Endoscopic optical coherence tomography : design and application

This thesis presents an investigation on endoscopic optical coherence tomography (OCT). As a noninvasive imaging modality, OCT emerges as an increasingly important diagnostic tool for many clinical applications. Despite of many of its merits, such as high resolution and depth resolvability, a major limitation is the relatively shallow penetration depth in tissue (about 2∼3 mm). This is mainly due to tissue scattering and absorption. To overcome this limitation, people have been developing many different endoscopic OCT systems. By utilizing a minimally invasive endoscope, the OCT probing beam can be brought to the close vicinity of the tissue of interest and bypass the scattering of intervening tissues so that it can collect the reflected light signal from desired depth and provide a clear image representing the physiological structure of the region, which can not be disclosed by traditional OCT. In this thesis, three endoscope designs have been studied. While they rely on vastly different principles, they all converge to solve this long-standing problem.

A hand-held endoscope with manual scanning is first explored. When a user is holding a hand- held endoscope to examine samples, the movement of the device provides a natural scanning. We proposed and implemented an optical tracking system to estimate and record the trajectory of the device. By registering the OCT axial scan with the spatial information obtained from the tracking system, one can use this system to simply ‘paint’ a desired volume and get any arbitrary scanning pattern by manually waving the endoscope over the region of interest. The accuracy of the tracking system was measured to be about 10 microns, which is comparable to the lateral resolution of most OCT system. Targeted phantom sample and biological samples were manually scanned and the reconstructed images verified the method.

Next, we investigated a mechanical way to steer the beam in an OCT endoscope, which is termed as Paired-angle-rotation scanning (PARS). This concept was proposed by my colleague and we further developed this technology by enhancing the longevity of the device, reducing the diameter of the probe, and shrinking down the form factor of the hand-piece. Several families of probes have been designed and fabricated with various optical performances. They have been applied to different applications, including the collector channel examination for glaucoma stent implantation, and vitreous remnant detection during live animal vitrectomy.

Lastly a novel non-moving scanning method has been devised. This approach is based on the EO effect of a KTN crystal. With Ohmic contact of the electrodes, the KTN crystal can exhibit a special mode of EO effect, termed as space-charge-controlled electro-optic effect, where the carrier electron will be injected into the material via the Ohmic contact. By applying a high voltage across the material, a linear phase profile can be built under this mode, which in turn deflects the light beam passing through. We constructed a relay telescope to adapt the KTN deflector into a bench top OCT scanning system. One of major technical challenges for this system is the strong chromatic dispersion of KTN crystal within the wavelength band of OCT system. We investigated its impact on the acquired OCT images and proposed a new approach to estimate and compensate the actual dispersion. Comparing with traditional methods, the new method is more computational efficient and accurate. Some biological samples were scanned by this KTN based system. The acquired images justified the feasibility of the usage of this system into a endoscopy setting. My research above all aims to provide solutions to implement an OCT endoscope. As technology evolves from manual, to mechanical, and to electrical approaches, different solutions are presented. Since all have their own advantages and disadvantages, one has to determine the actual requirements and select the best fit for a specific application.

Terminal interruption of relux source technique in the treatment of active venous ulcers

Introduction: The treatment for venous ulcers in most cases is unsatisfactory, with recurrences and poor healing. Objective: to evaluate adjuvant therapy in the treatment of active venous ulcers. Methods: We analyzed 20 patients with active venous ulcers attending the general Surgery outpatient clinic at the “Dr. José eleuterio gonzález” University Hospital from October 2012 to January 2013. they were randomly divided into 2 groups: group A (11 patients) underwent compression therapy and group B (9 patients) underwent compression therapy plus removal of the vein that gives terminal relux to the ulcer, guided by ultrasound (microphlebectomy). Patients were evaluated weekly (8 weeks). At each assessment, photographs and lesion measurements were taken and pain was evaluated using the visual analog scale. Results: No significant differences were found between the study groups in terms of age, weight, height, body mass index (BMi), ankle-brachial index, and baseline measurement of the ulcer (p>0.05). Group B showed a greater reduction in ulcer size and a statistically signiicant lower score on the visual analog pain scale (p<0.05) from the second and third week of treatment, respectively. Conclusions: the results obtained in patients with surgical procedure (group B) are consistent with the reported eficacy of chronic venous ulcer treatment with saphenectomy (conventional surgery), the difference is that in this study we used a minimally invasive procedure (microphlebectomy).

