Communicating diagnostic uncertainty in the acute and emergency medical setting: A systematic review and ethical analysis of the empirical literature.

BACKGROUND: diagnostic uncertainty is ubiquitous. Its communication to patients requires further investigation. AIMS: To determine: 1) What is known about how and why diagnostic uncertainty is communicated in acute care; 2) evidence of the effects of (not) communicating diagnostic uncertainty in the acute setting; 3) associated ethical issues. METHODS: systematic review of Medline, Web of Science and SCOPUS for (acute or emergency care) AND (diagnostic uncertainty) AND (ethics OR behaviours). Critical interpretive synthesis and ethical analysis were conducted. RESULTS AND CONCLUSION: Nine studies (primarily surveys and interviews) were identified. Doctors are not trained in communicating diagnostic uncertainty and perceive it to have negative effects on patients; however not communicating diagnostic uncertainty can disempower patients, resulting in delayed/missed diagnoses or inappropriate use of resource.

D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence.

Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine's ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague-Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH-treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent-exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse.

Cryptic genetic diversity and complex phylogeography of the boreal North American scorpion, Paruroctonus boreus (Vaejovidae).

Diverse studies in western North America have revealed the role of topography for dynamically shaping genetic diversity within species though vicariance, dispersal and range expansion. We examined patterns of phylogeographical diversity in the widespread but poorly studied North American vaejovid scorpion, Paruroctonus boreus Girard 1854. We used mitochondrial sequence data and parsimony, likelihood, and Bayesian inference to reconstruct phylogenetic relationships across the distributional range of P. boreus, focusing on intermontane western North America. Additionally, we developed a species distribution model to predict its present and historical distributions during the Last Glacial Maximum and the Last Interglacial Maximum. Our results documented complex phylogeographic relationships within P. boreus, with multiple, well-supported crown clades that are either geographically-circumscribed or widespread and separated by short, poorly supported internodes. We also observed subtle variation in predicted habitat suitability, especially at the northern, eastern and southern edges of the predicted distributional range under past climatic conditions. The complex phylogenetic relationships of P. boreus suggests that historical isolation and expansion of populations may have occurred. Variation in the predicted distributional range over time may implicate past climatic fluctuations in generating the patterns of genetic diversity observed in P. boreus. These findings highlight both the potential for cryptic biodiversity in widespread North American scorpion species and the importance of phylogeographical studies for understanding the factors responsible for generating the biodiversity of western North America.

Cell's intrinsic biophysical properties play a role in the systematic decrease in time-locking ability of central auditory neurons.

Studies in the vertebrates have shown that the time-locking ability of central auditory neurons decreases progressively along the ascending auditory pathway. This decrease is presumably attributed to a progressive reduction in the fidelity of synaptic transmission and an increase in the influence of synaptic inhibition along the cascade. The extent to which neurons' intrinsic biophysical properties contribute to the change in time-locking ability is unclear. We carried out whole-cell patch clamp recordings from the auditory thalamus of leopard frogs and compared their biophysical properties and time-locking abilities (determined by cell's responses to depolarizing pulse trains applied intracellularly) with those of lower auditory brainstem neurons. We found that frog thalamic neurons were homogeneous, exhibiting uniformly sustained, regular firing patterns, but not having low-threshold transient Ca2+ current which mammal thalamic neurons generally possess. Furthermore, intrinsic biophysical properties of the thalamic neurons are such that the time-locking ability of these neurons was very poor. The homogeneity of thalamic auditory neurons is in contrast to the heterogeneity of lower auditory brainstem neurons, with different phenotypes exhibiting different time-locking abilities and with sustained-regular phenotype consistently showing the worst time-locking ability among all biophysical phenotypes. Auditory nuclei along the ascending auditory pathway showed a progressive increase in the population of sustained-regular phenotype-this corresponded to a systematic decrease in the overall time-locking ability, with neurons in the dorsal medullary nucleus showing the best, and thalamic neurons exhibiting the poorest time-locking ability, whereas neurons in the torus semicircularis displayed intermediate time-locking ability. These results suggest that the biophysical characteristics of single neurons also likely play a role in the change in temporal coding ability along the ascending auditory pathway.

Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women.

