Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats

Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1 h) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120 mm Hg, group 1, n=6) or hypertension (160-170 mm Hg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 vs. group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke. Published by Elsevier B.V.

Transient Lymphadenopathy Secondary to Nephrotic Syndrome

Mediastinal lymphadenomegaly secondary to hypervolemia is an underdiagnosed tomographic finding. Herein we describe, in a patient with normal cardiac function, findings of pulmonary congestion associated to lymph node enlargement. The nephrotic syndrome causing hypoalbuminemia, low plasma colloid osmotic pressure and augmented transcapillary fluid leakage was the probable cause of the radiological findings.

C-Phycocyanin protects SH-SY5Y cells from oxidative injury, rat retina from transient ischemia and rat brain mitochondria from Ca2+/phosphate-induced impairment

Oxidative stress and mitochondrial impairment are essential in the ischemic stroke cascade and eventually lead to tissue injury. C-Phycocyanin (C-PC) has previously been shown to have strong antioxidant and neuroprotective actions. In the present study, we assessed the effects of C-PC on oxidative injury induced by tert-butylhydroperoxide (t-BOOH) in SH-SY5Y neuronal cells, on transient ischemia in rat retinas, and in the calcium/phosphate-induced impairment of isolated rat brain mitochondria (RBM). In SH-SY5Y cells, t-BOOH induced a significant reduction of cell viability as assessed by an MTT assay, and the reduction was effectively prevented by treatment with C-PC in the low micromolar concentration range. Transient ischemia in rat retinas was induced by increasing the intraocular pressure to 120 mmHg for 45 min, which was followed by 15 min of reperfusion. This event resulted in a cell density reduction to lower than 50% in the inner nuclear layer (INL), which was significantly prevented by the intraocular pre-treatment with C-PC for 15 min. In the RBM exposed to 3 mM phosphate and/or 100 mu M Ca2+, C-PC prevented in the low micromolar concentration range, the mitochondrial permeability transition as assessed by mitochondrial swelling, the membrane potential dissipation, the increase of reactive oxygen species levels and the release of the pro-apoptotic cytochrome c. In addition, C-PC displayed a strong inhibitory effect against an electrochemically-generated Fenton reaction. Therefore, C-PC is a potential neuroprotective agent against ischemic stroke, resulting in reduced neuronal oxidative injury and the protection of mitochondria from impairment. (C) 2012 Elsevier Inc. All rights reserved.

Determination of carrier mobility in MEH-PPV thin-films by stationary and transient current techniques

Charge transport and shelf-degradation of MEH-PPV thin-films were investigated through stationary (e.g. current versus voltage - JxV) and transient (e.g. Time-of-Flight - ToF, Dark-Injection Space-Charge-Limited Current - DI-SCLC, Charge Extraction by Linearly Increasing Voltage - CELN) current techniques. Charge carrier mobility in nanometric films was best characterized through JxV and DI-SCLC. It approaches 10(-6) cm(2)Ns under a SCLC regime with deep traps for light-emitting diode applications. ToF measurements performed on micrometric layers (i.e. - 3 mu m) confirmed studies in 100 nm-thick films as deposited in OLEDs. All results were comparable to a similar poly(para-phenylene vinylene) derivative, MDMO-PPV. Electrical properties extracted from thin-film transistors demonstrated mobility dependence on carrier concentration in the channel (similar to 10(-7)-10(-4) cm(2)/Vs). At low accumulated charge levels and reduced free carrier concentration, a perfect agreement to the previously cited techniques was observed. Degradation was verified through mobility reduction and changes in trap distribution of states. (C) 2011 Elsevier B.V. All rights reserved.

HIV-1 Proviral DNA Loads (as Determined by Quantitative PCR) in Patients Subjected to Structured Treatment Interruption after Antiretroviral Therapy Failure

The impact of Structured Treatment Interruption (STI) in peripheral blood mononuclear cell (PBMC) proviral reservoirs in 41 highly active antiretroviral therapy (HAART)-treated viremic individuals at baseline and 12 weeks after STI was determined using quantitative PCR (qPCR). Viral load increased 0.7 log(10) and CD4 decreased 97.5 cells/mm(3) after 12 weeks. A total of 28 of the 41 individuals showed an increased proviral load, 19 with a statistically significant increase above 10%. An increase in active viral replication is an important factor in the replenishment of the proviral reservoir even for short time periods.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack

Background-Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. Methods and Results-We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Conclusions-Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.

