A comparative study of peripherally-inserted and Broviac catheter complications in home parenteral nutrition patients.

BACKGROUND & AIMS: Peripherally inserted central venous catheters (PICC) have become increasingly popular for medium to long-term parenteral nutrition (PN) but there is limited data on the complication rates in this sub-group. We aimed to compare the rates of complications associated with tunneled catheters (Broviac) and PICC in home PN (HPN) patients. METHODS: All adult patients in an HPN program with a new Broviac or new PICC between 2009 and 2011 were included in this prospective observational study. Complication rates were compared by using Poisson regression and Kaplan Meier survival curves were used to compare the first complications that occurred. RESULTS: 204 catheters (133 Broviac and 71 PICC) were inserted in 196 adult patients. Mean follow-up from catheter insertions to their removal was 276 ± 219 days for Broviac (n = 86) vs. 74 ± 140.70 days for PICC (n = 56); p < 0.001. Complications were similar between Broviac and PICC (91/133 vs. 26/71). Catheter infection rate was lower in PICC (1.87 vs. 1.05 per 1000 catheter-days; p = 0.01). Catheter obstruction rates were similar for both catheters. Only PICC experienced venous thrombosis (0.4/1000). The proportion of catheters removed was lower in the Broviac group than in the PICC group (62.4% vs. 78.8%; p = 0.01) but those removed for complications were not different (28.6.7%vs. 25.3%; p = 0.64). CONCLUSIONS: In HPN patients, overall complications were similar in both the PICC and the Broviac groups. However, the Broviac catheter could be associated with an increase in catheter infection.

5-Hydroxytryptamine action in the rat olfactory bulb: in vitro electrophysiological patch-clamp recordings of juxtaglomerular and mitral cells.

The olfactory bulb, first relay of olfactory pathways, is densely innervated by serotoninergic centrifugal fibers originating from the raphe nuclei. Although serotonin innervation was reported to be involved in olfactory learning in mammals, the action of this neurotransmitter on its putative cellular targets has been never described through unitary recordings. This lack of data initiated the present study where the effects of 5HT on juxtaglomerular and mitral cells are analyzed using whole-cell recordings on olfactory bulb slices. Serotonin depolarizes 34% of 525 JG cells. A multivariate statistical analysis of juxtaglomerular cells characteristics shows that the serotonin responsive cell group can be individualized regarding their tonic discharge-mode in response to a direct current injection, their lower expression of hyperpolarization-activated cation current and their low membrane capacities. The use of ion channel blockers and ramp voltage protocol indicate that serotoninergic depolarization of juxtaglomerular cells may be due to a nonselective cation current with a reversal potential of -44 mV. Pharmacological tests with serotonin receptor antagonists and agonists reveal that 5HT action on juxtaglomerular cells would be mainly mediated by 5HT2C receptors. In mitral cells, serotonin acts on 49.1% of the 242 tested cells, inducing two types of responses. A first subset of mitral cells (26.8%, n=65) were hyperpolarized by serotonin. This response would be indirect and mediated by action of GABA on GABAA receptors since it was antagonized by bicuculline. The involved GABAergic neurons are hypothesized to be juxtaglomerular and granular cells, on which serotonin would act mainly via 5HT2C and via 5HT2A receptors respectively. The second subset of mitral cells (22.3%, n=54) were directly depolarized by serotonin acting through 5HT2A receptors. Our data on serotonin action on juxtaglomerular cells and mitral cells reveal a part of functional mechanisms whereby serotonin can act on olfactory bulb network. This is expected to enrich the understanding of its determining role in olfactory learning.

GABA(B) receptor-mediated inhibition of mitral/tufted cell activity in the rat olfactory bulb: a whole-cell patch-clamp study in vitro.