An Assessment of Novel Biodegradable Magnesium Alloys for Endovascular Biomaterial Applications

Magnesium alloys have been widely explored as potential biomaterials, but several limitations to using these materials have prevented their widespread use, such as uncontrollable degradation kinetics which alter their mechanical properties. In an attempt to further the applicability of magnesium and its alloys for biomedical purposes, two novel magnesium alloys Mg-Zn-Cu and Mg-Zn-Se were developed with the expectation of improving upon the unfavorable qualities shown by similar magnesium based materials that have previously been explored. The overall performance of these novel magnesium alloys has been assessesed in three distinct phases of research: 1) analysing the mechanical properties of the as-cast magnesium alloys, 2) evaluating the biocompatibility of the as-cast magnesium alloys through the use of in-vitro cellular studies, and 3) profiling the degradation kinetics of the as-cast magnesium alloys through the use of electrochemical potentiodynamic polarization techqnique as well as gravimetric weight-loss methods. As compared to currently available shape memory alloys and degradable as-cast alloys, these experimental alloys possess superior as-cast mechanical properties with elongation at failure values of 12% and 13% for the Mg-Zn-Se and Mg-Zn-Se alloys, respectively. This is substantially higher than other as-cast magnesium alloys that have elongation at failure values that range from 7-10%. Biocompatibility tests revealed that both the Mg-Zn-Se and Mg-Zn-Cu alloys exhibit low cytotoxicity levels which are suitable for biomaterial applications. Gravimetric and electrochemical testing was indicative of the weight loss and initial corrosion behavior of the alloys once immersed within a simulated body fluid. The development of these novel as-cast magnesium alloys provide an advancement to the field of degradable metallic materials, while experimental results indicate their potential as cost-effective medical devices.

The development of an algorithm to track blood pressure accurately based on the pulse transit time method

Oscillometric blood pressure (BP) monitors are currently used to diagnose hypertension both in home and clinical settings. These monitors take BP measurements once every 15 minutes over a 24 hour period and provide a reliable and accurate system that is minimally invasive. Although intermittent cuff measurements have proven to be a good indicator of BP, a continuous BP monitor is highly desirable for the diagnosis of hypertension and other cardiac diseases. However, no such devices currently exist. A novel algorithm has been developed based on the Pulse Transit Time (PTT) method, which would allow non-invasive and continuous BP measurement. PTT is defined as the time it takes the BP wave to propagate from the heart to a specified point on the body. After an initial BP measurement, PTT algorithms can track BP over short periods of time, known as calibration intervals. After this time has elapsed, a new BP measurement is required to recalibrate the algorithm. Using the PhysioNet database as a basis, the new algorithm was developed and tested using 15 patients, each tested 3 times over a period of 30 minutes. The predicted BP of the algorithm was compared to the arterial BP of each patient. It has been established that this new algorithm is capable of tracking BP over 12 minutes without the need for recalibration, using the BHS standard, a 100% improvement over what has been previously identified. The algorithm was incorporated into a new system based on its requirements and was tested using three volunteers. The results mirrored those previously observed, providing accurate BP measurements when a 12 minute calibration interval was used. This new system provides a significant improvement to the existing method allowing BP to be monitored continuously and non-invasively, on a beat-to-beat basis over 24 hours, adding major clinical and diagnostic value.

