'I think there is nothing . . . that is really comprehensive': healthcare professionals' views on recommending online resources for pain self-management.

OBJECTIVES: To explore healthcare professionals' views on, and attitudes, towards recommending online resources for persistent pain self-management. METHODS: This study was the qualitative phase of a two-phase mixed method study. Thirty-one New Zealand health professionals involved in the management of persistent pain were interviewed via focus groups and individual interviews. Data were analysed using the general inductive approach. RESULTS: The major themes were as follows: (1) risks and limits of online information outweigh benefits, (2) a blended model, of online resources with healthcare professional support, could work, (3) only trustworthy resources can be recommended, (4) need for personalisation and (5) perceived barriers to adoption. CONCLUSION: Online resources were perceived as a useful adjunct to support pain self-management; however, due to potential risks of misinterpretation and misinformation, healthcare professionals proposed a 'blended model' where curated online resources introduced during face-to-face consultations could be used to support self-management. Participants needed 'trustworthy online resources' that provide evidence-based, updated information that is personalised to clients' health literacy and cultural beliefs. PRACTICE IMPLICATIONS: Training for healthcare professionals on critical appraisal of online resources or curation of evidence-based online resources could increase recommendation of online resources to support pain self-management as an adjunct to in-person care.

Transmural gradient of leukocyte-endothelial interaction in the rat gastrointestinal tract.

Gastrointestinal injury usually starts in the superficial mucosa. We investigated whether leukocyte-endothelial interactions were greater in the gastrointestinal mucosa than the submucosa and muscularis in control tissue and after upregulation of adhesion molecules with endotoxin and after chemical insult with nonsteroidal anti-inflammatory drugs. Inactin-anesthetized rats were given either endotoxin, flurbiprofen, or nitric oxide (NO)-flurbiprofen, after which ICAM-1 and P-selectin expression was measured with the dual-label antibody technique. Leukocyte-endothelial interactions in the different gastric layers were assessed after endotoxin using intravital microscopy. Endotoxin caused a two- to threefold increase in ICAM-1 expression in the stomach and duodenum. There was, however, a gradient in expression across the gut wall with the level of expression in the superficial mucosa (per g) being only 10-25% of that in the deeper layers in both control and endotoxin-treated animals. Constituitive expression of P-selectin in control animals was barely detectable. Endotoxin caused a modest increase in mucosal P-selectin but a very significant increase in the deeper layers. Flurbiprofen caused a slight upregulation of ICAM-1 in the gastric mucosa and duodenum, whereas NO-flurbiprofen had no affect on expression. Intravital microscopy revealed no adhesion and virtually no leukocyte rolling in the vessels of the gastric mucosa despite endotoxin treatment. There was, however, some adhesion and significant leukocyte rolling in the submucosa and muscularis. Thus the superficial gastric and duodenal mucosal microcirculations have a much lower density of ICAM-1 and P-selectin and less leukocyte-endothelial interactions than occurs in the deeper layers of the gut wall even during stimulated upregulation with endotoxin.

NMDA receptor involvement in the effects of low dose domoic acid in neonatal rats.

We have previously reported that neonatal rats display enhanced sensitivity to domoic acid relative to adults, and that perinatal injections of low doses of domoic acid alter early associational learning in the newborn rat. The current study was designed to further investigate the effects of low dose domoic acid on neonatal odour conditioning and to determine if the observed effects are due in part to an action on NMDA receptors. Groups of rat pups were conditioned to a novel odour on postnatal day (PND) 8, injected with 20 microg/kg domoic acid either alone, or in combination with the NMDA antagonist CPP (or appropriate controls), daily from day 8-14, re-exposed to the conditioning odour or a novel odour on day 9, and tested for odour preference on day 13 using a standard 3-choice paradigm. Results indicated that rats treated with domoic acid spent significantly more time over the conditioning odour than did saline-treated rats when tested on PND 13. This effect was antagonized by concomitant injection of CPP, indicating an involvement of NMDA receptors in the actions of DOM in this paradigm. Rats injected with either saline or CPP alone showed the opposite effect, i.e. a preference for the alternate odour. The results indicate that a very low dose of DOM produces a conditioned odour preference in neonatal rats and that this effect is due in part to NMDA receptor involvement, thereby emphasizing a role for both kainate and NMDA glutamate receptors in implicit memory.

Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology.

It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 microg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 microg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid. In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.

NO-flurbiprofen maintains duodenal blood flow, enhances mucus secretion contributing to lower mucosal injury.

