Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog.

All vertebrates produce some form of respiratory rhythm, whether to pump water over gills or ventilate lungs. Yet despite the critical importance of ventilation for survival, the architecture of the respiratory central pattern generator has not been resolved. In frogs and mammals, there is increasing evidence for multiple burst-generating regions in the ventral respiratory group. These regions work together to produce the respiratory rhythm. However, each region appears to be pivotally important to a different phase of the motor act. Regions also exhibit differing rhythmogenic capabilities when isolated and have different CO2 sensitivity and pharmacological profiles. Interestingly, in both frogs and rats the regions with the most robust rhythmogenic capabilities when isolated are located in rhombomeres 7/8. In addition, rhombomeres 4/5 in both clades are critical for controlling phases of the motor pattern most strongly modulated by CO2 (expiration in mammals, and recruitment of lung bursts in frogs). These key signatures may indicate that these cell clusters arose in a common ancestor at least 400 million years ago.

Three brainstem areas involved in respiratory rhythm generation in bullfrogs.

For most multiphasic motor patterns, rhythm and pattern are produced by the same circuit elements. For respiration, however, these functions have long been assumed to occur separately. In frogs, the ventilatory motor pattern produced by the isolated brainstem consists of buccal and biphasic lung bursts. Previously, two discrete necessary and sufficient sites for lung and buccal bursts were identified. Here we identify a third site, the Priming Area, important for and having neuronal activity correlated with the first phase of biphasic lung bursts. As each site is important for burst generation of a separate phase, we suggest each major phase of ventilation is produced by an anatomically distinct part of an extensive brainstem network. Embedding of discrete circuit elements producing major phases of respiration within an extensive rhythmogenic brainstem network may be a shared architectural characteristic of vertebrates. ABSTRACT: Ventilation in mammals consists of at least three distinct phases: inspiration, post-inspiration and late-expiration. While distinct brainstem rhythm generating and pattern forming networks have long been assumed, recent data suggest the mammalian brainstem contains two coupled neuronal oscillators: one for inspiration and the other for active expiration. However, whether additional burst generating ability is required for generating other phases of ventilation in mammals is controversial. To investigate brainstem circuit architectures capable of producing multiphasic ventilatory rhythms, we utilized the isolated frog brainstem. This preparation produces two types of ventilatory motor patterns, buccal and lung bursts. Lung bursts can be divided into two phases, priming and powerstroke. Previously we identified two putative oscillators, the Buccal and Lung Areas. The Lung Area produces the lung powerstroke and the Buccal Area produces buccal bursts and - we assumed - the priming phase of lung bursts. However, here we identify an additional brainstem region that generates the priming phase. This Priming Area extends rostral and caudal of the Lung Area and is distinct from the Buccal Area. Using AMPA microinjections and reversible synaptic blockade, we demonstrate selective excitation and ablation (respectively) of priming phase activity. We also demonstrate that the Priming Area contains neurons active selectively during the priming phase. Thus, we propose that three distinct neuronal components generate the multiphase respiratory motor pattern produced by the frog brainstem: the buccal, priming and powerstroke burst generators. This raises the possibility that a similar multi-burst generator architecture mediates the three distinct phases of ventilation in mammals.

Intimidation and harassment in residency: a review of the literature and results of the 2012 Canadian Association of Interns and Residents National Survey.

BACKGROUND: Intimidation and harassment (I&H) have been longstanding problems in residency training. These behaviours continue to be prevalent, as evidenced by the 2012 Canadian Association of Interns and Residents (CAIR) National Resident Survey. More than seven in ten (72.9%) residents reported behaviour from others that made them feel diminished during their residency. We conducted a literature review to identify other surveys to determine the prevalence, key themes, and solutions to I&H across residency programs. METHOD: PubMed and MEDLINE searches were performed using the key words "intimidation," "harassment," "inappropriate behaviour," "abuse," "mistreatment," "discrimination," and "residency." The search was limited to English language articles published between 1996 and 2013, and to papers where ten or more residents were surveyed or interviewed. RESULTS: A total of ten articles were reviewed. Our findings showed that I&H continue to be highly prevalent with 45-93% of residents reporting this behaviour on at least one occasion. Verbal abuse was the most predominant form; staff physicians and nurses tended to be the dominant source. Residents reported that I&H caused significant emotional impact; however, very few incidents of inappropriate behaviour were reported. Very few solutions to I&H were proposed. CONCLUSIONS: I&H in residency education continue to be common problems that are under-reported and under-discussed. The opportunity exists to improve efforts in this area. Definitions of what incorporates I&H should be revisited and various educational and structural initiatives should be implemented.

