An infant mouse model of brain damage in pneumococcal meningitis

Bacterial meningitis due to Streptococcus pneumoniae is associated with an significant mortality rate and persisting neurologic sequelae including sensory-motor deficits, seizures, and impairments of learning and memory. The histomorphological correlate of these sequelae is a pattern of brain damage characterized by necrotic tissue damage in the cerebral cortex and apoptosis of neurons in the hippocampal dentate gyrus. Different animal models of pneumococcal meningitis have been developed to study the pathogenesis of the disease. To date, the infant rat model is unique in mimicking both forms of brain damage documented in the human disease. In the present study, we established an infant mouse model of pneumococcal meningitis. Eleven-days-old C57BL/6 (n = 299), CD1 (n = 42) and BALB/c (n = 14) mice were infected by intracisternal injection of live Streptococcus pneumoniae. Sixteen hours after infection, all mice developed meningitis as documented by positive bacterial cultures of the cerebrospinal fluid. Sixty percent of infected C57BL/6 mice survived more than 40 h after infection (50% of CD1, 0% of BALB/c). Histological evaluations of brain sections revealed apoptosis in the dentate gyrus of the hippocampus in 27% of infected C57BL/6 and in 5% of infected CD1 mice. Apoptosis was confirmed by immunoassaying for active caspase-3 and by TUNEL staining. Other forms of brain damage were found exclusively in C57BL/6, i.e. caspase-3 independent (pyknotic) cell death in the dentate gyrus in 2% and cortical damage in 11% of infected mice. This model may prove useful for studies on the pathogenesis of brain injury in childhood bacterial meningitis.

Rapid diagnosis of experimental meningitis by bacterial heat production in cerebrospinal fluid

BACKGROUND: Calorimetry is a nonspecific technique which allows direct measurement of heat generated by biological processes in the living cell. We evaluated the potential of calorimetry for rapid detection of bacterial growth in cerebrospinal fluid (CSF) in a rat model of bacterial meningitis. METHODS: Infant rats were infected on postnatal day 11 by direct intracisternal injection with either Streptococcus pneumoniae, Neisseria meningitidis or Listeria monocytogenes. Control animals were injected with sterile saline or heat-inactivated S. pneumoniae. CSF was obtained at 18 hours after infection for quantitative cultures and heat flow measurement. For calorimetry, 10 microl and 1 microl CSF were inoculated in calorimetry ampoules containing 3 ml trypticase soy broth (TSB). RESULTS: The mean bacterial titer (+/- SD) in CSF was 1.5 +/- 0.6 x 108 for S. pneumoniae, 1.3 +/- 0.3 x 106 for N. meningitidis and 3.5 +/- 2.2 x 104 for L. monocytogenes. Calorimetric detection time was defined as the time until heat flow signal exceeded 10 microW. Heat signal was detected in 10-microl CSF samples from all infected animals with a mean (+/- SD) detection time of 1.5 +/- 0.2 hours for S. pneumoniae, 3.9 +/- 0.7 hours for N. meningitidis and 9.1 +/- 0.5 hours for L. monocytogenes. CSF samples from non-infected animals generated no increasing heat flow (<10 microW). The total heat was the highest in S. pneumoniae ranging from 6.7 to 7.5 Joules, followed by L. monocytogenes (5.6 to 6.1 Joules) and N. meningitidis (3.5 to 4.4 Joules). The lowest detectable bacterial titer by calorimetry was 2 cfu for S. pneumoniae, 4 cfu for N. meningitidis and 7 cfu for L. monocytogenes. CONCLUSION: By means of calorimetry, detection times of <4 hours for S. pneumoniae and N. meningitidis and <10 hours for Listeria monocytogenes using as little as 10 microl CSF were achieved. Calorimetry is a new diagnostic method allowing rapid and accurate diagnosis of bacterial meningitis from a small volume of CSF.

