Comparison of SGA Oral Medications and a Long-Acting Injectable SGA: The PROACTIVE Study

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician\u27s choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials

Synaptic and Intrinsic Activation of GABAergic Neurons in the Cardiorespiratory Brainstem Network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration

Facilitated sequence assembly using densely labeled optical DNA barcodes:A combinatorial auction approach

<div><p>The output from whole genome sequencing is a set of contigs, i.e. short non-overlapping DNA sequences (sizes 1-100 kilobasepairs). Piecing the contigs together is an especially difficult task for previously unsequenced DNA, and may not be feasible due to factors such as the lack of sufficient coverage or larger repetitive regions which generate gaps in the final sequence. Here we propose a new method for scaffolding such contigs. The proposed method uses densely labeled optical DNA barcodes from competitive binding experiments as scaffolds. On these scaffolds we position theoretical barcodes which are calculated from the contig sequences. This allows us to construct longer DNA sequences from the contig sequences. This proof-of-principle study extends previous studies which use sparsely labeled DNA barcodes for scaffolding purposes. Our method applies a probabilistic approach that allows us to discard “foreign” contigs from mixed samples with contigs from different types of DNA. We satisfy the contig non-overlap constraint by formulating the contig placement challenge as a combinatorial auction problem. Our exact algorithm for solving this problem reduces computational costs compared to previous methods in the combinatorial auction field. We demonstrate the usefulness of the proposed scaffolding method both for synthetic contigs and for contigs obtained using Illumina sequencing for a mixed sample with plasmid and chromosomal DNA.</p></div

Capsaicin- resistant arterial baroreceptors

BACKGROUND: Aortic baroreceptors (BRs) comprise a class of cranial afferents arising from major arteries closest to the heart whose axons form the aortic depressor nerve. BRs are mechanoreceptors that are largely devoted to cardiovascular autonomic reflexes. Such cranial afferents have either lightly myelinated (A-type) or non-myelinated (C-type) axons and share remarkable cellular similarities to spinal primary afferent neurons. Our goal was to test whether vanilloid receptor (TRPV1) agonists, capsaicin (CAP) and resiniferatoxin (RTX), altered the pressure-discharge properties of peripheral aortic BRs. RESULTS: Periaxonal application of 1 μM CAP decreased the amplitude of the C-wave in the compound action potential conducting at <1 m/sec along the aortic depressor nerve. 10 μM CAP eliminated the C-wave while leaving intact the A-wave conducting in the A-δ range (<12 m/sec). These whole nerve results suggest that TRPV1 receptors are expressed along the axons of C- but not A-conducting BR axons. In an aortic arch – aortic nerve preparation, intralumenal perfusion with 1 μM CAP had no effect on the pressure-discharge relations of regularly discharging, single fiber BRs (A-type) – including the pressure threshold, sensitivity, frequency at threshold, or maximum discharge frequency (n = 8, p > 0.50) but completely inhibited discharge of an irregularly discharging BR (C-type). CAP at high concentrations (10–100 μM) depressed BR sensitivity in regularly discharging BRs, an effect attributed to non-specific actions. RTX (≤ 10 μM) did not affect the discharge properties of regularly discharging BRs (n = 7, p > 0.18). A CAP-sensitive BR had significantly lower discharge regularity expressed as the coefficient of variation than the CAP-resistant fibers (p < 0.002). CONCLUSION: We conclude that functional TRPV1 channels are present in C-type but not A-type (A-δ) myelinated aortic arch BRs. CAP has nonspecific inhibitory actions that are unlikely to be related to TRV1 binding since such effects were absent with the highly specific TRPV1 agonist RTX. Thus, CAP must be used with caution at very high concentrations

Firing properties of identified parasympathetic cardiac neurons in nucleus ambiguus

This study tests the hypothesis that identified parasympathetic cardiac neurons in the nucleus ambiguus possess pacemaker-like activity or, alternatively, that these neurons are inherently silent. To test this hypothesis and to examine the firing properties of these neurons, parasympathetic cardiac neurons were identified by the presence of a fluorescent tracer previously applied to their terminals surrounding the heart. Perforated patch-clamp electrophysiological techniques were used to study the spontaneous and depolarization-evoked firing patterns of these identified parasympathetic cardiac neurons in an in vitro brain stem slice. Parasympathetic cardiac neurons were silent. On injection of depolarizing current, however, these neurons fired with both little delay and spike frequency adaptation. Hyperpolarizing prepulses elicited a significant delay before depolarization-evoked firing. The Ca2+-activated K+ channel blocker apamin, but not charybdotoxin, increased the depolarization-activated firing frequency of these neurons and inhibited the afterhyperpolarization. In summary, parasympathetic cardiac neurons do not have pacemaker-like properties, but they do possess discharge characteristics that would enable them to closely follow excitatory synaptic activation for prolonged periods

Superior laryngeal neurons directly excite cardiac vagal neurons within the nucleus ambiguus

