The yield of long-term electrocardiographic recordings in refractory focal epilepsy

OBJECTIVE: To determine the incidence of clinically relevant arrhythmias in refractory focal epilepsy and to assess the potential of postictal arrhythmias as risk markers for sudden unexpected death in epilepsy (SUDEP). METHODS: We recruited people with refractory focal epilepsy without signs of ictal asystole and who had at least one focal seizure per month and implanted a loop recorder with 2-year follow-up. The devices automatically record arrhythmias. Subjects and caregivers were instructed to make additional peri-ictal recordings. Clinically relevant arrhythmias were defined as asystole ≥ 6 seconds; atrial fibrillation 200 bpm and duration > 30 seconds; persistent sinus bradycardia < 40 bpm while awake; and second- or third-degree atrioventricular block and ventricular tachycardia/fibrillation. We performed 12-lead electrocardiography (ECG) and tilt table testing to identify non-seizure-related causes of asystole. RESULTS: We included 49 people and accumulated 1060 months of monitoring. A total of 16 474 seizures were reported, of which 4679 were captured on ECG. No clinically relevant arrhythmias were identified. Three people had a total of 18 short-lasting (<6 seconds) periods of asystole, resulting in an incidence of 2.91 events per 1000 patient-months. None of these coincided with a reported seizure; one was explained by micturition syncope. Other non-clinically relevant arrhythmias included paroxysmal atrial fibrillation (n = 2), supraventricular tachycardia (n = 1), and sinus tachycardia with a right bundle branch block configuration (n = 1). SIGNIFICANCE: We found no clinically relevant arrhythmias in people with refractory focal epilepsy during long-term follow-up. The absence of postictal arrhythmias does not support the use of loop recorders in people at high SUDEP risk

The effect of intervertebral cartilage on neutral posture and range of motion in the necks of sauropod dinosaurs

The necks of sauropod dinosaurs were a key factor in their evolution. The habitual posture and range of motion of these necks has been controversial, and computer-aided studies have argued for an obligatory sub-horizontal pose. However, such studies are compromised by their failure to take into account the important role of intervertebral cartilage. This cartilage takes very different forms in different animals. Mammals and crocodilians have intervertebral discs, while birds have synovial joints in their necks. The form and thickness of cartilage varies significantly even among closely related taxa. We cannot yet tell whether the neck joints of sauropods more closely resembled those of birds or mammals. Inspection of CT scans showed cartilage:bone ratios of 4.5% for Sauroposeidon and about 20% and 15% for two juvenile Apatosaurus individuals. In extant animals, this ratio varied from 2.59% for the rhea to 24% for a juvenile giraffe. It is not yet possible to disentangle ontogenetic and taxonomic signals, but mammal cartilage is generally three times as thick as that of birds. Our most detailed work, on a turkey, yielded a cartilage:bone ratio of 4.56%. Articular cartilage also added 11% to the length of the turkey's zygapophyseal facets. Simple image manipulation suggests that incorporating 4.56% of neck cartilage into an intervertebral joint of a turkey raises neutral posture by 15°. If this were also true of sauropods, the true neutral pose of the neck would be much higher than has been depicted. An additional 11% of zygapophyseal facet length translates to 11% more range of motion at each joint. More precise quantitative results must await detailed modelling. In summary, including cartilage in our models of sauropod necks shows that they were longer, more elevated and more flexible than previously recognised

High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity

The RNA-programmable Cas9 endonuclease cleaves double-stranded DNA at sites complementary to a 20-base-pair guide RNA. The Cas9 system has been used to modify genomes in multiple cells and organisms, demonstrating its potential as a facile genome-engineering tool. We used in vitro selection and high-throughput sequencing to determine the propensity of eight Cas9:guide RNA complexes to cleave each of 10^12 potential off-target DNA sequences. The selection results predicted five off-target sites in the human genome that were confirmed to undergo genome cleavage in HEK293T cells upon expression of one of two Cas9:guide RNA complexes. In contrast to previous models, our results show that Cas9:guide RNA specificity extends past a 7- to 12-base pair seed sequence. Our results also suggest a tradeoff between activity and specificity both in vitro and in cells as a shorter, less-active guide RNA is more specific then a longer, more-active guide RNA. High concentrations of Cas9:guide RNA complexes can cleave off-target sites containing mutations near or within the PAM that are not cleaved when enzyme concentrations are limiting

Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of the intravitreal (IVT) injection of Triamcinolone Acetonide (TA) as compared to posterior subtenon (SBT) capsule injection for the treatment of cystoid diabetic macular edema.</p> <p>Methods</p> <p>Fourteen patients with type II diabetes mellitus and on insulin treatment, presenting diffuse cystoid macular edema were recruited. Before TA injection all focal lakes were treated by laser photocoagulation. In the same patients one eye was assigned to 4 mg IVT injection of TA and the fellow eye was then treated with 40 mg SBT injection of TA. Before and one, three and six months after treatment we measured visual acuity with ETDRS chart as well as thickness of the macula with optical coherence tomography (OCT) and intraocular pressure (IOP).</p> <p>Results</p> <p>The eyes treated with an IVT injection displayed significant improvement in visual acuity, both after one (0.491 ± 0.070; p < 0.001) and three months (0.500 ± 0.089; p < 0.001) of treatment. Significant improvement was displayed also in eyes treated with an SBT injection, again after one (0.455 ± 0.069; p < 0.001) and three months (0.427 ± 0.065; p < 0.001). The difference between an IVT injection (0.809 ± 0.083) and SBT injection (0.460 ± 0.072) becomes significant six months after the treatment (p < 0.001).</p> <p>Macular thickness of the eyes treated with IVT injection was significantly reduced both after one (222.7 ± 13.4 μm; p < 0.001) and after three months (228.1 ± 10.6 μm; p < 0.001) of treatment. The eyes treated with SBT injection displayed significant improvement after one (220.1 ± 15.1 μm; p < 0.001) and after three months (231.3 ± 10.9 μm; p < 0.001). The difference between the eyes treated with IVT injection (385.2 ± 11.3 μm) and those treated with SBT injection (235.4 ± 8.7 μm) becomes significant six months after the treatment (p < 0.001).</p> <p>Intraocular pressure of the eyes treated with IVT injection significantly increased after one month (17.7 ± 1.1 mm/Hg; p < 0.020), three (18.2 ± 1.2 mm/Hg; p < 0.003) and six month (18.1 ± 1.3 mm/Hg; p < 0.007) when compared to baseline value (16.1 ± 1.402 mm/Hg). In the SBT injection eyes we didn't display a significant increase of intraocular pressure after one (16.4 ± 1.2 mm/Hg; p < 0.450), three (16.3 ± 1.1 mm/Hg; p < 0.630) and six months (16.2 ± 1.1 mm/Hg; p < 0.720) when compared to baseline value (16.2 ± 1.3 mm/Hg).</p> <p>Conclusion</p> <p>The parabulbar subtenon approach can be considered a valid alternative to the intravitreal injection.</p> <p>Trial registration</p> <p>Current Controlled Trials <b>ISRCTN67086909</b></p

Exploring medical student learning in the large group teaching environment: examining current practice to inform curricular development

Background Lectures continue to be an efficient and standardised way to deliver information to large groups of students. It has been well documented that students prefer interactive lectures, based on active learning principles, to didactic teaching in the large group setting. Despite this, it is often the case than many students do not engage with active learning tasks and attempts at interaction. By exploring student experiences, expectations and how they use lectures in their learning we will provide recommendations for faculty to support student learning both in the lecture theatre and during personal study time. Methods This research employed a hermeneutic phenomenological approach. Three focus groups, consisting of 19 students in total, were used to explore the experiences of second year medical students in large group teaching sessions. Using generic thematic data analysis, these accounts have been developed into a meaningful account of experience. Results This study found there to be a well-established learning culture amongst students and with it, expectations as to the format of teaching sessions. Furthermore, there were set perceptions about the student role within the learning environment which had many implications, including the way that innovative teaching methods were received. Student learning was perceived to take place outside the lecture theatre, with a large emphasis placed on creating resources that can be taken away to use in personal study time. Conclusions Presented here is a constructive review of reasons for student participation, interaction and engagement in large group teaching sessions. Based on this are recommendations constructed with the view to aid educators in engaging students within this setting. Short term, educators can implement strategies that monopolise on the established learning culture of students to encourage engagement with active learning strategies. Long term, it would be beneficial for educators to consider ways to shift the current student learning culture to one that embraces an active learning curriculum