Effectiveness of a long-term use of a minimalist footwear versus habitual shoe on pain, function and mechanical loads in knee osteoarthritis: a randomized controlled trial

Background: Recent studies have shown an important reduction of joint overload during locomotion in elderly women with knee osteoarthritis (OA) after short- term use of minimalist shoes. Our aim is to investigate the chronic effect of inexpensive and minimalist footwear on the clinical and functional aspects of OA and gait biomechanics of elderly women with knee OA. Methods/Design: Fifty-six elderly women with knee OA grade 2 or 3 (Kellgren and Lawrence) are randomized into blocks and allocated to either the intervention group, which will use flexible, non-heeled shoes-Moleca (R)-for six months for at least six hours daily, or the control group, which could not use these shoes. Neither group is undergoing physical therapy treatment throughout the intervention period. Moleca (R) is a women's double canvas, flexible, flat walking shoe without heels, with a 5-mm anti-slip rubber sole and a 3-mm internal wedge of ethylene vinyl acetate. Both groups will be followed for six months and will be assessed at baseline condition, after three months, and after six months (end of intervention). All the assessments will be performed by a physiotherapist that is blind to the group allocation. The primary outcome is the pain Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score. The secondary outcomes are global WOMAC score; joint stiffness and disability WOMAC scores; knee pain with a visual analogue scale; walking distance in the six-minute walk test; Lequesne score; amount and frequency (number of days) of paracetamol (500 mg) intake over six months; knee adduction moment during gait; global medical assessment score; and global patient auto-assessment score. At baseline, all patients receive a diary to record the hours of daily use of the footwear intervention; every two weeks, the same physiotherapist makes phone calls to all patients in order to verify adherence to treatment. The statistical analysis will be based on intention to treat analysis, as well as general linear models of analysis of variance for repeated measure to detect treatment-time interactions (alpha = 5%). Discussion: This is the first randomized, clinical trial protocol to assess the chronic effect of minimalist footwear on the clinical and functional aspects and gait biomechanics of elderly women with knee osteoarthritis. We expect that the use of Moleca (R) shoes for six months will provide pain relief, reduction of the knee adduction moment when walking, and improve joint function in elderly women with knee OA, and that the treatment, thus, can be considered another inexpensive and easy-to-use option for conservative OA treatment.

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

Background In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Methods In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2-0-3.0). Patients and investigators were masked to treatment allocation. Between Dec 18,2006, and June 17,2009,14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2.79% rivaroxaban vs 2.96% warfarin; hazard ratio [HR] 0-94,95% CI 0.77-1.16) and those without (1.44% vs 1.88%; 0.77, 0.58-1-01; interaction p=0.23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13.31% rivaroxaban vs 13.87% warfarin; HR 0.96,95% CI 0.87-1-07) and those without (16.69% vs 15.19%; 1.10, 0.99-1.21; interaction p=0.08). Interpretation There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.

Transient transfection of serum-free suspension HEK 293 cell culture for efficient production of human rFVIII

Abstract Background Hemophilia A is a bleeding disorder caused by deficiency in coagulation factor VIII. Recombinant factor VIII (rFVIII) is an alternative to plasma-derived FVIII for the treatment of hemophilia A. However, commercial manufacturing of rFVIII products is inefficient and costly and is associated to high prices and product shortage, even in economically privileged countries. This situation may be solved by adopting more efficient production methods. Here, we evaluated the potential of transient transfection in producing rFVIII in serum-free suspension HEK 293 cell cultures and investigated the effects of different DNA concentration (0.4, 0.6 and 0.8 μg/106 cells) and repeated transfections done at 34° and 37°C. Results We observed a decrease in cell growth when high DNA concentrations were used, but no significant differences in transfection efficiency and in the biological activity of the rFVIII were noticed. The best condition for rFVIII production was obtained with repeated transfections at 34°C using 0.4 μg DNA/106 cells through which almost 50 IU of active rFVIII was produced six days post-transfection. Conclusion Serum-free suspension transient transfection is thus a viable option for high-yield-rFVIII production. Work is in progress to further optimize the process and validate its scalability.