BACKGROUND/OBJECTIVES: The results of short-term studies in humans suggest that, compared with glucose, acute consumption of fructose leads to increased postprandial energy expenditure and carbohydrate oxidation and decreased postprandial fat oxidation. The objective of this study was to determine the potential effects of increased fructose consumption compared with isocaloric glucose consumption on substrate utilization and energy expenditure following sustained consumption and under energy-balanced conditions. SUBJECTS/METHODS: As part of a parallel arm study, overweight/obese male and female subjects, 40-72 years, consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at baseline and during the 10th week of intervention. RESULTS: Consumption of fructose, but not glucose, led to significant decreases of net postprandial fat oxidation and significant increases of net postprandial carbohydrate oxidation (P<0.0001 for both). Resting energy expenditure (REE) decreased significantly from baseline values in subjects consuming fructose (P=0.031) but not in those consuming glucose. CONCLUSIONS: Increased consumption of fructose for 10 weeks leads to marked changes of postprandial substrate utilization including a significant reduction of net fat oxidation. In addition, we report that REE is reduced compared with baseline values in subjects consuming fructose-sweetened beverages for 10 weeks.

Dopamine enhances the excitability of somatosensory thalamocortical neurons.

The thalamus conveys sensory information from peripheral and subcortical regions to the neocortex in a dynamic manner that can be influenced by several neuromodulators. Alterations in dopamine (DA) receptor function in thalami of Schizophrenic patients have recently been reported. In addition, schizophrenia is associated with sensory gating abnormalities and sleep-wake disturbances, thus we examined the role of DA on neuronal excitability in somatosensory thalamus. The ventrobasal (VB) thalamus receives dopaminergic innervation and expresses DA receptors; however, the action of DA on VB neurons is unknown. In the present study, we performed whole cell current- and voltage-clamp recordings in rat brain slices to investigate the role of DA on excitability of VB neurons. We found that DA increased action potential discharge and elicited membrane depolarization via activation of different receptor subtypes. Activation of D2-like receptors (D(2R)) leads to enhanced action potential discharge, whereas the membrane depolarization was mediated by D1-like receptors (D(1R)). The D(2R-mediated) increase in spike discharge was mimicked and occluded by α-dendrotoxin (α-DTX), indicating the involvement of a slowly inactivating K(+) channels. The D1R-mediated membrane depolarization was occluded by barium, suggesting the involvement of a G protein-coupled K(+) channel or an inwardly rectifying K(+) channel. Our results indicate that DA produces dual modulatory effects acting on subtypes of DA receptors in thalamocortical relay neurons, and likely plays a significant role in the modulation of sensory information.

Predicting radial nerve location using palpable landmarks.

The purpose of this study is to predict the location of radial nerve (RN) utilizing palpable anatomic landmarks. Thirty-four paired upper limbs were dissected. The RN was localized: (1) at the humeral spiral groove (SG), (2) lateral intermuscular septum (LIS), and (3) at its' division into the posterior interosseous nerve (PIN) and radial sensory nerve (RSN). The PIN was located at the anterior aspect of the radial neck (AN). Humeral and radial lengths were measured. The RN traversed the SG, on average, 48% (36%-63%) of humeral length, distal to the greater tuberosity. The RN pierced the LIS, on average, 38% (29%-56%) of humeral length, proximal to the lateral epicondyle (LE). The PIN/RSN division occurred on average 1.0 cm (-11.4 to 3.5) distal to the LE. The PIN crossed the AN, on average, 10% (5%-14%) of radial length, distal to the radial head articular surface.

Two distinct populations of projection neurons in the rat lateral parafascicular thalamic nucleus and their cholinergic responsiveness.

The lateral parafascicular nucleus (lPf) is a member of the intralaminar thalamic nuclei, a collection of nuclei that characteristically provides widespread projections to the neocortex and basal ganglia and is associated with arousal, sensory, and motor functions. Recently, lPf neurons have been shown to possess different characteristics than other cortical-projecting thalamic relay neurons. We performed whole cell recordings from lPf neurons using an in vitro rat slice preparation and found two distinct neuronal subtypes that were differentiated by distinct morphological and physiological characteristics: diffuse and bushy. Diffuse neurons, which had been previously described, were the predominant neuronal subtype (66%). These neurons had few, poorly-branching, extended dendrites, and rarely displayed burst-like action potential discharge, a ubiquitous feature of thalamocortical relay neurons. Interestingly, we discovered a smaller population of bushy neurons (34%) that shared similar morphological and physiological characteristics with thalamocortical relay neurons of primary sensory thalamic nuclei. In contrast to other thalamocortical relay neurons, activation of muscarinic cholinergic receptors produced a membrane hyperpolarization via activation of M(2) receptors in most lPf neurons (60%). In a minority of lPf neurons (33%), muscarinic agonists produced a membrane depolarization via activation of predominantly M(3) receptors. The muscarinic receptor-mediated actions were independent of lPf neuronal subtype (i.e. diffuse or bushy neurons); however the cholinergic actions were correlated with lPf neurons with different efferent targets. Retrogradely-labeled lPf neurons from frontal cortical fluorescent bead injections primarily consisted of bushy type lPf neurons (78%), but more importantly, all of these neurons were depolarized by muscarinic agonists. On the other hand, lPf neurons labeled by striatal injections were predominantly hyperpolarized by muscarinic agonists (63%). Our results indicate two distinct subpopulations of lPf projection neurons, and interestingly lPf neurons respond differentially to muscarinic receptor activation based on their axonal target.