This study investigates possible mechanisms behind the reduced gastrointestinal ulcerogenicity of nitric oxide (NO)-flurbiprofen compared with flurbiprofen. The duodenal mucosa of Inactin-anaesthetised rats was exteriorized for intravital microscopy. Blood flow was measured with laser-Doppler flowmetry (LDF), mucus thickness with micropipettes, ICAM-1 and P-selectin expression with dual-labeled antibody technique, and mucosal integrity by (51)Cr-EDTA permeability. Exposure of the duodenum to flurbiprofen (1.0 mg/ml) for 90 min significantly reduced LDF to 70 +/- 4%, whereas NO-flurbiprofen (1.3 mg/ml) had no significant effect. Mucus accumulation after 60-min exposure was 75 +/- 23 microm (control), -1 +/- 17 microm (flurbiprofen), and 104 +/- 35 microm (NO-flurbiprofen). Mucosal permeability to (51)Cr-EDTA was unchanged in the control and NO-flurbiprofen groups but increased significantly from 1.0 +/- 0.2 to 3.7 +/- 0.7 microl x min(-1) x g(-1) after 90-min exposure to flurbiprofen. Expression of ICAM-1 was significantly increased after oral flurbiprofen but not by NO-flurbiprofen. Positive effects of NO-flurbiprofen compared with flurbiprofen on mucus formation, blood flow, and adhesion molecule expression likely contribute to the reduced mucosal injury observed with NO-flurbiprofen.

How can the uptake of cervical cytology screening be improved?

BACKGROUND: Cervical cancer remains a killer, despite a screening programme designed to detect cases in the early stages of development. A number of factors appear to influence a woman's decision to attend for a smear test. This literature review considers these factors, and whether nurses can play a part in reducing the death rate by dispelling the misapprehensions and misinformation that deter vulnerable women from attending. CONCLUSION: There is a great need for modification and improvement of the present screening programme if all women who are at risk from cervical cancer are to be encouraged to attend for screening. The attitude of those who conduct smear tests is often crucial in gaining women's confidence--an unpleasant experience might deter a patient from attending again. Other barriers to attendance include administrative errors and lack of knowledge. Given the impact of mass advertising and health promotion campaigns in other areas, such as smoking cessation, there is clearly a need for a similar strategy to be applied to cervical screening.

Bufokinin: immunoreactivity, receptor localization and actions in toad intestine and mesenteric circulation.

In this study, we have mapped the immunoreactivity and the binding sites for bufokinin, a tachykinin peptide from the toad intestine. Dense bufokinin-immunoreactive fibers were present at the myenteric plexus, but no cell bodies were stained, suggesting an extrinsic origin. Bufokinin nerve fibers were also associated with submucosal blood vessels and mesenteric arteries. Autoradiographic binding sites for [(125)I]Bolton-Hunter-bufokinin were densely localized over the intestinal circular and longitudinal muscle, submucosal blood vessels and the endothelium of mesenteric arteries. Mesenteric veins had minimal immunoreactivity and binding sites. In the anesthetized toad, topical application of bufokinin onto the mesentery caused a 2.7-fold increase in arterial blood flow, observed using intravital microscopy. This study supports a role for bufokinin as an endogenous spasmogen and hemodynamic regulator in the toad intestine.

Reflections on intuition and expertise.

Reflective practice now appears firmly established in the English speaking world of professional nursing practice and development. Outside this linguistic context, however, the concept seems less well-known. This paper describes an experience drawn from clinical practice and education in French-speaking Switzerland followed by explicit reflection grounded in questions generated by Johns' model for structured reflection. Thus, a concept well-described in the English-language literature underpins an innovative approach to a French-language clinical teaching situation. The professional implications of this situation are explored through meaningful reflection providing new insight into familiar circumstances as they relate to the nurse tutor's role. This exploration is followed by a critical approach to the experience and the subsequent structured reflection in order to address relationships between intuition and expertise and self-awareness through reflection. A hermeneutic perspective provides additional insight into the nurse-patient relationship where both come to the situation with their own 'pre-understandings'. Individual horizons thus endorse a new understanding going beyond taken-for-granted meanings.

Interrelations between plasma homocysteine and intracellular S-adenosylhomocysteine.

S-Adenosylhomocysteine, a potent intracellular methylation inhibitor, is suggested as a potential mediator for hyperhomocysteinemia-related vascular changes. We investigated the effect of acute and chronic hyperhomocysteinemia on intracellular S-adenosylhomocysteine and S-adenosylmethionine in rats and humans. Elevated plasma homocysteine in rats infused with homocysteine produced an increase in S-adenosylhomocysteine (P < 0.001) but not S-adenosylmethionine levels (P > 0.05) in various rat tissues. However intraerythrocyte S-adenosylhomocysteine and S-adenosylmethionine levels were not changed in homocysteine-infused rats and human subjects with experimentally acute hyperhomocysteinemia by methionine loading test. In contrast, erythrocyte S-adenosylhomocysteine levels were significantly higher in chronic renal failure patients, who had chronically elevated plasma homocysteine levels, than in either vascular disease patients or healthy controls (P < 0.05). In conclusion, acute hyperhomocysteinemia can increase intracellular S-adenosylhomocysteine levels in tissues actively involved in homocysteine metabolism. The findings are relevant to homocysteine-related endothelial dysfunction since S-adenosylhomocysteine modulates endothelial cell apoptosis.

