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.

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.

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.

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.

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.

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.

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.

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.

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.

The Memphis and Atlanta continuing care programs for diabetes. II. Comparative analyses of demographic characteristics, treatment methods, and outcomes over a 9-10-year follow-up period.

A total of 1467 black patients (911 in Atlanta, 556 in Memphis) were selected (1969-70) and followed longitudinally and prospectively until death (404 patients) or through 31 December 1979, when 676 were alive and active and 387 were lost to follow-up. The women/men ratio in each cohort was 4.7/1. Women had more excess body wt than men at maximum weight and at time of diagnosis. At selection, the Atlanta cohort was older (60.2 vs 56.8 yr), had diabetes longer (7.5 vs 5.2 yr), and had a higher initial mean random plasma glucose (MRPG) level (217 vs 195 mg/dl) than the Memphis cohort. The Atlanta cohort was on sulfonylurea/phenformin therapy, which was discontinued at entry. After 9-10 yr follow-up, the MRPG level was not significantly different from the initial level in either cohort, and the Atlanta cohort level was still significantly higher (221 vs 185 mg/dl). Mean weight loss after 9-10 yr follow-up was significantly greater in Atlanta (17.7 vs 6.8 lb). Those under good control in 1979, as indicated by random plasma glucose (RPG) of less than 150 mg/dl, lost more weight (means: Atlanta, 23 lb; Memphis, 8.7 lb) than those under poor control in 1979 (RPG greater than 300 mg/dl; means: Atlanta, 14.7 lb; Memphis, 1.3 lb). In the pooled alive and active cohorts (1979), 29.1% were under good control (RPG less than 150 mg/dl); 52.9%, fair control (RPG = 150-300 mg/dl); and 18.0%, poor control (RPG greater than 300 mg/dl). Of the 639 alive and active patients, paired plasma glucose levels were less than 200 mg/dl in 207 patients in 1969-70 and less than 200 mg/dl in 322 in 1979.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneous axonal arborizations of rat thalamic reticular neurons in the ventrobasal nucleus.

The gamma-aminobutyric acid (GABA)-containing neurons of the thalamic reticular nucleus (nRt) are a major source of inhibitory innervation in dorsal thalamic nuclei. Individual nRt neurons were intracellularly recorded and labelled in an in vitro rat thalamic slice preparation to investigate their projection into ventrobasal thalamic nuclei (VB). Camera lucida reconstructions of 37 neurons indicated that nRt innervation ranges from a compact, focal projection to a widespread, diffuse projection encompassing large areas of VB. The main axons of 65% of the cells gave rise to intra-nRt collaterals prior to leaving the nucleus and, once within VB, ramified into one of three branching patterns: cluster, intermediate, and diffuse. The cluster arborization encompassed a focal region averaging approximately 25,000 mu m2 and contained a high density of axonal swellings, indicative of a topographic projection. The intermediate structure extended across an area approximately fourfold greater and also contained numerous axonal swellings. The diffuse arborization of nRt neurons covered a large region of VB and contained a relatively low density of axonal swellings. Analysis of somatic size and shape revealed that diffuse arborizations arose from significantly smaller, fusiform-shaped somata. Cytochrome oxidase reactivity or parvalbumin immunoreactivity was used to delineate a discontinuous staining pattern representing thalamic barreloids. The size of a cluster arborization closely approximated that of an individual barreloid. The heterogeneous arborizations from nRt neurons may reflect a dynamic range of inhibitory influences of nRt on dorsal thalamic activity.

Argiotoxin-636 blocks excitatory synaptic transmission in rat hippocampal CA1 pyramidal neurons.