Diclofenaco comparado con ibuprofeno para el cierre de Ductus arterioso persistente, en recién nacidos prematuros

Introducción: El Ductus arterioso persistente (DAP), es uno de los defectos congénitos cardiacos más comunes, requiere manejo farmacológico y/o quirúrgico; presenta complicaciones hemodinámicas, respiratorias y muerte. Los medicamentos de elección para su manejo son indometacina e ibuprofeno, pero su costo y accesibilidad llevo al uso de diclofenaco como alternativa de manejo en algunos hospitales. Objetivo: Comparar respuesta al tratamiento con diclofenaco vs ibuprofeno en cierre de DAP. Materiales y Métodos: Estudio observacional analítico retrospectivo, que compara los resultados obtenidos al usar Diclofenaco e Ibuprofeno para el cierre del DAP en recién nacidos pretérmino. Se recolecto información de pacientes hospitalizados en la Unidad Neonatal de un Hospital II nivel de Bogotá. Se revisaron las historias clínicas de pacientes de edad gestacional entre 24 y 36 semanas por Ballard con los criterios para diagnóstico de DAP y recibieron tratamiento farmacológico con una de las siguientes opciones: Ibuprofeno 10 mg/Kg dosis inicial después 5mg/Kg a las 24 48 horas, o Diclofenaco 0.2 mg/Kg dosis cada 12 horas tres dosis. Se comparó el Diclofenaco y el Ibuprofeno para el tratamiento farmacológico de DAP en recién nacidos prematuros. Resultados: Fueron evaluados 103 pacientes, el diagnóstico de DAP se realizó con ecocardiograma transtorácico, el 66.6 % de los pacientes presentó cierre farmacológico con Diclofenaco y 69 % con Ibuprofeno, La mortalidad fue de 17.65 % con Diclofenaco y 11.54 % con ibuprofeno; en ambos casos asociadas a la prematurez. Conclusiones: El éxito farmacológico fue similar en ambos grupos, el diclofenaco es una alternativa interesante cuando la terapia convencional no esté disponible.

Cordectomía por sustracción pedicular en la columna dorsal y lumbar en fracturas traumáticas: experiencia en el hospital universitario mayor Mederi y revisión sistemática de la literatura

Objetivo: Presentar la experiencia con la técnica de corpectomia por sustracción pedicular en fracturas traumática a nivel de la columna dorsal y Lumbar en el Hospital Universitario Mayor en Bogotá y hacer una revisión sistemática de la literatura de esta técnica quirúrgica. Material y métodos: Se realizó un análisis retrospectivo de las historias clínicas de pacientes que consultaron al servicio de neurocirugía entre los años 2013 y 2015 con fracturas traumáticas a nivel de la columna dorsal y lumbosacra. Se realizó un análisis de déficit neurológico pre y posoperatorio por medio de la Clasificación neurológica estándar de lesión medular (ASIA), al igual que tiempos de cirugía, sangrado intraoperatorio y complicaciones. A su vez se realiza una revisión sistemática de la literatura sobre esta técnica quirúrgica. Resultados: El total de pacientes que se sometieron a cirugía fue de 32, de los cuales el tiempo quirúrgico promedio fue de 396 min, se obtuvo un ASIA prequirúrgico B: 50% C: 47% y E: 3%. El ASIA post operatorio fue de B: 9% C: 47% D: 38% E: 6%. Se obtuvo una mejoría del déficit neurológico en el 75% los pacientes intervenidos. El promedio de sangrado fue de 1,223 cc. Se tuvieron 4 complicaciones, 2 hematomas en lecho quirúrgico que requirió re intervención y dos fistulas de líquido cefalorraquídeo las cuales se manejaron con vendaje compresivo y reposo absoluto. Conclusiones: La corpectomia por sustracción pedicular requiere de un adecuado entrenamiento y un grupo multidisciplinario dentro de los que se incluye neuroanestesiologo, a su vez de neurocirujanos entrenados en columna. Este abordaje presenta grandes beneficios como disminución de tiempos quirúrgicos, disminución de sangrado intraoperatorio y disminución de morbilidad entre otras.

