Renal artery sympathetic denervation:observations from the UK experience

Background: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN. Methods: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. Results: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p < 0.2). Conclusion: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Minimizing activation of overlying axons with epiretinal stimulation: The role of fiber orientation and electrode configuration

<div><p>Currently, a challenge in electrical stimulation of the retina with a visual prosthesis (bionic eye) is to excite only the cells lying directly under the electrode in the ganglion cell layer, while avoiding excitation of axon bundles that pass over the surface of the retina in the nerve fiber layer. Stimulation of overlying axons results in irregular visual percepts, limiting perceptual efficacy. This research explores how differences in fiber orientation between the nerve fiber layer and ganglion cell layer leads to differences in the electrical activation of the axon initial segment and axons of passage. <i>Approach</i>. Axons of passage of retinal ganglion cells in the nerve fiber layer are characterized by a narrow distribution of fiber orientations, causing highly anisotropic spread of applied current. In contrast, proximal axons in the ganglion cell layer have a wider distribution of orientations. A four-layer computational model of epiretinal extracellular stimulation that captures the effect of neurite orientation in anisotropic tissue has been developed using a volume conductor model known as the cellular composite model. Simulations are conducted to investigate the interaction of neural tissue orientation, stimulating electrode configuration, and stimulation pulse duration and amplitude. <i>Main results</i>. Our model shows that simultaneous stimulation with multiple electrodes aligned with the nerve fiber layer can be used to achieve selective activation of axon initial segments rather than passing fibers. This result can be achieved while reducing required stimulus charge density and with only modest increases in the spread of activation in the ganglion cell layer, and is shown to extend to the general case of arbitrary electrode array positioning and arbitrary target volume. <i>Significance</i>. These results elucidate a strategy for more targeted stimulation of retinal ganglion cells with experimentally-relevant multi-electrode geometries and achievable stimulation requirements.</p></div

Preferential stimulation for two non-ideal electrode array placements.

<p>(a)-(b) Membrane potential along neurite axes for axons of passage and axon initial segments, with stimulus current chosen to maximally activate initial segments without activating any passing axons. Colors correspond to those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193598#pone.0193598.g006" target="_blank">Fig 6(a)</a>, with green parallel to axons of passage and brown perpendicular. Insets describe the geometry of each simulation, indicating target region (red), electrodes used (black), and the orientation of axons of passage (orange). (c)-(d) Ganglion cell layer activation level vs. activation radius for non-ideal and ideal (as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193598#pone.0193598.g008" target="_blank">Fig 8(f)</a>) geometries. Transitions from solid to dashed lines represent the transitions from axon initial segment to axon of passage preferential activation. (e)-(f) The spread of ganglion cell layer activation in the <i>x</i>-<i>y</i> plane. The dashed blue line corresponds to the one-dimensional inset. Colors are mapped according to the color bar in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193598#pone.0193598.g008" target="_blank">Fig 8</a>. All simulations used a pulse phase duration of 200 <i>μ</i>s and electrode-retina separation of 100 <i>μ</i>m.</p

Unwanted stimulation of retinal ganglion cell axons of passage.

<p>Retinal ganglion cell somas and axon initial segments represent the target regions for epiretinal stimulation (region shaded blue). Activation of passing axons in the nerve fiber layer (gray shaded region) results in long, arc-shaped visual percepts and degradation of the quality of artificial vision. Retinal ganglion cell axon bundles in the nerve fiber layer that pass close to stimulating electrodes may be stimulated preferentially to target locations in the ganglion cell layer. Activated retinal ganglion cells are colored red. Simulations presented in this research use epiretinal multi-electrode arrays (100 <i>μ</i>m diameter, 200 <i>μ</i>m pitch). Note that the orientation of initial axonal segments is much more varied in reality than shown in this schematic.</p

Model parameter values, unless stated otherwise.

<p>Model parameter values, unless stated otherwise.</p

Normalized spread of extracellular potential with distance from a stimulating electrode.

<p>Spread is shown in (a) the <i>y</i>-<i>z</i> plane, parallel to the orientation of AOPs, and in (b) the <i>x</i>-<i>z</i> plane, perpendicular to the orientation of AOPs. The simulated extracellular potential at each <i>z</i>-slice is normalized to the range [0, 1] by subtracting the minimum and scaling the maximum per slice to 1. This is done for illustrative purposes due to the rapid fall-off of extracellular potential with increasing distance from the electrode. Contour lines indicate the full-width at half-maximum potential. Stimulation is with a single electrode located 100 <i>μ</i>m above the retinal surface at the origin in the <i>x</i>-<i>y</i> plane. Dashed lines indicate layer boundaries.</p

Geometry and simulated membrane potentials for axons of passage and axon initial segments at a variety of <i>x</i>-<i>y</i> orientations.

<p>(a) Four-layer model geometry showing the electrode array, an example of a parallel axon of passage (orange), and the neurite orientations considered in the ganglion cell layer (green-brown). Membrane potential at the end of the cathodic phase is shown along the axes of the neurites being simulated for configurations of (b) one, (c) two, and (d) four electrodes aligned with the axon of passage. Dotted lines represent membrane thresholds for axons of passage (orange) and axon initial segments (black). Stimulus currents have been chosen such that they drive the axon of passage precisely to its threshold level. Colors in (b)-(d) indicate corresponding neurites in (a).</p

Proportion of axon initial segment orientations preferentially activated for different electrode-retina separations (<i>d</i>_ER) and pulse durations.

<p>Heat maps indicate the proportion of axon initial segments activated at a lower stimulus current than any fibers in the nerve fiber layer for (a) one-, (b) two- and (c) four-electrode configurations (aligned with the axon of passage). Regions of low (<10%), medium (10-40%), and high (>40%) stimulation selectivity are separated by dotted contours. White markers indicate the parameters used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193598#pone.0193598.g006" target="_blank">Fig 6</a>, and black markers indicate the parameters used for subplots (d), (e) and (f), which show examples of simulated membrane potentials for axons of passage and axon initial segments. Colors in (d)-(f) correspond to those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193598#pone.0193598.g006" target="_blank">Fig 6(a)</a>.</p