Serum concentration-guided intravenous magnesium sulfate administration for neuroprotection in patients with aneurysmal subarachnoid hemorrhage: a retrospective evaluation of a 12-year single-center experience.

Delayed cerebral infarction (DCI) is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). The benefits of magnesium sulfate as an alternative treatment are controversial, and most previous studies examined its benefits only as adjunctive treatment to traditional nimodipine. We retrospectively analyzed aSAH patients records with magnesium sulfate between 2010 and 2021. We aimed for a serum magnesium concentration of 2-2.5 mmol/l between post-hemorrhage days 3 and 12. The patients were separated in three groups based on average serum magnesium concentration (magnesium >2 mmol/l, reduced magnesium 1.1-1.9 mmol/l, and no magnesium). Additionally, we assessed delayed cerebral infarction (DCI) and clinical outcome at follow-up, using the modified Rankin Scale (mRS), categorized in favorable (0-3) and unfavorable outcome (4-5). In this analysis, 548 patients were included. Hereof, radiological evidence of DCI could be found in 23.0% (n = 126) of patients. DCI rates were lower if patients' average serum magnesium was higher than 2 mmol/l (magnesium 18.8%, n = 85; reduced magnesium 38.3%, n = 23; no magnesium 51.4%, n = 18; p < 0.001). Also, at the last follow-up, patients in the group with a higher serum magnesium concentration had better outcome (favorable outcome: magnesium 64.7%, n = 293; reduced magnesium 50.0%, n = 30; no magnesium 34.3%, n = 12; p < 0.001). This 12-year study reveals the value of serum concentration-guided magnesium administration in aSAH patients. Our findings demonstrate the safety and efficacy when titrated to a serum concentration of 2-2.5 mmol/l. We observed higher rates of delayed cerebral infarction and unfavorable outcomes in patients with serum concentrations below 2 mmol/l.

Beyond Optical Depth: Future Determination of Ionization History from the Cosmic Microwave Background.

We explore the fundamental limits to which reionization histories can be constrained using only large-scale cosmic microwave background (CMB) anisotropy measurements. The redshift distribution of the fractional ionization x e (z) affects the angular distribution of CMB polarization. We project constraints on the reionization history of the universe using low-noise full-sky temperature and E-mode measurements of the CMB. We show that the measured TE power spectrum, C ^ ℓ TE , has roughly one quarter of the constraining power of C ^ ℓ EE on the reionization optical depth τ, and its addition improves the precision on τ by 20% over using C ^ ℓ EE only. We also use a two-step reionization model with an additional high-redshift step, parameterized by an early ionization fraction x e min , and a late reionization step at z re. We find that future high signal-to-noise measurements of the multipoles 10 ⩽ ℓ < 20 are especially important for breaking the degeneracy between x e min and z re. In addition, we show that the uncertainties on these parameters determined from a map with sensitivity 10 µK arcmin are less than 5% larger than the uncertainties in the noiseless case, making this noise level a natural target for future large sky area E-mode measurements.

Testing stimulus protocols in retinal-prosthesis patients.

Retinal prostheses have demonstrated the capability to give blind patients the ability to detect motion and locate large objects. High-resolution retinal prostheses require precise activation of retinal cells to elicit a small visual phosphine that can serve as a building block to make patterns. Each electrode should activate only nearby cells, however patients receiving single electrode stimulation often report a streak-shaped phosphene rather than a focal spot. It is important to investigate stimulus paradigms that will provide better control over the spatial patterns of activation. During this study a 55 year old patient implanted with the Argus II system on August 2015 was tested with single electrode stimulation and pattern stimulation experiments. Tasks were performed using Argus II normal parameters.

Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia.

Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL.

Improved electrode material for deep brain stimulation.

Deep brain stimulation (DBS) devices have been implanted for treatment of basic tremor, Parkinson's disease and dystonia. These devices use electrodes in contact with tissue to deliver electrical pulses to targeted cells, to elicit specific therapeutic responses. In general, the neuromodulation industry has been evolving towards smaller, less invasive electrodes. However, current electrode materials do not support small sizes without severely restricting the stimulus output. Hence, an improved electrode material will benefit present and future DBS systems. In this study, five DBS leads were modified using a cost-effective and materials-efficient process for applying an ultra-low impedance platinum-iridium alloy coating. One DBS lead was used for insertion test and four DBS leads were chronically pulsed for 12 weeks. The platinum-iridium alloy significantly improved the electrical properties of the DBS electrodes and was robust to insertion into brain and to 12 weeks of chronic pulsing.