GABA, the major inhibitory neurotransmitter involved in information processing in the olfactory bulb, is hypothesized to act through GABA(B) receptors by depressing primary neurotransmitter release at the level of olfactory nerve axon endings. The present study was designed to analyze GABA(B) receptor-mediated inhibition mechanisms by performing whole-cell patch-clamp recordings of mitral/tufted cell activity in the rat in vitro. To do so, GABA(B) receptor-mediated action was mimicked by baclofen and antagonized by saclofen. Our protocol led us to provide an original description of GABA(B) receptor-mediated inhibition exerted on mitral/tufted cells. First, their spontaneous activity was shown to be drastically abolished by baclofen. Second, their responses to olfactory nerve electrical stimulation were graded by GABA(B) receptor-mediated inhibition. Indeed, this inhibition may be described as inducing effects ranked from a slight increase in response latency to a complete response suppression.Altogether, our results corroborate the hypothesis of a presynaptic extrasynaptic GABA(B) receptor-mediated inhibition influencing mitral/tufted cell olfactory nerve responsivity. However, the involvement of postsynaptic receptors, with different properties or with different anatomical locations, cannot be ruled out, particularly in the control of spontaneous activity. In conclusion, we underline that, in the vertebrate olfactory bulb, GABA(B) receptor-mediated action appears to contribute to make mitral/tufted cell responses more salient by reducing their resting activity.

GABA(B)-mediated action in the frog olfactory bulb makes odor responses more salient.

In the olfactory bulb, GABA(B) receptors are selectively located in the glomerular layer. A current hypothesis is that GABAergic inhibition mediated through these receptors would be, at least partly, presynaptic and would exerted by decreasing the release of the olfactory receptor neuron excitatory neurotransmitter. Here, we assessed, in the frog, the in vivo action of baclofen, a GABA(B) agonist, on single-unit mitral cell activity in response to odors. Local application of baclofen in the glomerular region of the olfactory bulb was shown to drastically affect mitral cell spontaneous activity, since they became totally silent. Moreover, under baclofen, mitral cells still responded to odors and still specified odor concentration increases through their temporal response patterns. The pharmacological specificity of the GABA(B) agonist action was confirmed by showing that saclofen, a GABA(B) antagonist, partly prevented the inhibitory action of baclofen and restored the initial rate of mitral cell spontaneous activity. The results show that GABA(B)-mimicked inhibition suppressed mitral cell spontaneous activity while odor responses were maintained. This suggests that olfactory receptor neurons partly drive spontaneous mitral cell activity. Moreover, the effect of GABA(B)-mediated inhibition was seen to be very close to that described previously for dopamine D(2) receptor-mediated inhibition. In conclusion, we propose that these two inhibitory mechanisms would offer the possibility to reduce or suppress mitral cell spontaneous activity so as to make their responses to odor especially salient.

Peripheral odor coding in the rat and frog: quality and intensity specification.

In mammals, two recent studies have shown recently that one odor molecule can be recognized by several molecular olfactory receptors (ORs), and a single OR can recognize multiple odor molecules. In addition, one olfactory receptor neuron (ORN) may respond to different stimuli chosen as representative of distinct odor qualities. The aim of the present study was to analyze quality and intensity coding abilities of rat single ORNs, comparing them with previous extensive data gathered in the frog to get insight into the generality of olfactory coding mechanisms over vertebrates. Response properties of 90 rat ORNs to different odors or to one odor at different concentrations were analyzed. In the rat and the frog, odor quality appears to be specified through the identity of activated ORNs. However, rat ORNs have higher response thresholds. This lower sensitivity may be interpreted as an increase in selectivity of rat ORNs for low or medium odor intensities. In these conditions, the lower proportion of activated ORNs could be counterbalanced by their number, as well as by their higher glomerular convergence ratio in the olfactory bulb. From amphibians to mammals, the olfactory system appears to use universal mechanisms based on a combinatorial-coding mode that may allow quasi-infinite possibilities of adaptation to various olfactory environments.