Seguridad del monitoreo hemodinámico invasivo versus mínimamente invasivo en pacientes con choque cardiogénico en cuidado intensivo adultos. Revisión sistemática

Introducción: El monitoreo hemodinámico es una herramienta para diagnosticar el choque cardiogénico y monitorear la respuesta al tratamiento; puede ser invasivo, mínimamente invasivo o no invasivo. Se realiza rutinariamente con catéter de arteria pulmonar (CAP) o catéter de Swan Ganz; nuevas técnicas de monitoreo hemodinámico mínimamente invasivo tienen menor tasa de complicaciones. Actualmente se desconoce cuál técnica de monitoreo cuenta con mayor seguridad en el paciente con choque cardiogénico. Objetivo: Evaluar la seguridad del monitoreo hemodinámico invasivo comparado con el mínimamente invasivo en pacientes con choque cardiogénico en cuidado intensivo adultos. Diseño: Revisión sistemática de la literatura. Búsqueda en Pubmed, EMBASE, OVID - Cochrane Library, Lilacs, Scielo, registros de ensayos clínicos, actas de conferencias, repositorios, búsqueda de literatura gris en Google Scholar, Teseo y Open Grey hasta agosto de 2016, publicados en inglés y español. Resultados: Se identificó un único estudio con 331 pacientes críticamente enfermos que comparó el monitoreo hemodinámico con CAP versus PiCCO que concluyó que después de la corrección de los factores de confusión, la elección del tipo de monitoreo no influyó en los resultados clínicos más importantes en términos de complicaciones y mortalidad. Dado que se incluyeron otros diagnósticos, no es posible extrapolar los resultados sólo a choque cardiogénico. Conclusión: En la literatura disponible no hay evidencia de que el monitoreo hemodinámico invasivo comparado con el mínimamente invasivo, en pacientes adultos críticamente enfermos con choque cardiogénico, tenga diferencias en cuanto a complicaciones y mortalidad.

Tratamiento quirúrgico del síndrome de apnea hipopnea obstructiva del sueño en la Clínica Rivas, Bogotá – Colombia

Introducción: El Síndrome de Apnea Hipopnea Obstructiva del Sueño es un trastorno respiratorio del sueño mayor ampliamente conocido, con importantes implicaciones para los pacientes y cuya incidencia ha venido en aumento durante los últimos años; comprende diversas manifestaciones clínicas que varían desde el ronquido hasta consecuencias cardiovasculares importantes. Objetivo: Describir la experiencia de los procedimientos quirúrgicos más utilizados para el tratamiento de pacientes con Trastornos Respiratorios del Sueño en la Clínica Rivas. Diseño: Estudio observacional descriptivo. Métodos: Revisión de 366 historias clínicas de pacientes con diagnóstico clínico y Polisomnográfico de SAHOS intervenidos quirúrgicamente debido al Trastorno Respiratorio del Sueño por rechazo de terapia de presión positiva en 3 años de observación. Resultados: Se evaluaron diferencias en medianas de los cambios del IAH, índice de Saturación de oxigeno basal y mínima, y el índice de microdespertares nocturnos tanto prequirúrgica como postquirúrgicamente. Como medida de evaluación secundaria se evaluaron las complicaciones quirúrgicas. Conclusión: En nuestra institución, como centro de referencia en apnea del sueño, la cirugía ha demostrado que disminuye de forma significativa gravedad del SAHOS y disminuye el riesgo de los pacientes con trastornos respiratorios del sueño que han rechazado el dispositivo de presión positiva.

Percutaneous vertebroplasty: a new animal model.

