loss, however they develop excessive redundant skin and become physical problems affecting their quality of life. In severe cases, the conventional body contouring techniques are not able to solve this large alterations, being necessary to use more extensive procedures. The Upper Body Lift is a technique that offers integral management of the upper trunk. Objectives: To describe a case series of patients submitted to Upper Body Lift and present the surgical technique. Materials and Methods: Prospective case series of patients with Upper Body Lift between January 2013 and June 2016 in a clinical hospital. Patients with incomplete information or operated in another center were excluded. Descriptive statistics was used. Results: 8 patients were included, age 39.75 ± 9.37 years, 6 (75%) women. Prior to the contouring surgery they lose 36.75 ± 9.11 kg, reaching a BMI of 25.97 ± 2.35 kg/m2. In men the chest region was managed with liposuction and subsequent nipple graft, in women mastopexy without implants was performed in 5. No major complications was observed, 4 had minor complications during the postoperative period. Discussion: This series presents similar results to those described by other authors. Conclusions: The Upper Body Lift offers comprehensive and successful management in patients with large upper body disturbance.

Cirugía de contorno corporal en pacientes con pérdida masiva de peso en un hospital universitario: estudio de frecuencias / Body contouring surgery in patients with massive weight loss in a university hospital: study of frequencies

Resumen Introducción La pérdida masiva de peso en obesos, presenta efectos beneficiosos para la salud, sin embargo esto pacientes suelen cursar exceso de adiposidad y piel redundante, generando problemas físicos y psicológicos. La cirugía de contorno corporal busca modificar el contorno del cuerpo para lograr una armonía estética. Existen pocos estudios a nivel nacional que aborden la epidemiología de la cirugía de contorno corporal en pacientes con baja masiva de peso. Objetivos Describir una serie de pacientes con baja masiva de peso sometidos a cirugía de contorno corporal y sus complicaciones. Materiales Métodos Serie de casos prospectiva, de pacientes sometidos a cirugía de contorno corporal con antecedente de baja masiva de peso, entre enero de 2013 y junio de 2016, en un hospital universitario. Se excluyó a pacientes con información incompleta u operados en otro Centro. Utilizando estadística descriptiva. Resultados 120 pacientes con cirugía de contorno corporal y baja masiva de peso, con edad de 38,4 ± 10,4 años, 105 (87,5%) mujeres. La pérdida de peso fue en 110 (91.67%) con cirugía bariátrica. Alcanzando un IMC de 26,56 ± 3,26 Kg/m2, con una pérdida de peso 39,06 ± 14,1 7 Kg. Las cirugías más frecuentes fueron la abdominoplastía estándar 79 (65,83%) y la mastopexia con implantes 21 (17,5%). Uno (0,83%) presentó complicación mayor y 33 (27,5%) alguna complicación menor durante posoperatorio. Discusión Esta serie presenta resultados similares a lo descrito por otros autores, observándose una menor tasa de complicaciones en posoperatorio. Conclusiones La cirugía de contorno corporal en este grupo de pacientes es un procedimiento seguro, que ofrece solución a las secuelas corporales pospérdida masiva de peso según nuestra experiencia.

Introduction Massive weight loss in obese, has beneficial health effects, however patients usually presents excessive adiposity and redundant skin, that generates physical and psychological problems. The body contouring surgery helps to modify the contour of the body to achieve aesthetic harmony. There are few national studies that describe the epidemiology of body contour surgery in patients with massive weight loss. Objectives Describes a series of patients with massive weight loss with body contour surgery and its complications. Materials and Methods A prospective series of patients with body contouring surgery with a history of low body mass, between January 2013 and June 2016, in a university hospital. Patients with incomplete information or operated at another center were excluded. Descriptive statistics was used. Results 120 patients with body contouring surgery and low weight mass were included. Age of 38.4 ± 10.4 years, 105 (87.5%) were women. 110 (91.67%) were bariatric patients. BMI of 26.56 ± 3.26 kg/m2 and a weight loss of 39.06 ± 14.17 Kg were reached previous the contouring surgery. The most frequent surgery was the standard abdominoplasty 79 (65.83%), followed by mastopexy with implants 21 (17.5%). 1 (0.83%) presented major complication and 33 (27.5%) had a minor complication during the postoperative period. Discussion This series presents results similar to other authors, with a lower rate of postoperative complications. Conclusion The Body contouring surgery are safe procedures, which provides a solution to the bodily sequels after massive weight loss according to our experience.