Spiking frequency versus odorant concentration in olfactory receptor neurons.

The spiking response of receptor neurons to various odorants has been analyzed at different concentrations. The interspike intervals were measured extracellularly before, during and after the stimulation from the olfactory epithelium of the frog Rana ridibunda. First, a quantitative method was developed to distinguish the spikes in the response from the spontaneous activity. Then, the response intensity, characterized by its median instantaneous frequency, was determined. Finally, based on statistical analyses, this characteristic was related to the concentration and quality of the odorant stimulus. It was found that the olfactory neuron is characterized by a low modulation in frequency and a short range of discriminated intensities. The significance of the results is discussed from both a biological and a modelling point of view.

Odor response properties of rat olfactory receptor neurons.

Molecular biology studies of olfaction have identified a multigene family of molecular receptors that are likely to be involved in odor transduction mechanisms. However, because previous functional data on peripheral coding were mainly collected from inferior vertebrates, it has been difficult to document the degree of specificity of odor interaction mechanisms. As a matter of fact, studies of the functional expression of olfactory receptors have not demonstrated the low or high specificity of olfactory receptors. In this study, the selectivity of olfactory receptor neurons was investigated in the rat at the cellular level under physiological conditions by unitary extracellular recordings. Individual olfactory receptor neurons were broadly responsive to qualitatively distinct odor compounds. We conclude that peripheral coding is based on activated arrays of olfactory receptor cells with overlapping tuning profiles.

Sensory information processing in the frog olfactory pathways. Experimental basis for modeling studies.

In the frog, unitary electrophysiological recordings have been extensively used to investigate odor processing along the olfactory pathways. By comparing spontaneous and odor-evoked activities of neuroreceptor, mitral and cortical cells, we have collected fundamental data relating to coding abilities of the three olfactory levels, the olfactory mucosa, the bulb and the cortex. Based on a synthesis of our experimental data related to GABAergic and dopaminergic involvement in the olfactory bulb, this paper aims to match this information with computational data and to discuss some questions on bulbar processing. This paper is also devoted to further analyze original results on coding properties of two functionally evidenced neuron subpopulations in the olfactory cortex. Thus, the assumption according to which some cortical neurons may work as temporal integrators while others as coincidence detectors is presented. Moreover, the pertinence that the neural code may be carried by a single spike with varying latency was demonstrated.

Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study.

Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D2 type in mammals. The present study assessed, in the frog, both the anatomical localization of D2-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [125I]iodosulpride-labelled D2 binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D2 antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity. In the frog olfactory bulb, both anatomical localization of D2-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio.

Odor processing in the frog olfactory system.

In the frog, unitary electrophysiological recordings have been extensively used to investigate odor processing along the olfactory pathways. From the responses of primary second-order neurons, neuroreceptor and mitral cells, odor stimuli could be classified in qualitative groups, revealing that neuronal discriminative mechanisms are partly based on the structure of odor molecule. In the olfactory bulb, thanks both to the anatomical convergence of primary afferences and intrinsic network properties, mitral cells have been demonstrated to gain in odor discrimination and detection power abilities. GABAergic bulbar interneurons were found to be involved in the control of mitral cell excitability, adjusting response thresholds and duration and promoting a progressive increase of burst discharges with stimulus concentration. Otherwise, dopamine was observed to shunt off mitral cell spontaneous activity without altering their odor responsivity properties. Dopamine was demonstrated to act through D2 receptors. Matching anatomical and electrophysiological data, D2 receptors are assumed to be localized on mitral cells. The frog olfactory cortex neurons, silent at rest, could be segregated in two functional groups basing on their odor response properties. The first group shared most intensity coding properties with mitral cells while showing a lower discriminative power, similar to that of neuroreceptor cells. By contrast, the second group provided only minimal intensity coding and, basing on its high discrimination power, was assumed to be mainly devoted to odor discrimination. Thus, along the olfactory pathways, intensity and quality odor parameters which are simultaneously encoded by a neuroreceptor or mitral cell, become specified by two distinct populations in the cortex.

