Safety of nurse-directed triage intranasal fentanyl protocol for acute pain management in a European pediatric emergency department: A retrospective observational analysis.

Background: Nurse-directed pain protocols for intranasal fentanyl administration are not widely implemented in European (EU) pediatric emergency departments (PED). Barriers include perceived safety concerns for intranasal (IN) fentanyl. The aim of this study is to describe our experience with a nurse-directed triage IN fentanyl protocol with a focus on safety in a tertiary EU PED. Methods: We conducted a retrospective analysis of patient records of children aged 0-16 years who received nurse-directed IN fentanyl between January 2019 and December 2021 at the PED of the University Children's Hospital of Bern, Switzerland. Extracted data points included demographics, presenting complaint, pain score, IN fentanyl dosage, concomitant pain medication use, and adverse events. Results: A total of 314 patients were identified with ages ranging from 9 months to 15 years. The main indication for nurse-directed fentanyl administration was musculoskeletal pain due to trauma (n = 284, 90%). Mild adverse events (vertigo) were reported in two patients (0.6%), without a correlation to concomitant pain medication or protocol violation. The only reported severe adverse event of syncope and hypoxia in a 14-year-old adolescent occurred in a setting where the institutional nurse-directed protocol was violated. Conclusion: In accordance with previous studies outside of Europe, our data support the case that when appropriately used, nurse-directed IN fentanyl is a safe potent opioid analgesic for pediatric acute pain management. We strongly encourage the introduction of nurse-directed triage fentanyl protocols Europe-wide in order to provide effective and adequate acute pain management in children.

Both monovalent cations and plectin are potent modulators of mechanical properties of keratin K8/K18 networks.

Intermediate filament (IF) networks are a major contributor to cell rigidity and thus serve as vital elements to preserve the integrity of entire cell layers. Keratin K8 and K18 IFs are the basic constituents of the cytoskeleton of epithelial cells. The mechanical properties of K8/K18 networks depend on the structural arrangements of individual filaments within the network. This paper investigates the architecture of these networks in vitro under the influence of the monovalent cation potassium and that of the cytolinker protein plectin. Whereas increasing amounts of potassium ions lead to filament bundling, plectin interlinks filaments at filament intersection points but does not lead to bundle formation. The mechanics of the resulting networks are investigated by microrheology with assembled K8/K18 networks. It is shown that bundling induced by potassium ions significantly stiffens the network. Furthermore, our measurements reveal an increase in plectin-mediated keratin network rigidity as soon as an amount corresponding to more than 20% of the plectin present in cells is added to the keratin IF networks. In parallel, we investigated the influence of plectin on cell rigidity in detergent-extracted epithelial vulva carcinoma derived A431 cells in situ. These cytoskeletons, containing mostly IFs, actin filaments and associated proteins, exhibit a significantly decreased stiffness, when plectin is downregulated to ≈10% of the normal value. Therefore, we assume that plectin, via the formation of IF-IF connections and crosslinking of IFs to actin filaments, is an important contributor to cell stiffness.

Strong dipole-quadrupole coupling and Fano resonance in H-like metallic nanostructures.

Under certain conditions of the incident light polarization direction a Fano resonance arises in small gold nanorods arranged in a H-like configuration. This stems from the coupling between a bright dipole plasmon mode excited in the horizontal rod and dark quadrupole plasmon modes in both vertical rods. We investigate these surface plasmon modes, and analyze the dependence of the Fano resonance on the geometry parameters such as rod size and interparticle separation, and refractive index of embedding medium. To describe the degree of this energy transfer, we introduce a new parameter: the Fano resonance efficiency. We calculate absorption cross-sections for visible and NIR spectrum in each element of the structure, and near-field distributions at different wavelengths. We show that Fano resonance in small H-like structures exhibits high sensitivity with respect to the refractive index of the host medium, outperforming the values for larger plasmonic structures based on nanorods already investigated.

Genetic mapping, synteny, and physical location of two loci for Fusarium oxysporum f. sp. tracheiphilum race 4 resistance in cowpea [Vignaunguiculata (L.) Walp].