Diferencias en calidad de vida asociado a la apariencia nasal en pacientes operados de rinoplastia comparado con grupo control: validez del instrumento rhinoplasty outcome evaluation / Evaluation of the rhinoplasty outcome evaluation among chilean participants

Background: The Rhinoplasty Outcome Evaluation (ROE) is an instrument to assess the cosmetic and functional aspects of the nose from the patient's perspective. Its construct validity in Chilean subjects has been published previously. Aim: To compare the ROE scores in different groups of participants. Material and Methods: The questionnaire was applied to patients waiting for a rhinoplasty, patients hospitalized for other causes and medical students. Results: The overall reliability of the scale was 84.8 percent. Significant differences between groups in the total scores of four out of six items were observed. Conclusions: The Spanish version of the ROE is adequate to evaluate the satisfaction with nasal appearance and function among Chilean individuals.

Objetivo: El Rhinoplasty Outcome Evaluation (ROE) es un instrumento específico para la evaluación cosmética y funcional de la nariz desde la perspectiva del paciente, desarrollado originalmente en inglés. El objetivo del presente estudio es comparar las distribuciones en distintas poblaciones. Material y Método: El instrumento validado en español chileno ROE fue sometido a prueba para evaluar su validez de criterio comparando los resultados de la escala en pacientes programados que deseaban someterse a rinoplastía versus 2 grupos control: 1) Pacientes hospitalizados por otras causas y 2) Estudiantes de medicina. La validez de constructo ya ha sido publicada por los creadores de la escala. Para la comparación de variables se utilizaron las pruebas t de Student, ANOVA, Wilcoxon, Kruskall Wallis, prueba exacta de Fisher o χ² según correspondiera. Para todas las pruebas se utilizó un nivel alfa de 5 por ciento. Resultados: Se aplicó la encuesta a 45 pacientes. La edad promedio de la muestra fue de 35,4 años. La confiabilidad de la escala fue de 84,78 por ciento. Se observaron diferencias estadísticamente significativas en el puntaje total (p = 0,0047) en 4 de los 6 ítems. Conclusión: Los resultados preliminares de nuestro estudio sugieren que la versión en Español del Rhinoplasty Outcomes Evaluation es útil para evaluar la satisfacción con la apariencia nasal en chilenos.

Medición de los resultados estéticos y funcionales desde la perspectiva del paciente en rinoplastía: creación del instrumento nose-qol / Development of a new patient-reported outcome measure for rhinoplasty suergery: the Nose-QoL

Background: Instruments that assess the results of plastic surgery from patient's perspective allow a multidimensional evaluation of surgical results. Aim: To develop a new instrument to assess the functional and esthetic results of rhinoplasty from the point of view of the patient. Material and Methods: A conceptual framework about important results for nasal image was developed using information from in depth interviews to patients, focal groups with experts and interviews to esthetic surgeons and patients subjected to rhinoplasty. Results: Four patients and four plastic surgeons were interviewed. The three sub scales identified for the conceptual framework were quality of life, postoperative disability and pain and surgeon's objective evaluation scale. Five domains for quality of life were identified including nose size and form, self-image and esteem, third party perceptions and social relationships, nasal function and segmental nasal analysis. Conclusions: After completion of the psychometric assessment, the Nose-QoL instrument will become a valuable instrument to measure the impact and effectiveness of rhinoplasty from the patient's perspective.