Cancer information and support needs of statutory and voluntary sector staff working with people from ethnically diverse communities.

Cancer is difficult for people from ethnically diverse communities to cope with, because there is inequality in getting information and services to meet their needs for prevention, prompt diagnosis, treatment, care and support. Research with black minority ethnic (BME) communities indicates a lack of knowledge about cancer, and a desire for more information, yet research is highly equivocal with regard to health and social care workers' ability to provide this. The study described in this article aimed to identify the educational and support needs of health and social care workers from statutory and voluntary sectors, working with people affected by cancer in one London borough. Qualitative research methods of one-to-one interview and focus group discussion were used among 33 staff working in various community, organizational and professional settings. Two focus groups were held with cancer patients and carers to gain complementary understanding of their needs for support and information. Health and social care workers are challenged when providing cancer information and support to people from BME communities, even when the worker is of the same cultural background as the person affected by cancer. Interviewees considered that in most respects, the challenges for improving cancer care for people from BME communities are those common for all, and that the difficulty in providing and sustaining improved cancer information and support services to BME communities in their borough lies in poverty, low literacy and social exclusion as much as cultural difference.

Re-engineering the target specificity of Clostridial neurotoxins - a route to novel therapeutics.

The ability to chemically couple proteins to LH(N)-fragments of clostridial neurotoxins and create novel molecules with selectivity for cells other than the natural target cell of the native neurotoxin is well established. Such molecules are able to inhibit exocytosis in the target cell and have the potential to be therapeutically beneficial where secretion from a particular cell plays a causative role in a disease or medical condition. To date, these molecules have been produced by chemical coupling of the LH(N)-fragment and the targeting ligand. This is, however, not a suitable basis for producing pharmaceutical agents as the products are ill defined, difficult to control and heterogeneous. Also, the molecules described to date have targeted neuroendocrine cells that are susceptible to native neurotoxins, and therefore the benefit of creating a molecule with a novel targeting domain has been limited. In this paper, the production of a fully recombinant fusion protein from a recombinant gene encoding both the LH(N)-domain of a clostridial neurotoxin and a specific targeting domain is described, together with the ability of such recombinant fusion proteins to inhibit secretion from non-neuronal target cells. Specifically, a novel protein consisting of the LH(N)-domains of botulinum neurotoxin type C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

Excitatory actions of synaptically released catecholamines in the rat lateral geniculate nucleus.

The gating properties of thalamic relay neurons are influenced by the actions of a variety of neuromodulators in concert with the intrinsic properties of these relay neurons. In this study, we have investigated the consequences of synaptically released catecholamines on the excitability of neurons in the rat dorsal lateral geniculate nucleus. Tetanic stimulation of the optic tract, in which catecholamine fibers also course near or through, produced a strong depolarization that consisted of a fast and slow component. The fast excitatory postsynaptic potential was attenuated by ionotropic glutamate receptor antagonists and further unmasked the slow excitatory postsynaptic potential. The amplitude of the slow excitatory postsynaptic potential was dependent on the frequency and intensity of the tetanic stimulation. The alpha1-adrenergic receptor antagonist, prazosin, and the D1-like dopamine receptor antagonist, SCH23390, attenuated the slow excitatory postsynaptic potential; however, the slow excitatory postsynaptic potential was unaltered by metabotropic glutamate, cholinergic, alpha2-adrenergic, and beta-adrenergic receptor antagonists. On the other hand, tetanic stimulation of the optic radiations (corticothalamic axons) evoked a slow excitatory postsynaptic potential that was completely attenuated by metabotropic glutamate receptor antagonists. Our results suggest that tetanic stimulation of catecholamine fibers within the optic tract produces synaptic release of norepinephrine and dopamine that in turn activates both alpha(1)-adrenergic and D1-like dopamine receptors leading to a robust membrane depolarization. By altering the excitability of relay neurons, ascending activating systems may modulate the efficacy of information transfer through the thalamus.

Morphological correlates of triadic circuitry in the lateral geniculate nucleus of cats and rats.