Fusarium wilt is a vascular disease caused by the fungus Fusariumoxysporum f.sp. tracheiphilum (Fot) in cowpea [Vignaunguiculata (L.) Walp]. In this study, we mapped loci conferring resistance to Fot race 4 in three cowpea RIL populations: IT93K-503-1 × CB46, CB27 × 24-125B-1, and CB27 × IT82E-18/Big Buff. Two independent loci which confer resistance to Fot race 4 were identified, Fot4-1 and Fot4-2. Fot4-1 was identified in the IT93K-503-1 (resistant) × CB46 (susceptible) population and was positioned on the cowpea consensus genetic map, spanning 21.57-29.40 cM on linkage group 5. The Fot4-2 locus was validated by identifying it in both the CB27 (resistant) × 24-125B-1 (susceptible) and CB27 (resistant) × IT82E-18/Big Buff (susceptible) populations. Fot4-2 was positioned on the cowpea consensus genetic map on linkage group 3; the minimum distance spanned 71.52-71.75 cM whereas the maximum distance spanned 64.44-80.23 cM. These genomic locations of Fot4-1 and Fot4-2 on the cowpea consensus genetic map, relative to Fot3-1 which was previously identified as the locus conferring resistance to Fot race 3, established that all three loci were independent. The Fot4-1 and Fot4-2 syntenic loci were examined in Glycine max, where several disease-resistance candidate genes were identified for both loci. In addition, Fot4-1 and Fot4-2 were coarsely positioned on the cowpea physical map. Fot4-1 and Fot4-2 will contribute to molecular marker development for future use in marker-assisted selection, thereby expediting introgression of Fot race 4 resistance into future cowpea cultivars.

Microrheology of keratin networks in cancer cells.

Microrheology is a valuable tool to determine viscoelastic properties of polymer networks. For this purpose measurements with embedded tracer beads inside the extracted network of pancreatic cancer cells were performed. Observing the beads motion with a CCD-high-speed-camera leads to the dynamic shear modulus. The complex shear modulus is divided into real and imaginary parts which give insight into the mechanical properties of the cell. The dependency on the distance of the embedded beads to the rim of the nucleus shows a tendency for a decreasing storage modulus. We draw conclusions on the network topology of the keratin network types based on the mechanical behavior.

New laser apparatus to measure oscillation amplitude down to picometer at megahertz frequencies.

A laser setup to study shear oscillations at small amplitudes with resonance frequencies up to 3 MHz is presented. The new approach combines gauging of the Gaussian laser beam and a lock-in amplifier. The device is tested with a 3 MHz AT-cut quartz crystal. The oscillation amplitude at the edge of the electrode on the quartz crystal is measured with a resolution of 2 pm.

Influence of the light-scattering form factor on the Bragg diffraction patterns of arrays of metallic nanoparticles.

Accurate models for the light-scattering form factors of nanoparticles are of crucial importance to characterize the optical properties of the particles and to develop new photonic devices. Analytical or semi-empirical models exist for particles of spherical and cylindrical shape. The angular spectrum of scattering for particles of more complex shape is very complex and can only be obtained by numerical simulations. Moreover, the light scattering of metallic particles depends on many parameters as size, shape, optical constants, substrate and polarization of light. Experimental verification of the differential scattering cross-sections obtained from different calculation methods is always necessary. Measurements done on single nanoparticles are very sensitive to their local properties and the signal-to-noise ratio may be very poor. Arrays of identical particles illuminated by a planes waves produce Bragg diffraction and the resultant patterns depend on the averaged values of the form factors of the particles. In order to test the validity of models for the scattering form factor, we present an experimental setup capable of measuring Bragg diffraction patterns of arrays of nanoparticles in the visible and near-infrared regions of the spectrum. The approach is similar to that of X-ray diffraction of crystals.