Supplemental oxygen, but not supplemental crystalloid fluid, increases tissue oxygen tension in healthy and anastomotic colon in pigs

BACKGROUND: Low tissue oxygen tension is an important factor leading to the development of wound dehiscence and anastomotic leakage after colon surgery. We tested whether supplemental fluid and supplemental oxygen can increase tissue oxygen tension in healthy and injured, perianastomotic, and anastomotic colon in an acutely instrumented pig model of anastomosis surgery. METHODS: Sixteen Swiss Landrace pigs were anesthetized (isoflurane 0.8%-1%) and their lungs ventilated. The animals were randomly assigned to low fluid treatment ("low" group, 3 mL x kg(-1) x h(-1) lactated Ringer's solution) or high fluid treatment ("high" group, 10 mL/kg bolus, 18 mL x kg(-1) x h(-1) lactated Ringer's solution) during colon anastomosis surgery and a subsequent measurement period (4 h). Two-and-half hours after surgery, tissue oxygen tension was recorded for 30 min during ventilation with 30% oxygen. Three hours after surgery, the animals' lungs were ventilated with 100% oxygen for 60 min. Tissue oxygen tension was recorded in the last 30 min. Tissue oxygen tension was measured with polarographic Clark-type electrodes, positioned in healthy colonic wall, close (2 cm) to the anastomosis, and in the anastomosis. RESULTS: In every group, tissue oxygen tension during ventilation with 100% oxygen was approximately twice as high as during ventilation with 30% oxygen, a statistically significant result. High or low volume crystalloid fluid treatment had no effect on colon tissue oxygen tension. CONCLUSIONS: Supplemental oxygen, but not supplemental crystalloid fluid, increased tissue oxygen tension in healthy, perianastomotic, and anastomotic colon tissue.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL(diff)) and active efflux clearance (CL(active)) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL(diff), and efflux clearance is the sum of CL(diff), CL(active), and bulk flow clearance (CL(bulk)). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL(bulk) of 0.01 ml/min, CL(active) was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

Gentamicin increases the efficacy of vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

In experimental meningitis a single dose of gentamicin (10 mg/kg of body weight) led to gentamicin levels in around cerebrospinal fluid (CSF) of 4 mg/liter for 4 h, decreasing slowly to 2 mg/liter 4 h later. The CSF penetration of gentamicin ranged around 27%, calculated by comparison of areas under the curve (AUC in serum/AUC in CSF). Gentamicin monotherapy (-1.24 log(10) CFU/ml) was inferior to vancomycin monotherapy (-2.54 log(10) CFU/ml) over 8 h against penicillin-resistant pneumococci. However, the combination of vancomycin with gentamicin was significantly superior (-4.48 log(10) CFU/ml) compared to either monotherapy alone. The synergistic activity of vancomycin combined with gentamicin was also demonstrated in vitro in time-kill assays.

Efficacy of gatifloxacin alone and in combination with cefepime against penicillin-resistant Streptococcus pneumoniae in a rabbit meningitis model and in vitro

Gatifloxacin penetrated well into cerebrospinal fluid (CSF) (49 +/- 11%), measured by comparison of AUC(CSF)/AUC(serum), and showed good bactericidal activity (leading to a decrease of 0.75 +/- 0.17 log10 cfu/mL/h) in the treatment of experimental meningitis in rabbits caused by a penicillin-resistant pneumococcal strain (MIC 4 mg/L). It was significantly more effective than the standard regimen, ceftriaxone with vancomycin, which led to a decrease of 0.53 +/- 0.17 log10 cfu/mL/h. The addition of cefepime to gatifloxacin slightly improved the killing rates (giving a decrease of 0.84 +/- 0.14 log10 cfu/mL/h). In vitro, synergy was demonstrated between cefepime and gatifloxacin by the chequerboard method (fractional inhibitory concentration index = 0.5) and by viable counts over 8 h.

Comparative efficacies of antibiotics in a rat model of meningoencephalitis due to Listeria monocytogenes

The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to Listeria monocytogenes in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (P < 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 +/- 0.5 log10 CFU/ml for amoxicillin-gentamicin, 5.0 +/- 0.4 log10 CFU/ml for trovafloxacin, and 5.8 +/- 0.5 log10 CFU/ml for TMP-SMX; P < 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 +/- 0.8 and 2.7 +/- 0.8 log10 CFU/ml, respectively) but more active than TMP-SMX (4.4 +/- 0. 6 log10 CFU/ml; P < 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment of Listeria infections may be warranted.