Analysis and Implementation of Multiphase-Multilevel Inverter for Open-Winding Loads

Research work carried out in focusing a novel multiphase-multilevel ac motor drive system much suitable for low-voltage high-current power applications. In specific, six-phase asymmetrical induction motor with open-end stator winding configuration, fed from four standard two-level three-phase voltage source inverters (VSIs). Proposed synchronous reference frame control algorithm shares the total dc source power among the 4 VSIs in each switching cycle with three degree of freedom. Precisely, first degree of freedom concerns with the current sharing between two three-phase stator windings. Based on modified multilevel space vector pulse width modulation shares the voltage between each single VSIs of two three-phase stator windings with second and third degree of freedom, having proper multilevel output waveforms. Complete model of whole ac motor drive based on three-phase space vector decomposition approach was developed in PLECS - numerical simulation software working in MATLAB environment. Proposed synchronous reference control algorithm was framed in MATLAB with modified multilevel space vector pulse width modulator. The effectiveness of the entire ac motor drives system was tested. Simulation results are given in detail to show symmetrical and asymmetrical, power sharing conditions. Furthermore, the three degree of freedom are exploited to investigate fault tolerant capabilities in post-fault conditions. Complete set of simulation results are provided when one, two and three VSIs are faulty. Hardware prototype model of quad-inverter was implemented with two passive three-phase open-winding loads using two TMS320F2812 DSP controllers. Developed McBSP (multi-channel buffered serial port) communication algorithm able to control the four VSIs for PWM communication and synchronization. Open-loop control scheme based on inverse three-phase decomposition approach was developed to control entire quad-inverter configuration and tested with balanced and unbalanced operating conditions with simplified PWM techniques. Both simulation and experimental results are always in good agreement with theoretical developments.

Subject-specific musculoskeletal models of the lower limbs for the prediction of skeletal loads during motion

The determination of skeletal loading conditions in vivo and their relationship to the health of bone tissues, remain an open question. Computational modeling of the musculoskeletal system is the only practicable method providing a valuable approach to muscle and joint loading analyses, although crucial shortcomings limit the translation process of computational methods into the orthopedic and neurological practice. A growing attention focused on subject-specific modeling, particularly when pathological musculoskeletal conditions need to be studied. Nevertheless, subject-specific data cannot be always collected in the research and clinical practice, and there is a lack of efficient methods and frameworks for building models and incorporating them in simulations of motion. The overall aim of the present PhD thesis was to introduce improvements to the state-of-the-art musculoskeletal modeling for the prediction of physiological muscle and joint loads during motion. A threefold goal was articulated as follows: (i) develop state-of-the art subject-specific models and analyze skeletal load predictions; (ii) analyze the sensitivity of model predictions to relevant musculotendon model parameters and kinematic uncertainties; (iii) design an efficient software framework simplifying the effort-intensive phases of subject-specific modeling pre-processing. The first goal underlined the relevance of subject-specific musculoskeletal modeling to determine physiological skeletal loads during gait, corroborating the choice of full subject-specific modeling for the analyses of pathological conditions. The second goal characterized the sensitivity of skeletal load predictions to major musculotendon parameters and kinematic uncertainties, and robust probabilistic methods were applied for methodological and clinical purposes. The last goal created an efficient software framework for subject-specific modeling and simulation, which is practical, user friendly and effort effective. Future research development aims at the implementation of more accurate models describing lower-limb joint mechanics and musculotendon paths, and the assessment of an overall scenario of the crucial model parameters affecting the skeletal load predictions through probabilistic modeling.

Power Transient Analysis of Experimental Devices for Jules Horowitz Material Testing Reactor (JHR)

The objective of this thesis is the power transient analysis concerning experimental devices placed within the reflector of Jules Horowitz Reactor (JHR). Since JHR material testing facility is designed to achieve 100 MW core thermal power, a large reflector hosts fissile material samples that are irradiated up to total relevant power of 3 MW. MADISON devices are expected to attain 130 kW, conversely ADELINE nominal power is of some 60 kW. In addition, MOLFI test samples are envisaged to reach 360 kW for what concerns LEU configuration and up to 650 kW according to HEU frame. Safety issues concern shutdown transients and need particular verifications about thermal power decreasing of these fissile samples with respect to core kinetics, as far as single device reactivity determination is concerned. Calculation model is conceived and applied in order to properly account for different nuclear heating processes and relative time-dependent features of device transients. An innovative methodology is carried out since flux shape modification during control rod insertions is investigated regarding the impact on device power through core-reflector coupling coefficients. In fact, previous methods considering only nominal core-reflector parameters are then improved. Moreover, delayed emissions effect is evaluated about spatial impact on devices of a diffuse in-core delayed neutron source. Delayed gammas transport related to fission products concentration is taken into account through evolution calculations of different fuel compositions in equilibrium cycle. Provided accurate device reactivity control, power transients are then computed for every sample according to envisaged shutdown procedures. Results obtained in this study are aimed at design feedback and reactor management optimization by JHR project team. Moreover, Safety Report is intended to utilize present analysis for improved device characterization.