Evaluation of Effects of Electrical Stimulation in the Retina with Optical Coherence Tomography.

Retinal prostheses provide the capability to blind patients to detect motion and locate large objects. To avoid activating axons of passage, which can create streak-like perceptions, long pulse stimulation can be used to bypass axons and achieve focal retinal activation. Safety is a concern because long pulses require more charge than short pulses to elicit a response from neural tissue. Future implants will require smaller electrodes to improve resolution, but increased charge density may result, which is another safety concern. We developed a method to study the effects of electrical stimulation in the retina in real time using OCT (Optical Coherence Tomography) imaging combined with micropositioning of a stimulating electrode over the retina in an animal model. When using a 250-micron diameter electrode and stimulating for 30 minutes (frequency: 333 Hz), charge density: 1.22 mC/cm2, we observed an increase in retinal thickness from 154.3 µm ± 7.04 µm to 179.67 µm ± 0.47µm, a 16.66 % ± 5.49% increase compared to baseline. The region of increased thickness extended laterally for 0.56 mm ± 0.009 mm. When stimulating with a charge density of 1.63 mC/cm2, we observed an increase in retinal thickness from 160.3 µm ± 2.05 µm to 190 µm ± 0.81µm, a 19.52 % ± 1.86% increase compared to baseline. The region of increased thickness expanded laterally for 1.27 mm ± 0.19 mm.

First Report of Phytophthora cactorum and P. citrophthora Causing Root Rot of Ribes lobbii in Oregon.

Ribes lobbii (Gray) is a native, deciduous shrub from British Columbia, California, Oregon, and Washington that is grown for its pendulous red and white flowers, bristly fruit, and attractive, aromatic foliage. It is uncommon in nature and has only recently begun being propagated for sale in ornamental and native nurseries. In April 2013, 2-year-old containerized plants (15/50 plants) were found with severe wilt and chlorosis symptoms at a nursery production facility in western Oregon. Most fine roots were completely rotted and larger roots exhibited numerous black lesions. By the end of August, 50% of the plants were affected and most died within a few weeks of initial symptom development. At least three initially asymptomatic plants developed symptoms after being sold and planted. Isolation was attempted from 10 plants by plating pieces of necrotic root tissue (3 mm2) that had been surface disinfested for 1 min in 10% bleach and 1 min in 70% ethanol onto PARP medium (2). Eight Phytophthora isolates were recovered and identified as P. cactorum (seven isolates, GenBank Accession No. KM085441) and P. citrophthora (one isolate, KM085442) on the basis of morphology and 99 to 100% internal transcribed spacer (ITS) sequence similarity to published sequence data (1). One isolate of each species was used to prepare vermiculite inoculum (3) and subsequently to infest potting media (Sunshine Professional Growing Mix) at 100 propagules per gram. Due to the scarcity of R. lobbii in nature and the nursery trade, only a limited number of plants were available for pathogenicity tests. Three 1-year-old rooted cuttings of R. lobbii (~15 to 30 cm tall) were transplanted into individual 10-cm2 pots containing 175 g of the respective infested media for each pathogen. Three plants transplanted into individual pots of noninfested media served as negative controls. Plants were then watered to pot capacity and incubated in a greenhouse at 28/24°C day/night. The entire experiment was repeated 2 weeks later. Within 1 week after inoculation, all inoculated plants in both trials wilted and died, regardless of the Phytophthora species used; negative control plants remained healthy. Each pathogen (with identity confirmed by ITS sequence analysis) was re-isolated from the roots and stem of each respective inoculated plant, but was not isolated from negative controls, thus fulfilling Koch's postulates. Therefore, to my knowledge, this is the first report of P. cactorum and P. citrophthora as root rot pathogens of R. lobbii. The use of infected, but asymptomatic native plants in habitat restoration efforts will likely compromise success and there is considerable risk to nearby plant species given the broad host range of both pathogens. References: (1) D. E. L. Cooke et al. Fungal Genet. Biol. 30:17, 2000. (2) M. E. Kannwischer and D. J. Mitchell. Phytopathology 68:1760, 1978. (3) J. E. Weiland et al. Plant Dis. 97:744, 2013.