The aim of this study was to test whether superior laryngeal neurons have axon collaterals that synapse upon cardiac vagal neurons. Superior laryngeal neurons were tested as likely mediators of cardio-respiratory interaction because these neurons are active in post-inspiration, co- localized with cardiac vagal neurons, and have many axon collaterals within the nucleus ambiguus. Nontoxic fluorescent tracers were utilized to identify, in vitro, both superior laryngeal neurons that innervated the crico-thyroid muscle, and cardiac vagal neurons that projected to cardiac ganglia. Co- localization of these two populations of neurons demonstrated that cardiac vagal and superior laryngeal neurons are both co-localized in the nucleus ambiguus. Simultaneous dual patch clamp recordings were used to either inject depolarizing current and evoke an action potential (current clamp configuration) or control the voltage and depolarize an identified single superior laryngeal neuron (voltage clamp configuration) while simultaneously recording from a cardiac vagal neuron. Depolarization of some, but not all, individual superior laryngeal neurons elicited post-synaptic excitatory currents in cardiac vagal neurons, indicating that at least some superior laryngeal neurons monosynaptically synapse upon cardiac vagal neurons within the nucleus ambiguus. (C) 2000 Elsevier Science Inc

Musings on the wanderer: what\u27s new in our understanding of vago-vagal reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia

To understand vago-vagal reflexes, one must have an appreciation of the events surrounding the encoding, integration, and central transfer of peripheral sensations by vagal afferent neurons. A large body of work has shown that vagal afferent neurons have nonuniform properties and that distinct subpopulations of neurons exist within the nodose ganglia. These sensory neurons display a considerable degree of plasticity; electrophysiological, pharmacological, and neurochemical properties have all been shown to alter after peripheral tissue injury. The validity of claims of selective recordings from populations of neurons activated by peripheral stimuli may be diminished, however, by the recent demonstration that stimulation of a subpopulation of nodose neurons can enhance the activity of unstimulated neuronal neighbors. To better understand the neurophysiological processes occurring after vagal afferent stimulation, it is essential that the electrophysiological, pharmacological, and neurochemical properties of nodose neurons are correlated with their sensory function or, at the very least, with their specific innervation target

Characterization of calcium currents in aortic baroreceptor neurons

1. Calcium currents in identified rat aortic baroreceptors were characterized with the perforated patch whole-cell voltage-clamp technique. Aortic baroreceptors were distinguished from other neurons by the presence of a fluorescent tracer that was previously applied to the aortic depressor nerve. The diversity of calcium currents in unidentified neurons dissociated from neonatal rat nodose ganglia were also examined. 2. A population of aortic baroreceptors (63%, 7 of 11) possessed a low-threshold, also referred to as a T-type, calcium current. This current was typically \u3c100 pA in 2 mM Ca [72.7 ± 20.9 (SE) pA, n = 7], had a rapid activation and inactivation, and inactivated completely at conditioning voltages positive to -50 mV. 3. All aortic baroreceptors possessed high-threshold calcium currents that were activated at voltages positive to -30 mV, with typical maximum amplitudes of 600-1,000 pA (826 ± 79 pA, n = 11). 4. The high-threshold current inactivated with three exponential rates of decay of τ = 10.7 ± 2.2 ms, 138 ± 14.6 ms, and a third τ \u3e 3 s. It was not possible to separate the kinetic components of inactivation with conditioning voltages (voltage-dependent inactivation), activation thresholds, deactivation kinetics, or calcium- channel antagonists. 5. The voltage-dependent inactivation of high-threshold calcium currents began at voltages positive to -70 mV and became steeply voltage dependent between -60 and -10 mV. Unexpectedly, the three decay constants were present after all conditioning voltages. There were no conditioning voltages that excluded any component. 6. ω-Conotoxin (GVIA) blocked ~70% of the high-threshold current and inhibited all kinetic components of inactivation equally. ω-Conotoxin (1 μM) inhibited the magnitude of calcium current activated after each conditioning voltage without any change in the voltage dependence of inactivation. The dihydropyridine antagonist nimodipine (2 μM) had little or no effect. 7. Analysis of tail currents indicated that high-threshold calcium currents activate at voltages positive to -30 mV. ω-Conotoxin inhibited the tail currents but did not alter the threshold or range of voltages over which activation occurred. 8. High-threshold tail currents deactivated with a single exponential rate after different test voltages and varying duration. 9. In conclusion, the calcium currents in aortic baroreceptors have been characterized. A population of aortic baroreceptors possess a low-threshold (T-type) calcium current. All aortic baroreceptors possess high-threshold calcium currents that inactivate with three rates of decay. The entire high- threshold calcium current profile activated at voltages positive to -30 mV, inactivated after conditioning voltages positive to -70 mV, and deactivated with a single rate of decay, was insensitive to nimodipine, and was blocked (70%) by ω-conotoxin