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

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

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

Pulsatile sinus pressure changes evoke sustained baroreflex responses in awake dogs

A modified Stephenson-Donald preparation was used to control pressure in an isolated carotid sinus in conscious dogs with all other arterial baroreceptors denervated. Sinus pressure was changed from preisolation control levels to either an elevated static or an elevated pulsatile pressure for 5 min. These sinus pressure changes evoked similar initial decreases in arterial pressure. The elevated static sinus pressure (150 or 175 mmHg) caused an initial depressor response of -32.7 ± 5.5 mmHg, which then decayed rapidly. Five minutes after the change in sinus pressure, the depressor response was abolished, as arterial pressure returned to control pressure. This decay of the response would be expected if resetting occurred. In contrast, when the sinus was exposed to elevated pulsatile pressures (125 or 150 mmHg mean, 50 mmHg pulse pressure) depressor responses were sustained throughout the sinus pressure change (-23.2 ± 5.3 mmHg initial, -29.0 ± 4.8 mmHg at 5 min; P \u3e 0.4). These results demonstrate that while the reflex responses rapidly reset to elevated static sinus pressures, elevated pulsatile pressures elicit sustained reflex responses

Pulsatile pressure can prevent rapid baroreflex resetting

In a previous study [Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H673-H678, 1988] we demonstrated that baroreflex responses decay (reset) to increased static sinus pressures, but with increased pulsatile pressure, responses are maintained. To determine more conclusively whether pulsatile pressure prevents rapid baroreflex resetting in this study we examined resetting as shifts of the baroreflex (sinus pressure-arterial pressure) curve. In seven anesthesized rabbits the left sinus was vascularly isolated and conditioned for 5 min to static or pulsatile pressures of 60, 100, or 140 mmHg mean pressure, 0 or 35-40 mmHg pulse pressure. The baroreflex curve was then determined by stepwise changing sinus pressure from 40 to 160 mmHg in 20-mmHg increments. Threshold, midpoint, and saturation sinus pressures shifted 25-39% with static conditioning pressures but did not shift significantly with pulsatile pressures. Also, the baroreflex responses to step increases in static sinus pressure decayed, as resetting occurred, but did not decay with pulsatile sinus pressure increases. Thus the baroreflex rapidly resets with static pressures, but there is minimal, if any, resetting with pulsatile pressures

Pulsatile sinus pressure changes evoke sustained baroreflex responses in awake dogs

A modified Stephenson-Donald preparation was used to control pressure in an isolated carotid sinus in conscious dogs with all other arterial baroreceptors denervated. Sinus pressure was changed from preisolation control levels to either an elevated static or an elevated pulsatile pressure for 5 min. These sinus pressure changes evoked similar initial decreases in arterial pressure. The elevated static sinus pressure (150 or 175 mmHg) caused an initial depressor response of -32.7 ± 5.5 mmHg, which then decayed rapidly. Five minutes after the change in sinus pressure, the depressor response was abolished, as arterial pressure returned to control pressure. This decay of the response would be expected if resetting occurred. In contrast, when the sinus was exposed to elevated pulsatile pressures (125 or 150 mmHg mean, 50 mmHg pulse pressure) depressor responses were sustained throughout the sinus pressure change (-23.2 ± 5.3 mmHg initial, -29.0 ± 4.8 mmHg at 5 min; P \u3e 0.4). These results demonstrate that while the reflex responses rapidly reset to elevated static sinus pressures, elevated pulsatile pressures elicit sustained reflex responses

Firing properties of identified superior laryngeal neurons in the nucleus ambiguus in the rat

Superior laryngeal motoneurons control muscles in the larynx and recent work has shown they also have axon collaterals that project to cardiac vagal neurons in the nucleus ambiguus. The present study was undertaken to identify and examine the firing properties of superior laryngeal neurons (SLNs) in the rat. SLNs typically fired spontaneously and repetitively at a rate of 4-7 Hz. The firing was continuous and showed little bursting activity. Firing evoked afterhyperpolarizations were insensitive to apamin but blocked by charybdotoxin. The voltage-gated currents in SLNs consist of a TTX-sensitive Na current and a 4-aminopyridine sensitive K current. It is likely that the activity of these neurons not only control respiratory laryngeal muscles, but may also provide an interaction between the respiratory system and the control of the heart rate. © 2001 Elsevier Science Ireland Ltd