Performance of visually guided tasks using simulated prosthetic vision and saliency-based cues.

OBJECTIVE: The objective of this paper is to evaluate the benefits provided by a saliency-based cueing algorithm to normally sighted volunteers performing mobility and search tasks using simulated prosthetic vision. APPROACH: Human subjects performed mobility and search tasks using simulated prosthetic vision. A saliency algorithm based on primate vision was used to detect regions of interest (ROI) in an image. Subjects were cued to look toward the directions of these ROI using visual cues superimposed on the simulated prosthetic vision. Mobility tasks required the subjects to navigate through a corridor, avoid obstacles and locate a target at the end of the course. Two search task experiments involved finding objects on a tabletop under different conditions. Subjects were required to perform tasks with and without any help from cues. RESULTS: Head movements, time to task completion and number of errors were all significantly reduced in search tasks when subjects used the cueing algorithm. For the mobility task, head movements and number of contacts with objects were significantly reduced when subjects used cues, whereas time was significantly reduced when no cues were used. The most significant benefit from cues appears to be in search tasks and when navigating unfamiliar environments. SIGNIFICANCE: The results from the study show that visually impaired people and retinal prosthesis implantees may benefit from computer vision algorithms that detect important objects in their environment, particularly when they are in a new environment.

Elastic and viscoelastic characterization of agar.

Agar is a biological polymer, frequently used in tissue engineering research; due to its consistency, controllable size, and concentration-based properties, it often serves as a representative material for actual biological tissues. In this study, nanoindentation was used to characterize both the time-independent and time-dependent response of agar samples having various concentrations (0.5%-5.0% by weight). Quasi-static indentation was performed at different loads and depths using both open- and closed-loop controls. Reduced modulus (Er) values change with agar concentration, ranging from ∼30 kPa for 0.5% samples to ∼700 kPa for 5.0% samples, which is the same modulus range as usually encountered in soft biological materials. Dynamic indentation was performed to assess the effects of load, dynamic frequency and amplitude. Storage modulus values ranged from approximately 30 to 2300 kPa depending on agar concentration. Loss modulus remained consistently less than 30 kPa at all conditions, indicating a diminished damping response in agar.

A key to improved ion core confinement in the JET tokamak: ion stiffness mitigation due to combined plasma rotation and low magnetic shear.

New transport experiments on JET indicate that ion stiffness mitigation in the core of a rotating plasma, as described by Mantica et al. [Phys. Rev. Lett. 102, 175002 (2009)] results from the combined effect of high rotational shear and low magnetic shear. The observations have important implications for the understanding of improved ion core confinement in advanced tokamak scenarios. Simulations using quasilinear fluid and gyrofluid models show features of stiffness mitigation, while nonlinear gyrokinetic simulations do not. The JET experiments indicate that advanced tokamak scenarios in future devices will require sufficient rotational shear and the capability of q profile manipulation.

Continuous electrical stimulation decreases retinal excitability but does not alter retinal morphology.

Retinal prostheses aim to provide visual perception through electrical stimulation of the retina. Hence they have to operate between threshold charge density and maximum safe charge density. To date most studies in the retina have concentrated on understanding the threshold, while stimulation safety has predominantly been studied in structures other than the retina. Toward this end, the present study focuses on determining the effect of continuous electrical stimulation of the retina both on retinal morphology and on the electrically evoked responses in the superior colliculus in a rodent model. The results demonstrate that the retina is able to tolerate 1 h long stimulation with only minor changes evident in retinal histology when examined three to 14 days later, even at charge densities (0.68 mC cm(-2)) above the safe limit of platinum delivered at high stimulus frequency (300 Hz). However, this continuous electrical stimulation causes an elevation in the threshold of the electrically evoked response in the superior colliculus, indicating some form of adaptation to continuous stimulation.