An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production

The prevalence of type 2 diabetes in the United States is projected to double or triple by 2050. We reasoned that the genes that modulate insulin production might be new targets for diabetes therapeutics. Therefore, we developed an siRNA screening system to identify genes important for the activity of the insulin promoter in beta cells. We created a subclone of the MIN6 mouse pancreatic beta cell line that expresses destabilized GFP under the control of a 362 base pair fragment of the human insulin promoter and the mCherry red fluorescent protein under the control of the constitutively active rous sarcoma virus promoter. The ratio of the GFP to mCherry fluorescence of a cell indicates its insulin promoter activity. As G protein coupled receptors (GPCRs) have emerged as novel targets for diabetes therapies, we used this cell line to screen an siRNA library targeting all known mouse GPCRs. We identified several known GPCR regulators of insulin secretion as regulators of the insulin promoter. One of the top positive regulators was Gpr27, an orphan GPCR with no known role in beta cell function. We show that knockdown of Gpr27 reduces endogenous mouse insulin promoter activity and glucose stimulated insulin secretion. Furthermore, we show that Pdx1 is important for Gpr27's effect on the insulin promoter and insulin secretion. Finally, the over-expression of Gpr27 in 293T cells increases inositol phosphate levels, while knockdown of Gpr27 in MIN6 cells reduces inositol phosphate levels, suggesting this orphan GPCR might couple to Gq/11. In summary, we demonstrate a MIN6-based siRNA screening system that allows rapid identification of novel positive and negative regulators of the insulin promoter. Using this system, we identify Gpr27 as a positive regulator of insulin production

Detection of Gamma-Ray Emission from the Starburst Galaxies M82 and NGC 253 with the Large Area Telescope on Fermi

We report the detection of high-energy gamma-ray emission from two starburst galaxies using data obtained with the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. Steady point-like emission above 200 MeV has been detected at significance levels of 6.8 sigma and 4.8 sigma respectively, from sources positionally coincident with locations of the starburst galaxies M82 and NGC 253. The total fluxes of the sources are consistent with gamma-ray emission originating from the interaction of cosmic rays with local interstellar gas and radiation fields and constitute evidence for a link between massive star formation and gamma-ray emission in star-forming galaxies.Comment: Submitted to ApJ Letter

Fermi Gamma-ray Imaging of a Radio Galaxy

The Fermi Gamma-ray Space Telescope has detected the gamma-ray glow emanating from the giant radio lobes of the radio galaxy Centaurus A. The resolved gamma-ray image shows the lobes clearly separated from the central active source. In contrast to all other active galaxies detected so far in high-energy gamma-rays, the lobe flux constitutes a considerable portion (>1/2) of the total source emission. The gamma-ray emission from the lobes is interpreted as inverse Compton scattered relic radiation from the cosmic microwave background (CMB), with additional contribution at higher energies from the infrared-to-optical extragalactic background light (EBL). These measurements provide gamma-ray constraints on the magnetic field and particle energy content in radio galaxy lobes, and a promising method to probe the cosmic relic photon fields.Comment: 27 pages, includes Supplementary Online Material; corresponding authors: C.C. Cheung, Y. Fukazawa, J. Knodlseder, L. Stawar

Fermi Large Area Telescope observations of PSR J1836+5925

The discovery of the gamma-ray pulsar PSR J1836+5925, powering the formerly unidentified EGRET source 3EG J1835+5918, was one of the early accomplishments of the Fermi Large Area Telescope (LAT). Sitting 25 degrees off the Galactic plane, PSR J1836+5925 is a 173 ms pulsar with a characteristic age of 1.8 million years, a spindown luminosity of 1.1$\times10^{34}$ erg s$^{-1}$, and a large off-peak emission component, making it quite unusual among the known gamma-ray pulsar population. We present an analysis of one year of LAT data, including an updated timing solution, detailed spectral results and a long-term light curve showing no indication of variability. No evidence for a surrounding pulsar wind nebula is seen and the spectral characteristics of the off-peak emission indicate it is likely magnetospheric. Analysis of recent XMM observations of the X-ray counterpart yields a detailed characterization of its spectrum, which, like Geminga, is consistent with that of a neutron star showing evidence for both magnetospheric and thermal emission.Comment: Accepted to Astrophysical Journa