Background Context Percutaneous vertebroplasty (PVP) is a minimally invasive surgical procedure and is frequently performed in humans who need surgical treatment of vertebral fractures. PVP involves cement injection into the vertebral body, thereby providing rapid and significant pain relief. Purpose The testing of novel biomaterials depends on suitable animal models. The aim of this study was to develop a reproducible and safe model of PVP in sheep. Study Design This study used ex vivo and in vivo large animal model study (Merino sheep). Methods Ex vivo vertebroplasty was performed through a bilateral modified parapedicular access in 24 ovine lumbar hemivertebrae, divided into four groups (n=6). Cerament (Bone Support, Lund, Sweden) was the control material. In the experimental group, a novel composite was tested—Spine-Ghost—which consisted of an alpha-calcium sulfate matrix enriched with micrometric particles of mesoporous bioactive glass. All vertebrae were assessed by micro-computed tomography (micro-CT) and underwent mechanical testing. For the in vivo study, 16 sheep were randomly allocated into control and experimental groups (n=8), and underwent PVP using the same bone cements. All vertebrae were assessed postmortem by micro-CT, histology, and reverse transcription-polymerase chain reaction (rt-PCR). This work has been supported by the European Commission under the 7th Framework Programme for collaborative projects (600,000–650,000 USD). Results In the ex vivo model, the average defect volume was 1,275.46±219.29 mm3. Adequate defect filling with cement was observed. No mechanical failure was observed under loads which were higher than physiological. In the in vivo study, cardiorespiratory distress was observed in two animals, and one sheep presented mild neurologic deficits in the hind limbs before recovering. Conclusions The model of PVP is considered suitable for preclinical in vivo studies, mimicking clinical application. All sheep recovered and completed a 6-month implantation period. There was no evidence of cement leakage into the vertebral foramen in the postmortem examination.

Robotic Approach in the Treatment of Locally Advanced (Stage IIIA-pN2) non Small Cell Lung Cancer after Induction Therapy

Introduction: Despite there are already many studies on robotic surgery as minimally invasive approach for non-small cell lung cancer (NSCLC) patients, the use of this technique for stage III disease is still poorly described. These are the preliminary results of our prospective study on safety and effectiveness of robotic approach in patients with locally advanced NSCLC, in terms of postoperative complications and oncological outcome. Methods: Since 2016, we prospectively investigated, using standardized questionnaire and protocol, 21 consecutive patients with NSCLC stage IIIA-pN2 (diagnosed by EBUS-TBNA) who underwent lobectomy and radical lymph node dissection with robotic approach after induction treatment. Then, we performed a matched case-control study with 54 patients treated with open surgery during the same period of time, with similar age, clinical and pathological tumor stage. Results: The individual matched population was composed of 14 robot-assisted thoracic surgery and 14 patients who underwent open surgery. The median time range of resection was inferior in the open group compared to robotic lobectomy (148 vs 229 minutes; P=0.002). Lymph nodes resection and positivity were not statistically significantly different (p=0.66 and p=0.73 respectively). No difference was observed also for PFS (P=0.99) or OS (P=0.94). Conclusions: Our preliminary results demonstrated that the early outcomes and oncological results of N2-patients after robotic lobectomy were similar to open surgery. Considering the advantages of minimally invasive surgery, robotic assisted lobectomy should be a safe approach also to patients with local advanced disease.

Trattamento della stenosi valvolare aortica: nuovi scenari dalla biologia molecolare alle nuove tecnologie

La stenosi valvolare aortica è la più frequente patologia valvolare cardiaca nei paesi sviluppati come diretta conseguenza dell’aumentata aspettativa di vita. In Europa si stima che il numero di soggetti sintomatici per stenosi valvolare aortica aumenterà da 1.3 milioni nel 2025 a 2.1 milioni in 2050. Di conseguenza la stenosi aortica ha e avrà un forte impatto sulla salute pubblica e sui costi che ne determina, poiché spesso associata a un declino funzionale dei pazienti ed aumentata incidenza di ospedalizzazione. D’altra parte è noto che la stenosi valvolare aortica severa non trattata si associa a prognosi infausta con una sopravvivenza del 50% a 2 anni dall’insorgenza dei sintomi e del 20% a 5 anni. Ad oggi non esiste una terapia medica efficace per la stenosi valvolare aortica in quanto andando a costituire un’ostruzione meccanica, resta di competenza del cardiochirurgo o del cardiologo interventista. La sostituzione valvolare aortica, sia essa chirurgica o percutanea, resta pertanto il solo trattamento definitivo per la stenosi valvolare aortica. Nel tempo il rischio operatorio è estremamente diminuito e i vantaggi in termini di miglioramento della qualità di vita sono evidenti. Questo progetto di ricerca prevede pertanto un’analisi delle più recenti tecnologie per il trattamento chirurgico della stenosi valvolare aortica a partire dalla tipologia di approccio chirurgico, se mini-invasivo o tradizionale, fino all’utilizzo delle più recenti protesi biologiche sutureless studiandone i vantaggi, svantaggi e risultati. Prima ancora, tuttavia, saranno analizzati i meccanismi di biologia molecolare alla base dell’eziologia della stenosi aortica al fine di poter identificare precocemente i pazienti, di prevedere l’andamento della patologia e forse, in futuro, anche di ipotizzare una terapia farmacologica mirata.