Interphase gap decreases electrical stimulation threshold of retinal ganglion cells.

The most common electrical stimulation pulse used in retinal implants is a symmetric biphasic current pulse. Prior electrophysiological studies in peripheral nerve have shown that adding an interphase gap (IPG) between the two phases makes stimulation more efficient. We investigated the effect of IPG duration on retinal ganglion cell (RGC) electrical threshold. We used calcium imaging to measure the activity of RGCs in isolated retina in response to electrical stimulation. By varying IPG duration, we were able to examine the effect of duration on threshold. We further studied this effect by simulating RGC behavior with a Hodgkin-Huxley-type model. Our results indicate that the threshold for electrical activation of RGCs can be reduced by increasing the length of the IPG.

Saliency-based image processing for retinal prostheses.

We present a computationally efficient model for detecting salient regions in an image frame. The model when implemented on a portable, wearable system can be used in conjunction with a retinal prosthesis, to identify important objects that a retinal prosthesis patient may not be able to see due to implant limitations. The model is based on an earlier saliency detection model but has a reduced number of parallel streams. Results of a comparison between the areas detected as salient by the algorithm and areas gazed at by human subjects in a set of images show a correspondence which is greater than what would be expected by chance. Initial results for a comparison of the execution speed of the two algorithm models for each frame on the TMS320 DM642 Texas Instruments Digital Signal Processor suggest that the proposed model is approximately ten times faster than the original saliency model.

Finite element modeling of retinal prosthesis mechanics.

Epiretinal prostheses used to treat degenerative retina diseases apply stimulus via an electrode array fixed to the ganglion cell side of the retina. Mechanical pressure applied by these arrays to the retina, both during initial insertion and throughout chronic use, could cause sufficient retinal damage to reduce the device's effectiveness. In order to understand and minimize potential mechanical damage, we have used finite element analysis to model mechanical interactions between an electrode array and the retina in both acute and chronic loading configurations. Modeling indicates that an acute tacking force distributes stress primarily underneath the tack site and heel edge of the array, while more moderate chronic stresses are distributed more evenly underneath the array. Retinal damage in a canine model chronically implanted with a similar array occurred in correlating locations, and model predictions correlate well with benchtop eyewall compression tests. This model provides retinal prosthesis researchers with a tool to optimize the mechanical electrode array design, but the techniques used here represent a unique effort to combine a modifiable device and soft biological tissues in the same model and those techniques could be extended to other devices that come into mechanical contact with soft neural tissues.

Maize as a New Host for Oat blue dwarf virus.

Oat blue dwarf virus (OBDV) is a marafivirus present throughout the North American Great Plains and is found at low incidence levels in barley, oats, and flax in the Upper Midwest United States. Cropping patterns in this region have changed considerably in recent years, with much greater acreages devoted to maize in areas historically planted to small grains. Considering that OBDV is endemic in small grains in this region and that its aster leafhopper vector (Macrosteles quadrilineatus) is commonly detected in maize (2), we questioned whether maize might be a host for OBDV. Although Westdal (4) reported that maize was not a host for OBDV, it is the primary host for the related Maize rayado fino virus (MRFV) transmitted by Dalbulus maidis. MRFV is the type member of the marafiviruses and ranges from South America to the southern United States. To reevaluate the ability of maize to serve as a host for OBDV, viruliferous aster leafhoppers were allowed to feed on young maize seedlings for a 7-day inoculation access period. Plants were assayed for the presence of OBDV by ELISA 21 days after leafhopper removal. Initially, open-pollinated Sunglow sweet corn was tested in three experiments, with infection rates of 17 to 100%. A test of hybrid Sunglow resulted in 63% infection. These are comparable to transmission levels obtained when oat and barley plants are fed upon by viruliferous leafhoppers. Subsequently, 10 additional varieties of sweet and field corn were tested to determine if they could serve as hosts for OBDV. Sweet corn included Silver Queen, Peaches and Cream, Morning Star, Sugar Dots, Kandy Korn, and Golden Cross Bantam. Field corn included four lines provided by the maize breeding program of M. Carena at North Dakota State University (056640, 056643, 056612, and 056652). At least one plant was infected in all sweet and field corn varieties except 056612. Infected plants were largely asymptomatic, although a very faint stipple-striping was observed on some plants. To determine whether leafhoppers could acquire OBDV from infected maize and transmit the virus to other hosts, healthy leafhoppers were fed upon detached leaves of infected maize for 4 days (approximately 30 days after initial infection) and subsequently transferred three times at weekly intervals to barley and oats. Infection rates of 42 to 55% were observed in target plants, indicating efficient transmission from maize to other cereal hosts. The extent of natural infection of maize by OBDV or economic loss, if any, remains to be determined. This discovery extends the host range of OBDV to include maize and suggests that maize has the potential to serve as a natural reservoir for OBDV. The identification of hosts for known and new marafiviruses, such as those recently detected in citrus (3) and grape (1), will expand our understanding of the ecology and epidemiology of viruses within this group. References: (1) M. Al Rwahnih. Virology 387:395, 2009. (2) J. L. Capinera. Page 320 in: Encyclopedia of Entomology. 2nd ed. Springer Publishing, New York, NY, 2008. (3) W. Maccheroni et al. J. Virol. 79:3028, 2005. (4) P. Westdal. Can. J. Bot. 46:1431, 1968.