Fluid administration, brain edema, and cerebrospinal fluid lactate and glucose concentrations in experimental Escherichia coli meningitis

The effect of no fluids versus liberal fluid supplementation on brain edema and cerebrospinal fluid (CSF) lactate and glucose concentrations was compared in rabbits with experimental Escherichia coli meningitis. Fluid restriction for the duration of the experiment (19 h) led to a decrease in body weight by approximately 5%, while the high fluid regimen increased body weight by approximately 5%. Infected animals developed brain edema compared with controls, but the fluid regimen had no measurable effect on the degree of edema. In contrast, fluid-restricted animals had significantly higher CSF lactate and lower CSF glucose concentrations than fluid-supplemented animals (lactate, 13.5 +/- 3.5 vs. 10.1 +/- 3.3 mmol/L; glucose, 1.89 +/- 1.39 vs. 4.11 +/- 1.39 mmol/L). These results fail to support the hypothesis that administration of large amounts of fluid in this model of gram-negative bacterial meningitis aggravates brain edema.

Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis

Excitatory amino acids are increasingly implicated in the pathogenesis of neuronal injury induced by a variety of CNS insults, such as ischemia, trauma, hypoglycemia, and epilepsy. Little is known about the role of amino acids in causing CNS injury in bacterial meningitis. Several amino acids were measured in cerebrospinal fluid and in microdialysis samples from the interstitial fluid of the frontal cortex in a rabbit model of pneumococcal meningitis. Cerebrospinal fluid concentrations of glutamate, aspartate, glycine, taurine, and alanine increased significantly in infected animals. Among the amino acids with known excitatory or inhibitory function, interstitial fluid concentrations of glutamate were significantly elevated (by 470%). Alanine, a marker for anaerobic glycolysis, also increased in the cortex of infected rabbits. The elevated glutamate concentrations in the brain extracellular space suggest that excitotoxic neuronal injury may play a role in bacterial meningitis.

Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis

The effects of hydration status on cerebral blood flow (CBF) and development of cerebrospinal fluid (CSF) lactic acidosis were evaluated in rabbits with experimental pneumococcal meningitis. As loss of cerebrovascular autoregulation has been previously demonstrated in this model, we reasoned that compromise of intravascular volume might severely affect cerebral perfusion. Furthermore, as acute exacerbation of the inflammatory response in the subarachnoid space has been observed after antibiotic therapy, animals were studied not only while meningitis evolved, but also 4-6 h after treatment with antibiotics to determine whether there would also be an effect on CBF. To produce different levels of hydration, animals were given either 50 ml/kg per 24 h of normal saline ("low fluid") or 150 ml/kg 24 h ("high fluid"). After 16 h of infection, rabbits that were given the lower fluid regimen had lower mean arterial blood pressure (MABP), lower CBF, and higher CSF lactate compared with animals that received the higher fluid regimen. In the first 4-6 h after antibiotic administration, low fluid rabbits had a significant decrease in MABP and CBF compared with, and a significantly greater increase in CSF lactate concentration than, high fluid rabbits. This study suggests that intravascular volume status may be a critical variable in determining CBF and therefore the degree of cerebral ischemia in meningitis.

Crystalloids versus colloids for goal-directed fluid therapy in major surgery

INTRODUCTION: Perioperative hypovolemia arises frequently and contributes to intestinal hypoperfusion and subsequent postoperative complications. Goal-directed fluid therapy might reduce these complications. The aim of this study was to compare the effects of goal-directed administration of crystalloids and colloids on the distribution of systemic, hepatosplanchnic, and microcirculatory (small intestine) blood flow after major abdominal surgery in a clinically relevant pig model. METHODS: Twenty-seven pigs were anesthetized and mechanically ventilated and underwent open laparotomy. They were randomly assigned to one of three treatment groups: the restricted Ringer lactate (R-RL) group (n = 9) received 3 mL/kg per hour of RL, the goal-directed RL (GD-RL) group (n = 9) received 3 mL/kg per hour of RL and intermittent boluses of 250 mL of RL, and the goal-directed colloid (GD-C) group (n = 9) received 3 mL/kg per hour of RL and boluses of 250 mL of 6% hydroxyethyl starch (130/0.4). The latter two groups received a bolus infusion when mixed venous oxygen saturation was below 60% ('lockout' time of 30 minutes). Regional blood flow was measured in the superior mesenteric artery and the celiac trunk. In the small bowel, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: After 4 hours of treatment, arterial blood pressure, cardiac output, mesenteric artery flow, and mixed oxygen saturation were significantly higher in the GD-C and GD-RL groups than in the R-RL group. Microcirculatory flow in the intestinal mucosa increased by 50% in the GD-C group but remained unchanged in the other two groups. Likewise, tissue oxygen tension in the intestine increased by 30% in the GD-C group but remained unchanged in the GD-RL group and decreased by 18% in the R-RL group. Mesenteric venous glucose concentrations were higher and lactate levels were lower in the GD-C group compared with the two crystalloid groups. CONCLUSIONS: Goal-directed colloid administration markedly increased microcirculatory blood flow in the small intestine and intestinal tissue oxygen tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administrations had no such effects. Additionally, mesenteric venous glucose and lactate concentrations suggest that intestinal cellular substrate levels were higher in the colloid-treated than in the crystalloid-treated animals. These results support the notion that perioperative goal-directed therapy with colloids might be beneficial during major abdominal surgery.