Objetivo: Desarrollar un nuevo instrumento de resultados estéticos y funcionales desde la perspectiva del paciente, diseñado para medir la satisfacción de éstos en relación a rinoplastía. Métodos: Revisión de la literatura, entrevistas en profundidad a pacientes, grupos focales de discusión de expertos, a cirujanos plásticos y pacientes sometidos a rinoplastías, con lo que se desarrolló un marco conceptual en relación a los resultados considerados importantes para la imagen nasal. Resultados: Se entrevistó a cuatro pacientes y cuatro cirujanos plásticos. Las tres Subescalas identificadas para el marco conceptual incluyen: la Calidad de Vida (CdV), la Escala de Discapacidad y Dolor Post-operatorio (EDDP) y Escala de Evaluación Objetiva del Cirujano (EEOC). Se identificaron 5 dominios para la subescala CdV, que incluyen: tamaño y forma de la nariz, autoimagen y autoestima, percepción de terceros y relaciones sociales, función nasal y análisis nasal segmentario. Conclusiones: Una vez completada la evaluación psicométrica, el instrumento Nose-QoL y subescalas, proporcionará una herramienta confiable para cirujanos plásticos, investigadores y pacientes para medir el impacto y la eficacia de las rinoplastías, desde la perspectiva del paciente. Nivel de Evidencia: 1 -Estudio cualitativo, generación de instrumentos de medición de resultado desde la perspectiva del paciente.

Living with inborn errors of cholesterol biosynthesis: lessons from adult patients.

In the last decades, nine inherited errors of the distal part of cholesterol biosynthesis have been recognized. Affected patients present complex malformation syndromes involving different organs and systems with variable degrees of severity. We report on the phenotype evolution of three patients with enzymatic defects at three distinct steps of such pathway: Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata type 2 and congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. The patients' natural history, from childhood to adulthood, is thoroughly described in order to contribute for a better knowledge of these diseases. Our ultimate goals are to contribute for a better characterization of the long-term course of these metabolic disorders and for the recognition of such diseases in older patients.

Medición de los resultados desde la perspectiva del paciente en cirugía de contorno corporal: creación del instrumento Body-QoL / Development of an instrument to evaluate the results of plastic surgery from the perspective of the patient

Background: Body remodeling surgical procedures requires an assessment from the client's point of view in terms of esthetic satisfaction. Aim: To develop an instrument of assess body remodeling surgical results from the point of view of the patient. Material and Methods: A literature search for assessment methods was carried out. Posteriorly, in depth interviews and focus groups with plastic surgeons and patients subjected to plastic surgery procedures were performed. With this information, a conceptual framework was established to devise the instrument. Results: Sixteen patients and five plastic surgeons participated in the interviews and focus groups. The domains included in the conceptual framework were outfit and body image, affective and sexual life, self-image and esteem, social relationships and physical symptoms. Conclusions: The conceptual framework for the instrument is ready and the psychometric evaluation is the next step in its development.

Objetivo: Desarrollar un nuevo instrumento de resultados desde la perspectiva del paciente, diseñado para medir la satisfacción de éstos en relación a procedimientos de cirugía de contorno corporal, como li-poescultura, abdominoplastía, lifting corporal, lifting de muslos y brazos. Material y Método: Revisión de la literatura, entrevistas en profundidad a pacientes, grupos focales de discusión de expertos a cirujanos plásticos y pacientes sometidos a cirugías de contorno corporal con lo que se desarrolló un marco conceptual en relación a los resultados considerados importantes para la imagen corporal. Resultados: Dieciséis pacientes y cinco cirujanos plásticos fueron entrevistados. Los dominios identificados para el marco conceptual incluyeron vestimenta e imagen corporal, vida afectiva y sexual, autoimagen y autoestima, relaciones sociales y síntomas físicos. Conclusiones: Una vez completada la evaluación psicométrica, el instrumento Body-QoL y subescalas proporcionará una herramienta confiable para cirujanos plásticos, investigadores y pacientes para medir el impacto y la eficacia de los procedimientos de remodelamiento corporal, desde la perspectiva del paciente. Nivel de Evidencia: 1-Estudio cualitativo, generación de instrumentos de medición de resultado desde la perspectiva del paciente.