Development of wearable electrochemical sensors for the determination of biological analytes

Wearable biosensors are attracting interest due to their potential to provide continuous, real-time physiological information via dynamic, non-invasive measurements of biochemical markers in biofluids, such as interstitial fluid (ISF). One notable example of their applications is for glycemic monitoring in diabetic patients, which is typically carried out either by direct measurement of blood glucose via finger pricking or by wearable sensors that can continuously monitor glucose in ISF by sampling it from below the skin with a microneedle. In this context, the development of a new and minimally invasive multisensing tattoo-based platform for the monitoring of glucose and other analytes in ISF extracted through reverse iontophoresis in proposed by the GLUCOMFORT project. This elaborate describes the in-vitro development of flexible electrochemical sensors based on inkjet-printed PEDOT:PSS and metal inks that are capable of determining glucose and chloride at biologically relevant concentrations, making them good candidates for application in the GLUCOMFORT platform. In order to make PEDOT:PSS sensitive to glucose at micromolar concentrations, a biocompatible functionalization based on immobilized glucose oxidase and electrodeposited platinum was developed. This functionalization was successfully applied to bulk and flexible amperometric devices, the design of which was also optimized. Using the same strategy, flexible organic electrochemical transistors (OECTs) for glucose sensing were also made and successfully tested. For the sensing of chloride ions, an organic charge-modulated field-effect transistor (OCMFET) featuring a silver/silver chloride modified floating gate electrode was developed and tested.

Performance of an ICU ventilator and two turbin-based ventilators dedicated to non invasive ventilation (NIV) in simulated high inspiratory effort and rate: a NIV-bench-study.

INTRODUCTION. The role of turbine-based NIV ventilators (TBV) versus ICU ventilators with NIV mode activated (ICUV) to deliver NIV in case of severe respiratory failure remains debated. OBJECTIVES. To compare the response time and pressurization capacity of TBV and ICUV during simulated NIV with normal and increased respiratory demand, in condition of normal and obstructive respiratory mechanics. METHODS. In a two-chamber lung model, a ventilator simulated normal (P0.1 = 2 mbar, respiratory rate RR = 15/min) or increased (P0.1 = 6 mbar, RR = 25/min) respiratory demand. NIV was simulated by connecting the lung model (compliance 100 ml/mbar; resistance 5 or 20 l/mbar) to a dummy head equipped with a naso-buccal mask. Connections allowed intentional leaks (29 ± 5 % of insufflated volume). Ventilators to test: Servo-i (Maquet), V60 and Vision (Philips Respironics) were connected via a standard circuit to the mask. Applied pressure support levels (PSL) were 7 mbar for normal and 14 mbar for increased demand. Airway pressure and flow were measured in the ventilator circuit and in the simulated airway. Ventilator performance was assessed by determining trigger delay (Td, ms), pressure time product at 300 ms (PTP300, mbar s) and inspiratory tidal volume (VT, ml) and compared by three-way ANOVA for the effect of inspiratory effort, resistance and the ventilator. Differences between ventilators for each condition were tested by oneway ANOVA and contrast (JMP 8.0.1, p\0.05). RESULTS. Inspiratory demand and resistance had a significant effect throughout all comparisons. Ventilator data figure in Table 1 (normal demand) and 2 (increased demand): (a) different from Servo-i, (b) different from V60.CONCLUSION. In this NIV bench study, with leaks, trigger delay was shorter for TBV with normal respiratory demand. By contrast, it was shorter for ICUV when respiratory demand was high. ICUV afforded better pressurization (PTP 300) with increased demand and PSL, particularly with increased resistance. TBV provided a higher inspiratory VT (i.e., downstream from the leaks) with normal demand, and a significantly (although minimally) lower VT with increased demand and PSL.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity.