Análisis de resistencia insulínica, tolerancia a la glucosa y testosterona en mujeres con síndrome de ovario poliquístico agrupadas por índice de masa corporal / Insulin resistance, glucose and testosterone tolerance in women with polycystic ovary clustered by body mass index

Antecedentes: El síndrome de ovario poliquístico (SOP) es el desorden endocrino más común en las mujeres en edad reproductiva. Han sido asociadas al SOP resistencia a la insulina, obesidad y diabetes mellitus. Objetivo: Analizar en mujeres con SOP la relación entre testosterona, obesidad y problemas en el metabolismo de carbohidratos. Pacientes y Métodos: 60 pacientes, entre 14-32 años, fueron diagnosticadas según Consenso de Rotterdam. Se midió testosterona total (Ttotal), se realizó un test de tolerancia oral a glucosa e insulina (TTOG-I) y se calculó índice de masa corporal (IMC) en todas las pacientes. La distribución de cada variable y la relación entre testosterona y las otras variables fueron analizadas. Resultados: La media de Ttotal en todas las pacientes fue 2,2 nmol/L; 71,7 por ciento de los sujetos presentan IMC normal, 21,7 por ciento presentan IMC sobrepeso y 6,6 por ciento presenta IMC obeso. La media de Ttotal para cada grupo según IMC fue 2,2 nmol/L para normal y sobrepeso, y 2,75 nmol/L para obeso. Para TTOG-I, 43,3 por ciento tiene respuesta normal, con media de Ttotal = 2,2 nmol/L y media de IMC= 22,3 kg/m2, 56,7 por ciento tiene respuesta anormal, con media de Ttotal= 2,19 nmol/L e IMC= 23,1 kg/m2. Las pacientes normales y sobrepeso muestran respuesta similar al TTOG-I. Todas las pacientes obesas tienen TTOG-I alterado. Conclusiones: La alta prevalencia de desórdenes metabólicos apoya el hecho que éstos deben ser estudiados en estas pacientes. La ausencia de correlación significativa entre Ttotal y las otras variables sugiere que en el SOP múltiples factores están involucrados y que éste incluye diferentes subpoblaciones de pacientes, que requieren un diagnóstico adecuado. La clasificación de las pacientes con SOP en subgrupos podría ser útil antes del inicio del tratamiento.

Long-term effects of a single exposure to immobilization on the hypothalamic-pituitary-adrenal axis: neurobiologic mechanisms.

In apparent contrast to previous results from other labs, we have found that a single exposure to a severe stressor such as immobilization (IMO) caused a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the homotypic stressor. Because such HPA desensitization was not found in response to heterotypic stressors, it seemed at first that we were describing a habituation process already observed after a single experience with the stressor. However, a more detailed analysis revealed two main properties incompatible with the interpretation of the results in terms of habituation: (1) The intensity of desensitization increases over the course of days to weeks with no additional exposures to the stressor, and (2) the degree of desensitization was greater with more severe stressors. The long-term effects were also observed after a single exposure to a high dose of a systemic stressor such as endotoxin but not after insulin-induced hypoglycemia, suggesting that not all severe systemic stressors can induce such long-term desensitization. Because systemic stressors are known to be processed in specific brain areas and because we have found changes in c-fos mRNA response to the homotypic stressor in some brain areas as a consequence of previous experience with IMO, we hypothesize that some severe stressors do not induce long-term desensitization because they are not processed in brain areas sensitive to previous experience with the stressor. The neurochemical mechanisms involved in the induction of long-term effects on the HPA axis are in process, but our results suggest only a partial role of glucocorticoids and NMDA receptors.

Novel ligands for the investigation of imidazoline receptors and their binding proteins.

New ligands for imidazoline receptors are described so that these receptors can be more fully explored and understood. BU224, (2-(4,5-dihydroimidaz-2-yl)-quinoline, shows high affinity and is selective for the imidazoline-2 (I(2)) class of receptors. BU224 was tested in the rat Porsolt forced swim paradigm where it was found to decrease time spent immobile and increase the time spent swimming, consistent with an antidepressant profile. BU224 was tritiated and, in radioligand binding studies, was found to label a single population of saturable sites with high affinity. In vitro brain autoradiography with [(3)H]BU224 also showed a pattern of distribution similar to the known labeling of I(2) receptors. A new series of four 2BFI (2-(benzofuranyl)-2-imidazoline) derivatives were investigated as potential ligands for imaging brain I(2) receptors using positron emission tomography (PET). At least two, BU20012 and BU20013, retained high affinity and moderate selectivity and penetrated the brain when administered peripherally in the mouse. 2BFI has undergone the Mannich reaction to immobilized diaminodipropyl amine to fabricate an affinity column, which was used to isolate a protein from rabbit brain; this protein was sequenced and identified as the enzyme creatine kinase.