Odor coding properties of frog olfactory cortical neurons.

Until now, in amphibians, response odor properties of primary cortical neurons had never been investigated. Furthermore, very few data on this subject are available in other species. This prompted us to explore the functional properties of olfactory cortical neurons at rest and in response to odors. To achieve this, our experience with odor coding in the first two stages of the frog olfactory system, the olfactory mucosa and the olfactory bulb, led us to use odor stimuli which were chemical compounds with known stimulating properties, delivered to the mucosa in controlled conditions over a wide concentration range. Most of the cortical neurons were found to be very silent at rest, their average spontaneous activity being significantly lower than that of bulb neurons recorded previously in the same conditions. Cortical cells displayed, with all odors combined, 35% excitatory responses and 8% inhibitory responses. The excitatory response rate was similar to that of the bulb, while the inhibitory response rate was about 4.5-fold lower. Interestingly, two functional groups of cortical cells emerged based both on differences in response temporal patterning to odors delivered at increasing concentrations and in qualitative discrimination power. Regarding intensity coding, group 1 cells (53%) displayed "classical" temporal pattern evolution, increase of discharge frequencies and decrease of latency and burst duration, over the concentration range. The responses of group 2 cells (47%) were clearly original, since they consisted of a single spike (or more rarely two spikes) occurring with a strictly reproducible latency at a given concentration and a decreased latency as a function of increasing concentration. The dynamics of cell recruitment in the cortex showed that group 1 cell recruitment mimicked that of mitral cells, group 2 cells being recruited at higher concentrations. The analysis of qualitative discrimination properties of cortical cells regarding the eight-odor set revealed that the discrimination power of group 2 cells was similar to that of mitral cells. By contrast, the qualitative discrimination power of group 1 cells was found to be similar to that of neuroreceptor cells. In conclusion, this pioneer approach leads us to report that olfactory cortical neurons of the frog are responsive to odors and can be clearly divided into two groups based on functional criteria. Group 1 cells, which were relatively selective, poorly discriminating but sensitive, may be mainly devoted to intensity coding. By contrast, group 2 cells, which were not very sensitive but were selective and discriminating, were hypothesized to provide minimal intensity coding and thus to be mainly devoted to qualitative discrimination tasks.

Spontaneous activity of first- and second-order neurons in the frog olfactory system.

The spontaneous activity of first-order neurons (neuroreceptors of the mucosa) and second-order neurons (mitral cells of the bulb) was recorded extracellularly in the frog olfactory system. To assess the influence of peripheral inputs upon mitral cells, the bulb was either normally connected or partially deafferented. Our first set of findings concern the firing behavior. We found that most neurons generated interspike intervals (ISIs) that were stationary in mean and variance, and were not serially correlated at first and second order. Individual spikes in mitral cells and bursts of spikes in neuroreceptors were found to be generated by a Poisson process. Stochastic modeling suggests that the Poissonian behavior depends on the mean value of the membrane potential at the axon hillock. In these models, the mean potential in mitral cells would be far below the firing threshold and in neuroreceptors it would fluctuate at random between two states, one close to resting potential (between bursts) and the other close to the firing threshold with occasional crossings (within bursts). Secondly, partially deafferented mitral cells had significantly higher activity and lower variance than mitral cells receiving normal afferent input. This effect gives evidence that peripheral inputs influence mitral cells at rest not only through direct excitation but also through indirect inhibition exerted by local neurons. Thus, the unstimulated state of the olfactory bulb would not be qualitatively different from its stimulated state in the sense that both states involve the same types of synaptic interactions. Consequently, understanding the synaptic relationships that take place in the bulb network can benefit from studies of its spontaneous activity.

GABAergic control of odour-induced activity in the frog olfactory bulb: possible GABAergic modulation of granule cell inhibitory action.