Reynolds-stress turbulence model in the KIVA code for engine simulation

A Reynolds-Stress Turbulence Model has been incorporated with success into the KIVA code, a computational fluid dynamics hydrocode for three-dimensional simulation of fluid flow in engines. The newly implemented Reynolds-stress turbulence model greatly improves the robustness of KIVA, which in its original version has only eddy-viscosity turbulence models. Validation of the Reynolds-stress turbulence model is accomplished by conducting pipe-flow and channel-flow simulations, and comparing the computed results with experimental and direct numerical simulation data. Flows in engines of various geometry and operating conditions are calculated using the model, to study the complex flow fields as well as confirm the model’s validity. Results show that the Reynolds-stress turbulence model is able to resolve flow details such as swirl and recirculation bubbles. The model is proven to be an appropriate choice for engine simulations, with consistency and robustness, while requiring relatively low computational effort.

Experimental and modeling study of the filtration and oxidation characteristics of a diesel oxidation catalyst and a catalyzed particulate filter

A diesel oxidation catalyst (DOC) with a catalyzed diesel particulate filter (CPF) is an effective exhaust aftertreatment device that reduces particulate emissions from diesel engines, and properly designed DOC-CPF systems provide passive regeneration of the filter by the oxidation of PM via thermal and NO2/temperature-assisted means under various vehicle duty cycles. However, controlling the backpressure on engines caused by the addition of the CPF to the exhaust system requires a good understanding of the filtration and oxidation processes taking place inside the filter as the deposition and oxidation of solid particulate matter (PM) change as functions of loading time. In order to understand the solid PM loading characteristics in the CPF, an experimental and modeling study was conducted using emissions data measured from the exhaust of a John Deere 6.8 liter, turbocharged and after-cooled engine with a low-pressure loop EGR system and a DOC-CPF system (or a CCRT® - Catalyzed Continuously Regenerating Trap®, as named by Johnson Matthey) in the exhaust system. A series of experiments were conducted to evaluate the performance of the DOC-only, CPF-only and DOC-CPF configurations at two engine speeds (2200 and 1650 rpm) and various loads on the engine ranging from 5 to 100% of maximum torque at both speeds. Pressure drop across the DOC and CPF, mass deposited in the CPF at the end of loading, upstream and downstream gaseous and particulate emissions, and particle size distributions were measured at different times during the experiments to characterize the pressure drop and filtration efficiency of the DOCCPF system as functions of loading time. Pressure drop characteristics measured experimentally across the DOC-CPF system showed a distinct deep-bed filtration region characterized by a non-linear pressure drop rise, followed by a transition region, and then by a cake-filtration region with steadily increasing pressure drop with loading time at engine load cases with CPF inlet temperatures less than 325 °C. At the engine load cases with CPF inlet temperatures greater than 360 °C, the deep-bed filtration region had a steep rise in pressure drop followed by a decrease in pressure drop (due to wall PM oxidation) in the cake filtration region. Filtration efficiencies observed during PM cake filtration were greater than 90% in all engine load cases. Two computer models, i.e., the MTU 1-D DOC model and the MTU 1-D 2-layer CPF model were developed and/or improved from existing models as part of this research and calibrated using the data obtained from these experiments. The 1-D DOC model employs a three-way catalytic reaction scheme for CO, HC and NO oxidation, and is used to predict CO, HC, NO and NO2 concentrations downstream of the DOC. Calibration results from the 1-D DOC model to experimental data at 2200 and 1650 rpm are presented. The 1-D 2-layer CPF model uses a ‘2-filters in series approach’ for filtration, PM deposition and oxidation in the PM cake and substrate wall via thermal (O2) and NO2/temperature-assisted mechanisms, and production of NO2 as the exhaust gas mixture passes through the CPF catalyst washcoat. Calibration results from the 1-D 2-layer CPF model to experimental