Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax® and Turbuhaler® devices: a randomised, cross-over study.

BACKGROUND: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients

Subthreshold dynamics of the neural membrane potential driven by stochastic synaptic input

In the cerebral cortex, neurons are subject to a continuous bombardment of synaptic inputs originating from the network's background activity. This leads to ongoing, mostly subthreshold membrane dynamics that depends on the statistics of the background activity and of the synapses made on a neuron. Subthreshold membrane polarization is, in turn, a potent modulator of neural responses. The present paper analyzes the subthreshold dynamics of the neural membrane potential driven by synaptic inputs of stationary statistics. Synaptic inputs are considered in linear interaction. The analysis identifies regimes of input statistics which give rise to stationary, fluctuating, oscillatory, and unstable dynamics. In particular, I show that (i) mere noise inputs can drive the membrane potential into sustained, quasiperiodic oscillations (noise-driven oscillations), in the absence of a stimulus-derived, intraneural, or network pacemaker; (ii) adding hyperpolarizing to depolarizing synaptic input can increase neural activity (hyperpolarization-induced activity), in the absence of hyperpolarization-activated currents

Simple model for 1/f noise

We present a simple stochastic mechanism which generates pulse trains exhibiting a power law distribution of the pulse intervals and a $1/f^\alpha$ power spectrum over several decades at low frequencies with $\alpha$ close to one. The essential ingredient of our model is a fluctuating threshold which performs a Brownian motion. Whenever an increasing potential $V(t)$ hits the threshold, $V(t)$ is reset to the origin and a pulse is emitted. We show that if $V(t)$ increases linearly in time, the pulse intervals can be approximated by a random walk with multiplicative noise. Our model agrees with recent experiments in neurobiology and explains the high interpulse interval variability and the occurrence of $1/f^\alpha$ noise observed in cortical neurons and earthquake data.Comment: 4 pages, 4 figure

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 μg

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 μg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 μg contain equal amounts of lactose per carrier. However, 150 μg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 μg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 μg and 300 μg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 μm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 μm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 μg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

Septic physeal separation of proximal femur in a newborn

In newborns physeal separations and septic osteomyelitis or arthritis are unusual, representing a problem in diagnosis and treatment. Therapy needs to be carried out soon in order to prevent anatomical and functional consequences. Association between septic event and physeal separation is rare. We report a 28-day-old female, admitted for elevated temperature, who underwent three nonorthopaedic surgical procedures before, and orthopaedic evaluation 8 days after admission. After an X-ray and an ultrasonography a septic arthritis with consequent hip dislocation was supposed. Only at the time of surgery a separation between the epiphysio-trochanteric nuclei complex and the femoral shaft was observed, with clear hip joint. The interest in this case consists in the difficulty of the differential diagnosis at the first evaluation, the orthopaedic misdiagnosis based on the lack of complete preoperative imaging, and finally the long-term excellent result after a prompt surgical treatment

A Threshold Equation for Action Potential Initiation

In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about −55 mV), while its parameters are adjusted near half-activation voltage (about −30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold

Critical synchronization dynamics of the Kuramoto model on connectome and small world graphs

The hypothesis, that cortical dynamics operates near criticality also suggests, that it exhibits universal critical exponents which marks the Kuramoto equation, a fundamental model for synchronization, as a prime candidate for an underlying universal model. Here, we determined the synchronization behavior of this model by solving it numerically on a large, weighted human connectome network, containing 804092 nodes, in an assumed homeostatic state. Since this graph has a topological dimension $d < 4$, a real synchronization phase transition is not possible in the thermodynamic limit, still we could locate a transition between partially synchronized and desynchronized states. At this crossover point we observe power-law--tailed synchronization durations, with $\tau_t \simeq 1.2(1)$, away from experimental values for the brain. For comparison, on a large two-dimensional lattice, having additional random, long-range links, we obtain a mean-field value: $\tau_t \simeq 1.6(1)$. However, below the transition of the connectome we found global coupling control-parameter dependent exponents $1 < \tau_t \le 2$, overlapping with the range of human brain experiments. We also studied the effects of random flipping of a small portion of link weights, mimicking a network with inhibitory interactions, and found similar results. The control-parameter dependent exponent suggests extended dynamical criticality below the transition point.Comment: 12 pages, 9 figures + Supplemenraty material pdf 2 pages 4 figs, 1 table, accepted version in Scientific Report

Coherence Potentials: Loss-Less, All-or-None Network Events in the Cortex

Transient associations among neurons are thought to underlie memory and behavior. However, little is known about how such associations occur or how they can be identified. Here we recorded ongoing local field potential (LFP) activity at multiple sites within the cortex of awake monkeys and organotypic cultures of cortex. We show that when the composite activity of a local neuronal group exceeds a threshold, its activity pattern, as reflected in the LFP, occurs without distortion at other cortex sites via fast synaptic transmission. These large-amplitude LFPs, which we call coherence potentials, extend up to hundreds of milliseconds and mark periods of loss-less spread of temporal and amplitude information much like action potentials at the single-cell level. However, coherence potentials have an additional degree of freedom in the diversity of their waveforms, which provides a high-dimensional parameter for encoding information and allows identification of particular associations. Such nonlinear behavior is analogous to the spread of ideas and behaviors in social networks

Distributed processing and temporal codes in neuronal networks

The cerebral cortex presents itself as a distributed dynamical system with the characteristics of a small world network. The neuronal correlates of cognitive and executive processes often appear to consist of the coordinated activity of large assemblies of widely distributed neurons. These features require mechanisms for the selective routing of signals across densely interconnected networks, the flexible and context dependent binding of neuronal groups into functionally coherent assemblies and the task and attention dependent integration of subsystems. In order to implement these mechanisms, it is proposed that neuronal responses should convey two orthogonal messages in parallel. They should indicate (1) the presence of the feature to which they are tuned and (2) with which other neurons (specific target cells or members of a coherent assembly) they are communicating. The first message is encoded in the discharge frequency of the neurons (rate code) and it is proposed that the second message is contained in the precise timing relationships between individual spikes of distributed neurons (temporal code). It is further proposed that these precise timing relations are established either by the timing of external events (stimulus locking) or by internal timing mechanisms. The latter are assumed to consist of an oscillatory modulation of neuronal responses in different frequency bands that cover a broad frequency range from <2 Hz (delta) to >40 Hz (gamma) and ripples. These oscillations limit the communication of cells to short temporal windows whereby the duration of these windows decreases with oscillation frequency. Thus, by varying the phase relationship between oscillating groups, networks of functionally cooperating neurons can be flexibly configurated within hard wired networks. Moreover, by synchronizing the spikes emitted by neuronal populations, the saliency of their responses can be enhanced due to the coincidence sensitivity of receiving neurons in very much the same way as can be achieved by increasing the discharge rate. Experimental evidence will be reviewed in support of the coexistence of rate and temporal codes. Evidence will also be provided that disturbances of temporal coding mechanisms are likely to be one of the pathophysiological mechanisms in schizophrenia