In the olfactory bulb, the activity of the output neurons, the mitral cells, is under inhibitory control exerted by GABAergic interneurons, the granule cells. Although the mechanisms of this inhibition are well known from in vitro studies, its physiological role in controlling mitral cell activity in response to odours has never been investigated. This study planned to improve understanding of the involvement of granule cells. To do so, GABAA-synaptic mechanisms were altered using GABAA antagonists in order to observe the consequences on mitral cell electrophysiological responses to odours, delivered over a wide concentration range. Due to the laminar organization of bulbar cell populations, the antagonists picrotoxin or bicuculline were injected into the bulbar ventricle in order to block granule cell inhibitory action at first. Surprisingly, the early consequence of the antagonist injection was a decrease in cell responsivity: response spike frequencies were lowered while thresholds were occasionally shifted toward higher concentrations. This initial depressive effect was followed by a recovery of control excitability and, later, by an increase in excitability: spike bursts became more sustained in frequency and in duration. At the same time, in most of the cells studied, spontaneous activity became bursting. The early depressive effect of GABAA antagonists is discussed in terms of an enhancement of the inhibitory influence of granule cells on mitral cells. This might reflect a blocking action of the antagonists at the level of GABAergic synapses located on granule cells themselves. The late effect, an increase in excitability, is explained as the consequence of the alteration of the functioning of dendrodendritic synapses between granule and mitral cells leading to a disinhibition of the latter. The comparison of the present findings with others obtained when antagonists were applied on to glomerular layers led us to infer that granule cell inhibition would be devoted to limiting mitral cell responses in frequency and in duration rather than to adjusting their response threshold. The chronology of the effects observed strongly supports the fact that, following the intraventricular injection, the antagonists acted primarily in the deep layers of the bulb. Nevertheless, due to free diffusion starting from the injection site, the possibility that drugs act later in the glomerular layer can not be rejected. It can be concluded that, in addition to its extensive involvement through intrinsic interneurons, GABA might also control the strength of the inhibition exerted by granule cells on mitral cells via centrifugal fibres.

GABAergic control of odor-induced activity in the frog olfactory bulb: electrophysiological study with picrotoxin and bicuculline.

In the olfactory bulb, the first relay of the olfactory pathways, GABA, could be largely involved in the information processing since the two main populations of interneurons, periglomerular and granular cells, use it as neurotransmitter through reciprocal synapses with second-order neurons. This study planned to clarify the role of GABAergic inhibition in odor coding and, more precisely, the role of glomerular GABAergic inhibition. To do so, we attempted to specifically block in vivo GABAA receptors with either picrotoxin or bicuculline. The drug was applied at the level of the glomerular layer so that the antagonist could act primarily via periglomerular cells. The analysis of the effects of blocking GABAA on the coding was studied by recording the second-order neuron responses to odor stimuli delivered in a wide concentration range. Under drug treatment, the second-order neuron properties were deeply changed: response thresholds to odors were often lowered and spike bursts were more sustained in frequency and in duration. Thus, the GABAergic control on second-order neurons might be carried out by limiting the neuron excitability. GABAA antagonists applied in this manner could act to suppress the inhibitory effect of either the periglomerular cells or of the granule cells, both of which have been shown to contain enzymes for GABA production. The placement of the drug suggests to us that the action is primarily at the glomerulus. The results are consistent with periglomerular cells exerting a tonic inhibition on second-order neurons, an inhibition whose strength would be modulated by stimulus intensity. As a result, the amplifying role of glomerular convergence might be partly counterbalanced by input inhibition. Nevertheless, due to our procedure of drug application, one cannot rule out the possibility that the effects observed may partly reflect granular cell blocking. It can be concluded that the whole GABAergic inhibition, through GABAA receptors, permits a wide dynamic range of intensity coding.

Olfactory discrimination over a wide concentration range. Comparison of receptor cell and bulb neuron abilities.