A single lipopolysaccharide administration is sufficient to induce a long-term desensitization of the hypothalamic-pituitary-adrenal axis.

We have previously shown that a single exposure of adult rats to a severe emotional stressor such as immobilization is able to exert a long-term desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the same stimulus when applied days to weeks later. Surprisingly, the intensity of the effect increased with time elapsed between the two exposures, suggesting that we are dealing with a new type of stress-associated phenomenon. Taking into account the clinical importance of tolerance to endotoxin, in the present study we assessed whether a single exposure to an immunological stressor such as lipopolysaccharide can induce effects similar to those of immobilization. Rats injected with lipopolysaccharide (1 mg/kg) showed a reduction of the response of the corticotropin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus after a new lipopolysaccharide injection 4, but not 2 weeks later. In an additional experiment using a different blood sampling procedure, adrenocorticotropin hormone, corticosterone and tumor necrosis factor-alpha responses were reduced approximately to the same extent by previous experience with lipopolysaccharide either 1 or 4 weeks before. Our data suggest that a previous single exposure to lipopolysaccharide induces a long-lasting tolerance of the HPA axis that likely involves some kind of learning-like brain plasticity.

Simulating the amplification of orbital forcing by ocean feedbacks in the last glaciation.

According to Milankovitch theory, the lower summer insolation at high latitudes about 115,000 years ago allowed winter snow to persist throughout summer, leading to ice-sheet build-up and glaciation. But attempts to simulate the last glaciation using global atmospheric models have failed to produce this outcome when forced by insolation changes only. These results point towards the importance of feedback effects-for example, through changes in vegetation or the ocean circulation-for the amplification of solar forcing. Here we present a fully coupled ocean-atmosphere model of the last glaciation that produces a build-up of perennial snow cover at known locations of ice sheets during this period. We show that ocean feedbacks lead to a cooling of the high northern latitudes, along with an increase in atmospheric moisture transport from the Equator to the poles. These changes agree with available geological data and, together, they lead to an increased delivery of snow to high northern latitudes. The mechanism we present explains the onset of glaciation-which would be amplified by changes in vegetation-in response to weak orbital forcing.

Evidence that a single exposure to aversive stimuli triggers long-lasting effects in the hypothalamus-pituitary-adrenal axis that consolidate with time.

Because of its use as a negative reinforcer in animal studies and its potential pathological impact (e.g. post-traumatic stress disorder and depression), exposure to aversive stimuli is a relevant model for studying CNS plasticity. We present evidence that a single exposure to two predominantly emotional stressors [restraint in tubes and immobilization on wooden boards (IMO)] can modify the response of the hypothalamo-pituitary-adrenal (HPA) axis to a subsequent exposure to the same stressor days later in that a more rapid return to the baseline was observed in the poststress period. In addition, the effect was greater with IMO, the more severe stressor. Using IMO, we have further demonstrated that the effect of a previous single exposure to the stressor (i) increased with days elapsed between the two exposures; (ii) was specific for the previously experienced stressor; and (iii) was mediated via central-mediated effects [corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus]. These data suggest that animals retain memory about a single experience with stressors, resulting in an acceleration of the poststress recovery of the HPA axis that enhances progressively over a period of weeks. The extent to which the present data are relevant regarding post-traumatic stress disorders is unclear, but the study of the HPA response to severe stressors may be suitable for the study of the neurobiological basis of the progressive consolidation of learning over a long period of time (days to weeks).

Influence of single or repeated experience of rats with forced swimming on behavioural and physiological responses to the stressor.