We used an in vitro slice preparation of the lateral geniculate nucleus in cats and rats to study morphological correlates of triadic circuitry in relay cells. The three triadic elements involve a retinal synapse onto a GABAergic dendritic terminal of an interneuron, a synapse from the same retinal terminal onto a relay cell dendrite, and a synapse from the same interneuron terminal onto the same relay cell dendrite. We made whole cell recordings and labeled cells with biocytin. Previous methods were used to identify triadic circuitry based on evidence that the retinal terminal activates a metabotropic glutamate receptor on the interneuronal terminal. Thus application of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (an agonist to that receptor) increases the rate of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in the relay cell, and if some of this increase remains with further addition of TTX (a TTX-insensitive response), a triad is indicated. We quantified the extent of the TTX-insensitive response and sought morphological correlates. In both rats and cats, this response correlated (negatively) with the number of primary dendrites and (positively) with polarity of the dendritic arbor. There was no correlation with cell size. Curiously, in cats, this response correlated with the presence of appendages at primary dendritic branches, but there was no such correlation in rats. These observations in cats map onto the X/Y classification, with X cells having triads, but it is not clear from our results if a comparable classification exists for rats.

The relationship between maternal needs and priorities in a neonatal intensive care environment.

AIM: The aim of this study was to investigate the nature and organization of maternal needs and priorities in a neonatal unit. BACKGROUND: The relationship between maternal needs and priorities appears to be an under studied area in neonatal nursing. METHODS: A quantitative survey was carried out based on 209 mothers with premature infants. Two self-assessment schedules were used: critical care maternal needs inventory (J. Leske, Heart and Lung 15, 27-42) and a ranking scale. The data were analysed with multivariate analysis. FINDINGS: Data analysis revealed clear priorities in maternal needs. In particular the need for accurate infant related information was a priority for 93% of the mothers. Good communication practices with professionals were also valued. The mothers displayed altruistic behaviour, and self-related needs took second place. It is proposed that maternal needs demonstrate a hierarchical organization. CONCLUSION: It is important for nurses to consider the individual needs of the mothers, simply because the satisfaction of these needs is essential for maternal well-being.

Advanced nurse practitioners and physician assistants: what is the difference? Comparing the USA and UK.

With the reduction in junior doctors' hours and fewer doctors being trained in the UK, there is a need for other types of health-care practitioners to fill the gap. This article describes some of the background to the present situation and delineates two types of roles, the advanced nurse practitioner and the physician assistant, for consideration as alternatives to address the present and growing shortage of doctors.

Cutaneous alternariosis in a cat.

A 10-year-old male domestic shorthaired cat had a chronic, slowly enlarging subcutaneous mass on the right side of its nose. At the time of presentation, the nasal airflow was severely impeded on the affected side. The cat had been treated medically with various drugs. Oral itraconazole had been the most effective in reducing the size of the mass, but had caused hepatotoxicity and had to be withdrawn. The mass was finally removed surgically, and a diagnosis of granulomatous cellulitis caused by Alternaria alternata (phaeohyphomycosis) was established, based on histopathology and fungal isolation. There has been no recurrence of the lesion after 21 months and the cat remains clinically well at the time of writing. Subcutaneous phaeohyphomycosis caused by A alternata has not, to the authors' knowledge, been previously described in small domestic animals in the UK.

Dynamics of low-threshold spike activation in relay neurons of the cat lateral geniculate nucleus.

The low-threshold spike (LTS), generated by the transient Ca(2+) current I(T), plays a pivotal role in thalamic relay cell responsiveness and thus in the nature of the thalamic relay. By injecting depolarizing current ramps at various rates to manipulate the slope of membrane depolarization (dV/dt), we found that an LTS occurred only if dV/dt exceeded a minimum value of approximately 5-12 mV/sec. We injected current ramps of variable dV/dt into relay cells that were sufficiently hyperpolarized to de-inactivate I(T) completely. Higher values of dV/dt activated an LTS. However, lower values of dV/dt eventually led to tonic firing without ever activating an LTS; apparently, the inactivation of I(T) proceeded before I(T) could be recruited. Because the maximum rate of rise of the LTS decreased with slower activating ramps of injected current, we conclude that slower ramps allow increasing inactivation of I(T) before the threshold for its activation gating is reached, and when the injected ramps have a sufficiently low dV/dt, the inactivation is severe enough to prevent activation of an LTS. In the presence of Cs(+), we found that even the lowest dV/dt that we applied led to LTS activation, apparently because Cs(+) reduced the K(+) "leak" conductance and increased neuronal input resistance. Nonetheless, under normal conditions, our data suggest that there is neither significant window current (related to the overlap of the inactivation and activation curves for I(T)), rhythmogenic properties, nor bistability properties for these neurons. Our theoretical results using a minimal model of LTS excitability in these neurons are consistent with the experimental observations and support our conclusions. We suggest that inputs activating very slow EPSPs (i.e., via metabotropic receptors) may be able to inactivate I(T) without generating sizable I(T) and a spurious burst of action potentials to cortex.