Until now, olfactory discrimination had never been investigated using stimuli delivered over a wide concentration range. However, the fact that intensity variations might influence qualitative discrimination has been suggested in numerous physiological and psychophysical studies. The aim of the present work was to investigate qualitative coding mechanisms when stimulus intensity varies. For this purpose, receptor cell and olfactory bulb neuron unit activities were recorded in response to 2-s pulse delivery of 4 odorants available at 20 discrete concentration values over a range from 1 x 10(-6) to 5.62 x 10(-2) of saturation. Two types of mathematical analyses, Pearson's r correlation coefficient calculation and principal component factor analysis, were applied to odor-evoked discharge frequencies. In both receptor cells and bulb neurons, qualitative discrimination abilities were found to increase with stimulus concentration. Furthermore, the results suggest that the olfactory bulb can send a discriminant and specific message at lower concentrations than the olfactory mucosa. The amplifying role of convergence of primary afferences onto olfactory glomeruli could account for this ability of the bulb neurons.

Amplifying role of convergence in olfactory system a comparative study of receptor cell and second-order neuron sensitivities.

1. Extracellular unitary responses of receptor cells of second-order neurons identified as output cells were recorded in the frog. Four odorants of defined concentrations distributed over a wide range were delivered in the form of 2-s square pulses to the olfactory mucosa with a multistage dynamic flow dilution olfactometer. Bulbar responses were studied under two conditions, the stimuli being delivered either to the ventral or to the entire mucosa. 2. Overall responsiveness of the cells was compared. For the second-order neurons, the response ratio (excitation or inhibition) clearly depended on the condition of stimulation when the entire mucosa was stimulated, the bulbar response ratio was increased, as compared with that obtained when only the ventral mucosa received stimuli. Furthermore, when the stimuli were delivered to the whole mucosa, the bulbar excitation ratio was found to be similar to those of receptor cells and second-order neurons. 3. Response thresholds were determined from a comparison of the interspike interval values in the 30-s pre- and in the 12-s poststimulus time periods, using the Mann-Whitney U test (Table 2). The distribution of response thresholds of receptor cells as a function of stimulus concentration did not significantly differ from that of second-order neurons as excited by stimulating the ventral mucosa. These two distributions differed significantly from the distribution of second-order neurons as stimulated through the entire mucosa. In this last experimental condition, the bulbar neurons displayed an improved sensitivity. 4. The overall recruitment process, represented by the cumulative percentage of cells responding with excitation as a function of concentration, was found to be continuous over the entire concentration range. At the bulbar level, when the entire mucosa was stimulated, the recruitment occurred at lower concentrations than when only the ventral mucosa was stimulated. In this last case, the dynamics of the bulbar recruitment did not differ from that of receptor cells. 5. The recruitment process was further studied for each stimulus, for receptor cells as well as for second-order neurons. Differences in recruitment were found between stimuli and, as for the bulbar neurons, they depended on the condition of stimulation. 6. The main outcome of these results is the demonstration that the convergence of receptor cells onto second-order neurons is functionally implicated in an amplification process of the primary signal in olfaction.(ABSTRACT TRUNCATED AT 400 WORDS)

A wide concentration range olfactometer for delivery of short reproducible odor pulses.

A multistage dynamic flow dilution olfactometer allowing the delivery of precisely controlled stimuli over a wide concentration range is presented. Discrete concentration values, in the range 10(-6) to 5.6 X 10(-2) of the saturated vapor of an odorous compound, are obtained from two original concentration by combining 4 dilution stages. Short stimulus pulses, of a known and reproducible concentration and with short rising and falling times, are sampled from steady concentration levels. A programmable controller manages the olfactometer dilution stage selection, the odor stimulus switch and starts the peripheral devices required by the experiment. The programming of olfactometer function makes it an extremely flexible system for various experimental projects in olfaction.