Argiotoxin 636, (AR636), a synaptic antagonist from orb weaver spider venom, is shown to produce reversible blockade of excitatory transmission in CA1 pyramidal neurons of the in vitro rat hippocampus. Microtopical application of AR636 (5-50 nM) resulted in a concentration-dependent suppression of the amplitude of the dendritic field EPSP recorded from stratum radiatum, and the amplitude of the population spike recorded from stratum pyramidale in response to stimulation of the Schaffer collaterals. The maximum effect of AR636 occurred at about 15-25 min. These effects were reversible after washing with toxin-free physiological solution with the rate of recovery having an inverse relationship to the concentration of AR636. In contrast to the effects observed with orthodromic stimulation, the amplitude of the antidromic spike was not affected by exposure to AR636. The temporal pattern of GABAergic paired-pulse inhibition was unaffected by exposure to AR636. Neuronal discharge elicited by pressure ejection of L-glutamate was abolished by AR636, whereas, responses to L-aspartate were not significantly affected. These data suggest that AR636 functions as a selective antagonist of glutamate-mediated synaptic transmission in rat hippocampus.

Synaptic potentials and effects of amino acid antagonists in the auditory cortex.

Neurons of in vitro guinea pig and rat auditory cortex receive a complex synaptic pattern of afferent information. As many as four synaptic responses to a single-stimulus pulse to the gray or white matter can occur; an early-EPSP followed, sequentially, by an early-IPSP, late-EPSP, and late-IPSP. Paired pulse stimulation and pharmacological studies show that the early-IPSP can modify information transmission that occurs by way of the early-EPSP. Each of these four synaptic responses differed in estimated reversal potential, and each was differentially sensitive to antagonism by pharmacological agents. DNQX (6,7-dinitroquinoxaline-2,3-dione), a quisqualate/kainate receptor antagonist, blocked the early-EPSP, and the late-EPSP was blocked by the NMDA receptor antagonist APV (D-2-amino-5-phosphonovalerate). The early-IPSP was blocked by the GABA-a receptor antagonist bicuculline, and the late-IPSP by the GABA-b receptor antagonists 2-OH saclofen or phaclofen. Presentation of stimulus trains, even at relatively low intensities, could produce a long-lasting APV-sensitive membrane depolarization. Also discussed is the possible role of these synaptic potentials in auditory cortical function and plasticity.

Willingness to sacrifice in close relationships.

The authors advance an interdependence analysis of willingness to sacrifice. Support for model predictions was revealed in 6 studies (3 cross-sectional survey studies, 1 simulation experiment, 2 longitudinal studies) that used a novel self-report measure and a behavioral measure of willingness to sacrifice. Willingness to sacrifice was associated with strong commitment, high satisfaction, poor alternatives, and high investments; feelings of commitment largely mediated the associations of these variables with willingness to sacrifice. Moreover, willingness to sacrifice was associated with superior couple functioning, operationalized in terms of level of dyadic adjustment and probability of couple persistence. In predicting adjustment, willingness to sacrifice accounted for significant variance beyond commitment, partially mediating the link between commitment and adjustment; such mediation was not significant for persistence.

Management of the difficult duodenal stump.

Leakage from the duodenal stump has been the most feared complication of the Billroth II reconstruction following gastric resection. The purpose of our study was to evaluate four methods of duodenal stump closure in 200 patients. One hundred and forty-seven (74%) patients had duodenal ulcers; 28 (14%) had gastric ulcers; and 25 (13%) had a variety of other inflammatory conditions. The most common indication for operation was acute hemorrhage (51%), followed by perforation (24%), intractability (15%), and obstruction (10%). Conventional duodenal closures were performed in 160 (80%) patients, Nissen's closure in 25 (13%), Bancroft's closure in 6 (3%), and tube duodenostomy in 9 (5%). Duodenal leaks occurred in four (2.5%) patients with conventional closures and in three (33%) patients with tube duodenostomies. No leaks occurred in patients with Nissen's or Bancroft's closures. The hospital mortality rate for the series was 9.5%; however, no patient who developed a duodenal leak died. We conclude that Nissen's and Bancroft's closures were safe and effective, but that tube duodenostomy did not reliably prevent uncontrolled leakage.