In the present work behavioural (struggling and immobility), physiological (hypothermia, glycaemia) and endocrine (hypothalamo-pituitary-adrenal (HPA) hormones) response to repeated forced swimming (FS) for 15 days was studied in adult male rats and compared with the response of rats having only one single experience with FS either 1 or 14 days before the last exposure to the stressor. Repeated experiences with FS reduced struggling and increased immobility as compared with stress-naïve rats, whereas a single previous exposure to FS, regardless of the time elapsed, had the same, but less marked, effect. Hypothermia followed the same trend. FS-induced hyperglycaemia was not sensitive to a previous single experience, but rather it was totally abolished in chronically stressed rats. Neither a single nor chronic exposure to FS modified the secretion of ACTH in response to the last FS session. However, repeated FS enhanced the speed of recovery of plasma corticosterone as compared to control rats, suggesting a dissociation between the two hormones. The present results revealed great differences in the sensitivity of various behavioural and physiological responses to repeated FS stress and suggest that reduced response to repeated FS, when found, is not a consequence of the time elapsed between exposures but to the repetition of the stressful situation.

Recovery of the hypothalamic-pituitary-adrenal response to stress. Effect of stress intensity, stress duration and previous stress exposure.

Pathological consequences of stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may be related to the duration rather than to the intensity of HPA axis activation after exposure to the stressor. Consequently a fine analysis of post-stress events is of importance. The present experiments were designed to study the importance of three key factors in HPA recovery: intensity of the stressor (experiment 1), duration of exposure to the stressor (experiment 2) and previous experience of the animals with the situation (experiments 3 and 4). In experiment 1, analysis of both the response to the stressor and the poststress period showed that the stronger the stressor, the greater the area under the curve of HPA activation. In experiment 2, different groups of rats were exposed to different periods of immobilization (IMO) (20 min, 1 h and 2 h) and sampled before, during and after exposure to IMO. The speed of recovery of plasma corticotropin (ACTH) levels was not related to the duration of exposure to the stressor. In experiments 3 and 4, the influence of previous experience with the stressor was studied in rats daily exposed to 20 min IMO or daily injected with hypertonic saline (HS) for 8 days and sampled on days 1, 2, 5 and 8. Whereas a significant decline in plasma ACTH levels was not observed immediately after IMO until day 8, a single previous exposure to IMO was enough to enhance recovery 90 min after the end of exposure to IMO. Corticosterone levels were related to the number of previous experiences with the stressor only in the post-IMO period. In response to a novel stressor (forced swimming), chronic IMO rats showed a slightly impaired recovery as compared to stress-naive rats, suggesting that enhanced recovery of the HPA axis was specific for the homotypic stressor. After daily HS injections, a pattern similar to that after IMO was observed, the delayed, but not the early response of the HPA axis being reduced as a function of the number of previous experiences with the situation. Taken together, the present results suggest that the speed of recovery of the HPA axis after its activation by stressors is sensitive to the intensity of the stressors but not to their duration, and that adaptation to a repeated stressor is more apparent during the delayed HPA response.

Near-field scanning optical microscopy of zinc-porphyrin crystals.

Using a near-field scanning optical microscope (NSOM), crystals of zinc-porphyrin network materials are characterized with respect to morphology and fluorescence. Needle-shaped crystals are observed. While the topography is flat, the fluorescence intensity profile in the width direction is approximately triangular. A numerical calculation shows that differences between the topographic and optical images cannot be due to an artifact. In some needle-shaped crystals, the fluorescence emission is strongly peaked at one or both ends, possibly indicating a polar crystal structure.

Single exposure to stressors causes long-lasting, stress-dependent reduction of food intake in rats.

A single exposure to severe stressors has been shown to cause anorexia in the next 24 h, but the duration of such alterations is not known. Male Sprague-Dawley rats were subjected to different stressors, and food intake was measured for several days after stress. In experiment 1, 2 h of immobilization (Imo) and lipopolysaccharide (LPS) administration (1,000 microgram/kg) caused a marked anorexia in the 24 h after stress, which persisted on poststress day 3. In experiment 2, changes in food intake after LPS and Imo were followed until total recovery. As in experiment 1, LPS caused initially a greater degree of anorexia than Imo, but normal food intake recovered much faster (poststress day 3 vs. poststress day 9). Changing the period of exposure to Imo between 20 min and 6 h (experiment 3) only slightly modified the pattern of response to the stressor. When different doses of LPS (50, 250, and 1,000 microgram/kg) were tested in experiment 4, a dose-dependent effect on food intake was observed, the greatest doses causing the most marked and lasting effect. The present results showed stressor-specific lasting changes in food intake caused by a single exposure to some stressors, the effect of a severe psychological stressor such as Imo being more lasting than that of LPS, despite a lower initial anorexia. A severe psychological stressor and a physical stressor such as LPS appear to change food intake in different ways.