Cellular mechanisms underlying activity patterns in the monkey thalamus during visual behavior.

We show for the first time with in vitro recording that burst firing in thalamic relay cells of the monkey is evoked by activation of voltage-dependent, low threshold Ca(2+) spikes (LTSs), as has been described in other mammals. Due to variations in LTS amplitude, the number of action potentials evoked by an LTS could vary between 1 and 8. These data confirm the presence of two modes of firing in the monkey for thalamic relay cells, tonic and burst, the latter related to the activation of LTSs. With these details of the cellular processes underlying burst firing, we could account for many of the firing patterns we recorded from the lateral geniculate nucleus of the thalamus in behaving monkeys. In particular, we found clear evidence of burst firing during alert wakefulness, which had been thought to occur only during sleep or certain pathological states. This makes it likely that the burst firing seen in awake humans has the same cellular basis of LTSs, and this supports previous suggestions that burst firing represents an important relay mode for visual processing.

Control of dendritic outputs of inhibitory interneurons in the lateral geniculate nucleus.

The thalamic relay to neocortex is dynamically gated. The inhibitory interneuron, which we have studied in the lateral geniculate nucleus, is important to this process. In addition to axonal outputs, these cells have dendritic terminals that are both presynaptic and postsynaptic. Even with action potentials blocked, activation of ionotropic and metabotropic glutamate receptors on these terminals increases their output, whereas activation of metabotropic (M2 muscarinic) but not nicotinic cholinergic receptors decreases their output. These actions can strongly affect retinogeniculate transmission.

Action potentials reliably invade axonal arbors of rat neocortical neurons.

Neocortical pyramidal neurons have extensive axonal arborizations that make thousands of synapses. Action potentials can invade these arbors and cause calcium influx that is required for neurotransmitter release and excitation of postsynaptic targets. Thus, the regulation of action potential invasion in axonal branches might shape the spread of excitation in cortical neural networks. To measure the reliability and extent of action potential invasion into axonal arbors, we have used two-photon excitation laser scanning microscopy to directly image action-potential-mediated calcium influx in single varicosities of layer 2/3 pyramidal neurons in acute brain slices. Our data show that single action potentials or bursts of action potentials reliably invade axonal arbors over a range of developmental ages (postnatal 10-24 days) and temperatures (24 degrees C-30 degrees C). Hyperpolarizing current steps preceding action potential initiation, protocols that had previously been observed to produce failures of action potential propagation in cultured preparations, were ineffective in modulating the spread of action potentials in acute slices. Our data show that action potentials reliably invade the axonal arbors of neocortical pyramidal neurons. Failures in synaptic transmission must therefore originate downstream of action potential invasion. We also explored the function of modulators that inhibit presynaptic calcium influx. Consistent with previous studies, we find that adenosine reduces action-potential-mediated calcium influx in presynaptic terminals. This reduction was observed in all terminals tested, suggesting that some modulatory systems are expressed homogeneously in most terminals of the same neuron.

Dendritic depolarization efficiently attenuates low-threshold calcium spikes in thalamic relay cells.

Thalamic relay cells respond in two distinct modes, burst and tonic, that depend on a voltage-dependent, low-threshold, transient Ca(2+) current (I(T)), and these modes relay different forms of information to cortex. I(T) activation evokes a low-threshold spike (LTS), producing a burst of action potentials. Modulatory inputs from cortex and brainstem are known to activate metabotropic receptors on relay cell dendrites at which the T channels underlying I(T) may be concentrated. We thus investigated the influence of activating these receptors on the LTS, using current-clamp intracellular recording in an in vitro slice preparation of the cat's lateral geniculate nucleus. We found a strong correlation between LTS amplitude and the number of action potentials evoked in the burst. We then found that activation of either metabotropic glutamate or muscarinic receptors produced a hyperpolarizing shift in the sigmoid relationship between LTS amplitude and the initial holding potential without affecting the maximum LTS amplitude or slope of the relationship. This hyperpolarizing shift in the voltage dependency of LTS amplitude is best explained by space-clamp limitations and significantly more depolarization of T channels near the dendritic location of activated receptors than at the soma. Thus, nonretinal modulatory inputs may have a stronger influence on I(T) and number of action potentials generated in a burst than previously imagined from somatic recording, because the EPSP amplitudes generated by these inputs at the dendritic location of most T channels are greater than after their electrotonic decay recorded at the soma.