A new double laser pulse pumping scheme for transient collisionally excited plasma soft X-ray lasers

Within this thesis a new double laser pulse pumping scheme for plasma-based, transient collisionally excited soft x-ray lasers (SXRL) was developed, characterized and utilized for applications. SXRL operations from ~50 up to ~200 electron volt were demonstrated applying this concept. As a central technical tool, a special Mach-Zehnder interferometer in the chirped pulse amplification (CPA) laser front-end was developed for the generation of fully controllable double-pulses to optimally pump SXRLs.rnThis Mach-Zehnder device is fully controllable and enables the creation of two CPA pulses of different pulse duration and variable energy balance with an adjustable time delay. Besides the SXRL pumping, the double-pulse configuration was applied to determine the B-integral in the CPA laser system by amplifying short pulse replica in the system, followed by an analysis in the time domain. The measurement of B-integral values in the 0.1 to 1.5 radian range, only limited by the reachable laser parameters, proved to be a promising tool to characterize nonlinear effects in the CPA laser systems.rnContributing to the issue of SXRL pumping, the double-pulse was configured to optimally produce the gain medium of the SXRL amplification. The focusing geometry of the two collinear pulses under the same grazing incidence angle on the target, significantly improved the generation of the active plasma medium. On one hand the effect was induced by the intrinsically guaranteed exact overlap of the two pulses on the target, and on the other hand by the grazing incidence pre-pulse plasma generation, which allows for a SXRL operation at higher electron densities, enabling higher gain in longer wavelength SXRLs and higher efficiency at shorter wavelength SXRLs. The observation of gain enhancement was confirmed by plasma hydrodynamic simulations.rnThe first introduction of double short-pulse single-beam grazing incidence pumping for SXRL pumping below 20 nanometer at the laser facility PHELIX in Darmstadt (Germany), resulted in a reliable operation of a nickel-like palladium SXRL at 14.7 nanometer with a pump energy threshold strongly reduced to less than 500 millijoule. With the adaptation of the concept, namely double-pulse single-beam grazing incidence pumping (DGRIP) and the transfer of this technology to the laser facility LASERIX in Palaiseau (France), improved efficiency and stability of table-top high-repetition soft x-ray lasers in the wavelength region below 20 nanometer was demonstrated. With a total pump laser energy below 1 joule the target, 2 mircojoule of nickel-like molybdenum soft x-ray laser emission at 18.9 nanometer was obtained at 10 hertz repetition rate, proving the attractiveness for high average power operation. An easy and rapid alignment procedure fulfilled the requirements for a sophisticated installation, and the highly stable output satisfied the need for a reliable strong SXRL source. The qualities of the DGRIP scheme were confirmed in an irradiation operation on user samples with over 50.000 shots corresponding to a deposited energy of ~ 50 millijoule.rnThe generation of double-pulses with high energies up to ~120 joule enabled the transfer to shorter wavelength SXRL operation at the laser facility PHELIX. The application of DGRIP proved to be a simple and efficient method for the generation of soft x-ray lasers below 10 nanometer. Nickel-like samarium soft x-ray lasing at 7.3 nanometer was achieved at a low total pump energy threshold of 36 joule, which confirmed the suitability of the applied pumping scheme. A reliable and stable SXRL operation was demonstrated, due to the single-beam pumping geometry despite the large optical apertures. The soft x-ray lasing of nickel-like samarium was an important milestone for the feasibility of applying the pumping scheme also for higher pumping pulse energies, which are necessary to obtain soft x-ray laser wavelengths in the water window. The reduction of the total pump energy below 40 joule for 7.3 nanometer short wavelength lasing now fulfilled the requirement for the installation at the high-repetition rate operation laser facility LASERIX.rn