Adhesin contribution to nanomechanical properties of the virulent Bordetella pertussis envelope.

Adherence to a biological surface allows bacteria to colonize and persist within the host and represents an essential first step in the pathogenesis of most bacterial diseases. Consequently, the physicochemical properties of the outer membrane in bacteria play a key role for attachment to surfaces and therefore for biofilm formation. Bordetella pertussis is a Gram-negative bacterium that colonizes the respiratory tract of humans, producing whooping cough or pertussis, a highly infectious disease. B. pertussis uses various adhesins exposed on its surface to promote cell-surface and cell-cell interactions. The most dominant adhesin function is displayed by filamentous hemagglutinin (FHA). B. pertussis Tohama I wild-type (Vir+) strain and two defective mutants, an avirulent (Vir-) and a FHA-deficient (FHA-) B. pertussis strains were studied by AFM under physiological conditions to evaluate how the presence or absence of adhesins affects the mechanical properties of the B. pertussis cell surface. Quantitative information on the nanomechanical properties of the bacterial envelope was obtained by AFM force-volume analysis. These studies suggested that the presence of virulence factors is correlated with an increase in the average membrane rigidity, which is largely influenced by the presence of FHA. Moreover, for this system we built a nanoscale stiffness map that reveals an inhomogeneous spatial distribution of Young modulus as well as the presence of rigid nanodomains on the cell surface.

Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function.

CD4+CD25+regulatory T cells (T(reg)) impair anti-tumor and anti-viral immunity. As there are higher T(reg) levels in cancer patients compared with healthy individuals, there is considerable interest in eliminating them or altering their function as part of cancer or viral immunotherapy strategies. The scurfin transcriptional regulator encoded by the member of the forkhead winged helix protein family (FOXP3) is critical for maintaining the functions of T(reg). We hypothesized that targeting FOXP3 expression with a novel arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino (PPMO) based antisense would eliminate T(reg) and enhance the induction of effector T-cell responses. We observed that the PPMO was taken up by activated T cells in vitro and could downregulate FOXP3 expression, which otherwise increases during antigen-specific T-cell activation. Generation of antigen-specific T cells in response to peptide stimulation was enhanced by pre-treatment of peripheral blood mononuclear cells with the FOXP3-targeted PPMO. In summary, modulation of T(reg) levels using the FOXP3 PPMO antisense-based genomic strategy has the potential to optimize immunotherapy strategies in cancer and viral immunotherapy.

Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers.

OBJECTIVE: This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction. METHODS: Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis). RESULTS: For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4-8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc. CONCLUSION: Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.

Pustular psoriasis and drug-induced pustulosis.

We report the case of a 65-year-old female patient that has suffered several flares of exanthematous pustulosis, some of them attributable to pustular psoriasis and others that were drug-induced, resembling acute generalized exanthematous pustulosis. In particular, we describe two severe flares that were induced by ciprofloxacin. Patch tests yielded positive results to ciprofloxacin and to other quinolones and reproduced the original lesional pattern both clinically and histologically. We discuss the diagnostic challenge that exanthematous pustulosis represents and the value of patch testing in this setting, as a helpful tool to assess drug participation in these eruptions.

Linear psoriasis - a case report.

A 56-year-old woman presented with a 3-month history of erythematous plaques covered by scales and limited to the right side of her body. The plaques were arranged along Blaschko's lines with a marked mid-line cutoff. The histopathologic analysis of a skin biopsy in conjunction with the anamnesis allowed the diagnosis of linear psoriasis. Our patient showed a good clinical response to antipsoriatic treatment.