Localization of essential rhombomeres for respiratory rhythm generation in bullfrog tadpoles using a binary search algorithm: Rhombomere 7 is essential for the gill rhythm and suppresses lung bursts before metamorphosis.

Frog metamorphosis includes transition from water breathing to air breathing but the extent to which such a momentous change in behavior requires fundamental changes in the organization of the brainstem respiratory circuit is unknown. Here, we combine a vertically mounted isolated brainstem preparation, "the Sheep Dip," with a search algorithm used in computer science, to identify essential rhombomeres for generation of ventilatory motor bursts in metamorphosing bullfrog tadpoles. Our data suggest that rhombomere 7, which in mammals hosts the PreBötC (PreBötzinger Complex; the likely inspiratory oscillator), is essential for gill and buccal bursts. Whereas rhombomere 5, in close proximity to a brainstem region associated with the mammalian expiratory oscillator, is essential for lung bursts at both stages. Therefore, we conclude there is no rhombomeric translocation of respiratory oscillators in bullfrogs as previously suggested. In premetamorphic tadpoles, functional ablation of rhombomere 7 caused ectopic expression of precocious lung bursts, suggesting the gill oscillator suppresses an otherwise functional lung oscillator in early development.

An update on amine oxidase inhibitors: multifaceted drugs.

Although not used as extensively as other antidepressants for the treatment of depression, the monoamine oxidase (MAO) inhibitors continue to hold a niche in psychiatry and to have a relatively broad spectrum with regard to treatment of psychiatric and neurological disorders. Experimental and clinical research on MAO inhibitors has been expanding in the past few years, primarily because of exciting findings indicating that these drugs have neuroprotective properties (often independently of their ability to inhibit MAO). The non-selective and irreversible MAO inhibitors tranylcypromine (TCP) and phenelzine (PLZ) have demonstrated neuroprotective properties in numerous studies targeting elements of apoptotic cascades and neurogenesis. l-Deprenyl and rasagiline, both selective MAO-B inhibitors, are used in the management of Parkinson's disease, but these drugs may be useful in the treatment of other neurodegenerative disorders given that they demonstrate neuroprotective/neurorescue properties in a wide variety of models in vitro and in vivo. Although the focus of studies on the involvement of MAO inhibitors in neuroprotection has been on MAO-B inhibitors, there is a growing body of evidence demonstrating that MAO-A inhibitors may also have neuroprotective properties. In addition to MAO inhibition, PLZ also inhibits primary amine oxidase (PrAO), an enzyme implicated in the etiology of Alzheimer's disease, diabetes and cardiovascular disease. These multifaceted aspects of amine oxidase inhibitors and some of their metabolites are reviewed herein.

Evidence for a distributed respiratory rhythm generating network in the goldfish (Carsssius auratus).

Central pattern generators located in the brainstem regulate ventilatory behaviors in vertebrates. The development of the isolated brainstem preparation has allowed these neural networks to be characterized in a number of aquatic species. The aim of this study was to explore the architecture of the respiratory rhythm-generating site in the goldfish (Carassius auratus) and to determine the utility of a newly developed isolated brainstem preparation, the Sheep Dip. Here we provide evidence for a distributed organization of respiratory rhythm generating neurons along the rostrocaudal axis of the goldfish brainstem and outline the advantages of the Sheep Dip as a tool used to survey neural networks.