A new method for predicting crashworthiness.

Consumer information concerning the predicted 'safeness' of a new car model is based on the results of crash tests. Unfortunately, because it allows comparisons only within size/weight groups, the information is somewhat incompatible with the normal car-purchase decision process since consumers often consider cars within different groups. In addition, based on past research, the association of the crash-test information with real-world crash outcomes is, at best, somewhat limited. The goal of this study was to explore a methodology for improving this information, a methodology which incorporates not only the crash-test information, but also information concerning real-world occupant injury experience in prior crashes involving similar vehicles ('clones'). The clone information included both driver injury severity in past clone crashes from the North Carolina accident file and various indicators of relative driver injury in clones extracted from published insurance-related data from the Highway Loss Data Institute (HLDI). Final models developed included both measures of the Head Index Criteria (HIC) from the crash test and some measure of clone performances as significant predictors. While the North Carolina clone data is intuitively 'cleaner' in that it describes injury level per crash rather than per insured year, the medical claims indices from the HLDI data consistently were shown to be the stronger predictors. Future research will need to look at ways of better combining the crash-test variables and of possible modifications to the HLDI indices. In general, the analyses generated encouraging results that appear to point to possible improvements in the crashworthiness information.

Capillary gas chromatographic analysis of trichlorfon in dosed feed formulations.

A method was developed for the analysis of trichlorfon as the intact molecule from feed formulations of the chemical. The method involved isolation of trichlorfon by a simple extraction procedure. Subsequent detection and quantitation of the trichlorfon was by gas chromatography with a DB-1 fused-silica wide-bore capillary column and flame photometric detection. Automated on-column injections were performed. The method was linear in the range 5-75 ng injected on-column and had an average recovery of 86%. The limit of detection for trichlorfon in feed was 1 ppm. The applicability of the method was tested by determining the stability of trichlorfon over a 21-day period in a feed blend of trichlorfon at the 50-ppm concentration level. Mass spectrometric analyses were performed to confirm that trichlorfon could be quantitated as the intact molecule.

Heterotopic neural tissue in the pharynx of a 7-week-old kitten.

A 7-week-old male kitten had a pharyngeal mass (1 x 2 cm) causing displacement of the tongue. The surgically resected tissue was seen to be a moderately discrete subepithelial mass comprising islands of neuroglia and neurons separated by dense collagenous connective tissue. It is not known whether this mass retained any connection with the brain. Histochemical and immunohistochemical examination confirmed the presence of neurons and a pleocellular glial population, supporting a diagnosis of heterotopic neural tissue. The cat remained well 20 months after surgical treatment. Heterotopic neural tissue is well-recognized in man but has not been described in animals.

The interaction model of client health behavior: application to the study of community-based elders.

The Interaction Model of Client Health Behavior (IMCHB) was used to direct a systematic and comprehensive description of community-based elders. The abstract concepts, constructs, factors, and variables described by one element of the model were able to account for 54% of the variance in elders' health status and 47% of the variance in their well-being. The model, as operationalized in this study, pointed to clear demographic, social, and health profiles that identified the elder at risk for decreased health, well-being, and self-care potential. The IMCHB would appear to be a useful framework with which to establish an empirical base on which nursing interventions could be developed.

Motivation in health behavior: measurement, antecedents, and correlates.

Additional reliability, validity, and information on health behavior correlates for a recently developed measure of intrinsic motivation in health behavior are reported. A randomly selected sample of 379 elders responded to a structured interview containing the Health Self-determinism Index (HSDI) and other relevant variables. The overall reliability of the HSDI was supported with an alpha coefficient of 0.78. The multidimensionality of the instrument was reconfirmed through principal components analysis, and factor invariance across study samples was established. The total HSDI and subscale scores were associated with the practice of selected life-style behaviors. The homogeneity of the sample raises significant considerations relative to contextual item sensitivity and sample-induced response tendencies.