On the thermal elevation of a 60-electrode epiretinal prosthesis for the blind.

In this paper, the thermal elevation in the human body due to the operation of a dual-unit epiretinal prosthesis to restore partial vision to the blind affected by irreversible retinal degeneration is presented. An accurate computational model of a 60-electrode device dissipating 97 mW power, currently under clinical trials is developed and positioned in a 0.25 mm resolution, heterogeneous model of the human head to resemble actual conditions of operation of the prosthesis. A novel simple finite difference scheme combining the explicit and the alternating-direction implicit (ADI) method has been developed and validated with existing methods. Simulation speed improvement up to 11 times was obtained for the the head model considered in this work with very good accuracy. Using this method, solutions of the bioheat equation were obtained for different placements of the implant. Comparison with in-vivo experimental measurements showed good agreement.

In vivo study of response threshold in retinal degenerate model at different degenerate stages.

Retinal prostheses are being developed to apply electrical stimulation to the retina in order to restore vision of individuals who suffer from diseases such as retinitis pigmentosa (RP) and aged related macular degeneration (AMD). Various electrical stimulus parameters have been extensively studied in both experimental and clinical settings. Both electrophysiological and psychophysical results have shown that outer retina disease exhibit higher stimulus threshold in one degenerate group versus the control group. Fewer studies have been conducted to investigate the change in threshold currents as a function of different degenerate stages. We propose to study the electrophysiological change in degenerate rat retinas by using an in vivo recording method. We recorded retinal-driven superior colliculus cells response in two control groups and four degenerate groups. Current pulses of seven different stimulus pulse durations were applied to the retinas to obtain strength duration curve per group. Preliminary results showed that for the postnatal (P) day 90 and 180 degenerate groups, threshold currents were not significantly different from the normal control group (P90 and P230). For P300 degenerate group, the threshold currents progressively increased. For P760 degenerate group, threshold currents were significantly elevated across all the stimulus pulse durations tested. Charge densities calculated for P760 degenerate group exceeded the safe limit of the stimulating electrode. Cell morphology in all control and degenerate groups is still under investigation for a correlation study.

Retinal prosthesis phosphene shape analysis.

A retinal prosthesis system to restore sight for the blind is under development. The system is analogous to cochlear implants, in which photoreceptor input is bypassed and replaced by direct electrical stimulation of the retinal ganglion cells. Currently, six test subjects have been implanted with a 4x4 electrode array and stimulator. We report here psychophysical clinical data examining how stimulation amplitude affects phosphene shape and repeatability on a single electrode. Phosphene shape data was quantified by a set of numerical descriptors calculated from image moments. Comparison of phosphene descriptors for a single electrode across repeated trials and amplitude levels measured the repeatability within an amplitude group. Our experimental findings show that stimulation of the retina creates repeatable percept shapes and that an increase in stimulation amplitude causes a significant change in size and shape of phosphenes.