data at 2200 rpm are presented. Comparisons of filtration and oxidation behavior of the CPF at sample load-cases in both configurations are also presented. The input parameters and selected results are also compared with a similar research work with an earlier version of the CCRT®, to compare and explain differences in the fundamental behavior of the CCRT® used in these two research studies. An analysis of the results from the calibrated CPF model suggests that pressure drop across the CPF depends mainly on PM loading and oxidation in the substrate wall, and also that the substrate wall initiates PM filtration and helps in forming a PM cake layer on the wall. After formation of the PM cake layer of about 1-2 µm on the wall, the PM cake becomes the primary filter and performs 98-99% of PM filtration. In all load cases, most of PM mass deposited was in the PM cake layer, and PM oxidation in the PM cake layer accounted for 95-99% of total PM mass oxidized during loading. Overall PM oxidation efficiency of the DOC-CPF device increased with increasing CPF inlet temperatures and NO2 flow rates, and was higher in the CCRT® configuration compared to the CPF-only configuration due to higher CPF inlet NO2 concentrations. Filtration efficiencies greater than 90% were observed within 90-100 minutes of loading time (starting with a clean filter) in all load cases, due to the fact that the PM cake on the substrate wall forms a very efficient filter. A good strategy for maintaining high filtration efficiency and low pressure drop of the device while performing active regeneration would be to clean the PM cake filter partially (i.e., by retaining a cake layer of 1-2 µm thickness on the substrate wall) and to completely oxidize the PM deposited in the substrate wall. The data presented support this strategy.

Structural response and dynamics of fluid-structure-control interaction in wind turbine blades

Reducing the uncertainties related to blade dynamics by the improvement of the quality of numerical simulations of the fluid structure interaction process is a key for a breakthrough in wind-turbine technology. A fundamental step in that direction is the implementation of aeroelastic models capable of capturing the complex features of innovative prototype blades, so they can be tested at realistic full-scale conditions with a reasonable computational cost. We make use of a code based on a combination of two advanced numerical models implemented in a parallel HPC supercomputer platform: First, a model of the structural response of heterogeneous composite blades, based on a variation of the dimensional reduction technique proposed by Hodges and Yu. This technique has the capacity of reducing the geometrical complexity of the blade section into a stiffness matrix for an equivalent beam. The reduced 1-D strain energy is equivalent to the actual 3-D strain energy in an asymptotic sense, allowing accurate modeling of the blade structure as a 1-D finite-element problem. This substantially reduces the computational effort required to model the structural dynamics at each time step. Second, a novel aerodynamic model based on an advanced implementation of the BEM(Blade ElementMomentum) Theory; where all velocities and forces are re-projected through orthogonal matrices into the instantaneous deformed configuration to fully include the effects of large displacements and rotation of the airfoil sections into the computation of aerodynamic forces. This allows the aerodynamic model to take into account the effects of the complex flexo-torsional deformation that can be captured by the more sophisticated structural model mentioned above. In this thesis we have successfully developed a powerful computational tool for the aeroelastic analysis of wind-turbine blades. Due to the particular features mentioned above in terms of a full representation of the combined modes of deformation of the blade as a complex structural part and their effects on the aerodynamic loads, it constitutes a substantial advancement ahead the state-of-the-art aeroelastic models currently available, like the FAST-Aerodyn suite. In this thesis, we also include the results of several experiments on the NREL-5MW blade, which is widely accepted today as a benchmark blade, together with some modifications intended to explore the capacities of the new code in terms of capturing features on blade-dynamic behavior, which are normally overlooked by the existing aeroelastic models.