Direct evidence of acute stress-induced facilitation of ACTH response to subsequent stress in rats.

To determine the role of glucocorticoids in the appearance of the facilitatory effect of stress on the ACTH response to a subsequent stress, sham-operated (Sham) rats and rats adrenalectomized (ADX) and supplemented with 50 mg/l corticosterone (B) in the drinking saline (ADX + B) were subjected to 1 min of immobilization stress (Imo) four consecutive times with an interstressor interval of 90 min. Sham rats showed a similar pattern of ACTH response to the first and fourth exposures to Imo. ADX + B rats showed an exacerbated ACTH response to the fourth Imo, despite higher prestress levels than those observed before the first Imo. In another experiment, no facilitatory effect of previous stress on ACTH response was found in ADX rats, but supplementation with B in the drinking saline for 1 wk resulted in facilitation of the ACTH response. We conclude that repeated exposure to a short-time stress induces a facilitatory effect on the ACTH response that is uncovered by eliminating stress-induced glucocorticoid release but needs B doses resulting in approximately basal circulating glucocorticoid levels to be induced or expressed.

Defective ACTH response to stress in previously stressed rats: dependence on glucocorticoid status.

The effect of previous exposure to stress on the pituitary-adrenal response to a further stress was characterized in rats with different glucocorticoid status: sham-operated rats (Sham), adrenalectomized (ADX) rats, and ADX rats supplemented with a low corticosterone (B) dose in the drinking saline (ADX + B). Previous exposure of Sham rats to 1 h of immobilization (Imo) reduced, 2 h later, the ACTH response to a second severe stressor (Imo) but not to a less severe stressor (tail shock). In ADX rats, previous Imo totally suppressed the ACTH response to Imo or to shock. In ADX + B rats the response to shock was blocked and that to Imo tended to be lower. These changes were not explained by depletion of adenohypophysial ACTH stores. After previous Imo, reduced response to corticotropin-releasing factor was observed in Sham and ADX + B, but not in ADX, rats. Taken together, the present results suggest that the reduced ACTH response of previously stressed rats to a second severe stress is observed in the presence and absence of glucocorticoids, but the main site at which such inhibition occurs might be critically dependent on the glucocorticoid status.

Activation of the hypothalamic-pituitary axis in adrenalectomised rats: potentiation by chronic stress.

The influence of chronic stress on the status of the hypothalamo-pituitary-adrenal (HPA) axis of sham-operated and adrenalectomised rats was assessed. Animals underwent bilateral adrenalectomy (ADX) and 3 days later they were either left undisturbed or subjected daily to immobilization for 2 h each morning for 14 days (chronic IMO). In situ hybridization histochemistry revealed that ADX increased corticotropin-releasing factor (CRF) mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) and proopiomelanocortin (POMC) mRNA levels in the anterior pituitary, in both control and chronically stressed rats as measured on the day following the last exposure to stress. Chronic IMO increased CRF mRNA levels in the PVN and POMC mRNA levels in the anterior pituitary of sham-operated rats, as measured on the day following the last exposure to stress. Chronic IMO potentiated the increase in CRF mRNA in the PVN following ADX and resulted in further increases in CRF mRNA above levels seen in adrenal-intact animals. Finally, chronic stress, while not altering basal ACTH levels of ADX rats, reduced the ACTH response of these animals to a novel stressor (tail-shock for 30 min). These results suggest that chronic stress exerts a stimulatory influence at the hypothalamic level that is partially restrained by daily stress-induced glucocorticoid release. Despite the potentiation by chronic stress of CRF mRNA content in the PVN of ADX rats, a blunted circulating ACTH response to an acute short-term stressor was apparent in ADX-chronically stressed rats, suggesting that chronic stress might also alter POMC processing and/or ACTH secretory patterns in the anterior pituitary in ADX animals.