Multiple sclerosis (MS), a variable and diffuse disease affecting white and gray matter, is known to cause functional connectivity anomalies in patients. However, related studies published to-date are post hoc; our hypothesis was that such alterations could discriminate between patients and healthy controls in a predictive setting, laying the groundwork for imaging-based prognosis. Using functional magnetic resonance imaging resting state data of 22 minimally disabled MS patients and 14 controls, we developed a predictive model of connectivity alterations in MS: a whole-brain connectivity matrix was built for each subject from the slow oscillations (<0.11Hz) of region-averaged time series, and a pattern recognition technique was used to learn a discriminant function indicating which particular functional connections are most affected by disease. Classification performance using strict cross-validation yielded a sensitivity of 82% (above chance at p<0.005) and specificity of 86% (p<0.01) to distinguish between MS patients and controls. The most discriminative connectivity changes were found in subcortical and temporal regions, and contralateral connections were more discriminative than ipsilateral connections. The pattern of decreased discriminative connections can be summarized post hoc in an index that correlates positively (ρ=0.61) with white matter lesion load, possibly indicating functional reorganisation to cope with increasing lesion load. These results are consistent with a subtle but widespread impact of lesions in white matter and in gray matter structures serving as high-level integrative hubs. These findings suggest that predictive models of resting state fMRI can reveal specific anomalies due to MS with high sensitivity and specificity, potentially leading to new non-invasive markers.

Intravesical Bacillus Calmette-guérin Efficiently Reduces P70s6k1 But Not 4e-bp1 Phosphorylation In Nonmuscle Invasive Bladder Cancer.

We characterized the functional consequences of intravesical bacillus Calmette-Guérin on the molecular mechanism of the AKT/mTOR signaling pathway in nonmuscle invasive bladder cancer. To our knowledge this has not been reported previously. At age 7 weeks female Fischer 344 rats received 1.5 mg/kg MNU intravesically every other week for 6 weeks. They were randomized at 10 per group to MNU (0.2 ml vehicle), bacillus Calmette-Guérin (10(6) cfu Connaught strain), rapamycin (15 μg/ml) and bacillus Calmette-Guérin plus simultaneous rapamycin, each intravesically for 6 weeks. At week 15 the bladders were collected for histopathology, immunohistochemistry and immunoblot to determine p-AKT, Rictor, Raptor, p-4E-BP1, p-p70S6K1, p-AMPK-α, p-mTOR and p-p53. Papillary carcinoma (pTa) and high grade intraepithelial neoplasia (pTis) predominated in the MNU group while normal urothelium, papillary and flat hyperplasia were more common in treated groups. Nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin showed suppression of p70S6K1 but not 4E-BP1 phosphorylation. This suggests that 4E-BP1 is regulated differently than p70S6K1, escaping the bacillus Calmette-Guérin action that occurs in a mTOR independent manner. The association of bacillus Calmette-Guérin with rapamycin but not rapamycin monotherapy affected p70S6K1 and 4E-BP1 phosphorylation with no features of in situ carcinoma (pTis). The activation status of p70S6K1 and 4E-BP1 might be used to stratify patients who could benefit from targeting such molecular elements with multitarget/multidrug intravesical therapy. In the future 4E-BP1 might be a worthwhile new target for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.