A combination of midazolam and ketamine for procedural sedation and analgesia in adult emergency department patients.

OBJECTIVE: To describe the clinical characteristics of a combination of midazolam and ketamine for procedural sedation and analgesia in adult emergency department (ED) patients. METHODS: This was a prospective, observational trial, conducted in the ED of an urban level II trauma center. Patients > or = 18 years of age requiring procedural sedation and analgesia were eligible, and enrolled patients received 0.07 mg/kg of intravenous midazolam followed by 2 mg/kg of intravenous ketamine. Vital signs were recorded at regular intervals. The adequacy of sedation, adverse effects, patient satisfaction, and time to reach discharge alertness were determined. Descriptive statistics were calculated using statistical analysis software. RESULTS: Seventy-seven patients were enrolled. Three were excluded due to protocol violations, three due to lack of documentation, and one due to subcutaneous infiltration of ketamine, leaving 70 patients for analysis. The average age was 31 years, and 41 (59%) were female. Indications for procedural sedation and analgesia included abscess incision and drainage (66%), fracture/joint reduction (26%), and other (8%). The mean dose of midazolam was 5.6 +/- 1.4 mg and the mean dose of ketamine was 159 +/- 42 mg. The mean time to achieve discharge criteria was 64 +/- 24 minutes. Five patients experienced mild emergence reactions, but there were no episodes of hallucinations, delirium, or other serious emergence reactions. Eighteen (25%) patients recalled dreaming while sedated; twelve (17%) were described as pleasant, two (3%) unpleasant, three (4%) both pleasant and unpleasant, and one (1%) neither pleasant nor unpleasant. There were four (6%) cases of respiratory compromise, two (3%) episodes of emesis, and one (1%) case of myoclonia. All of these were transient and did not result in a change in the patient's disposition. Only one (1%) patient indicated that she was not satisfied with the sedation regimen. CONCLUSIONS: The combination of midazolam and ketamine provides effective procedural sedation and analgesia in adult ED patients, and appears to be safe.

Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats In vivo.

Despite intense investigation, mechanisms linking the development of occlusive vascular disease with elevated levels of homocysteine (HCY) are still unclear. The vascular endothelium plays a key role in regulating thrombogenesis and thrombolysis. We hypothesized that vascular lesions in individuals with elevated plasma HCY may be related to a dysfunction of the endothelium triggered by HCY. We investigated the effect of HCY on human neutrophil adhesion to and migration through endothelial monolayers. We also examined the effect of HCY on leukocyte adhesion and migration in mesenteric venules of anesthetized rats. We found that pathophysiological concentrations of HCY in vitro induce increased adhesion between neutrophils and endothelial cells. This contact results in neutrophil migration across the endothelial layer, with concurrent damage and detachment of endothelial cells. In vivo, HCY infused in anesthetized rats caused parallel effects, increasing leukocyte adhesion to and extravasation from mesenteric venules. Our results suggest that extracellular H2O2, generated by adherent neutrophils and/or endothelial cells, is involved in the in vitro endothelial cell damage. The possibility exists that leukocyte-mediated changes in endothelial integrity and function may lead to the vascular disease seen in individuals with elevated plasma HCY.

Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappa-opioid agonist but not by NSAID.

OBJECTIVE: To quantify intercellular adhesion molecule-1 (ICAM-1) expression in normal and adjuvant arthritic rats and to determine the extent to which ICAM-1 expression in arthritic animals is altered by treatment with a prototype nonsteroidal antiinflammatory drug (NSAID) and a kappa-opioid agonist. METHODS: Unilateral hind paw inflammation was induced by intradermal injection of Freund's complete adjuvant (FCA) into the right hind paw of female Lewis rats. Polyarthritis was induced by intradermal injection of FCA into the base of the tail of female dark Agouti rats. The NSAID naproxen [5 mg/kg intraperitoneally (ip)] or the kappa-opioid PD117302 (15 mg/kg ip) was administered twice daily throughout the experiment (21 days). ICAM-1 expression was quantified using monoclonal antibodies against rat ICAM-1 that bind to the endothelium in proportion to the degree of adhesion molecule expression. RESULTS: ICAM-1 expression was significantly upregulated in the joints of affected limbs of animals with both unilateral hind paw inflammation and polyarthritis. In animals treated with PD 117302 and naproxen there was a significant attenuation of arthritis; however, only treatment with PD117302 was able to significantly inhibit the upregulation of ICAM-1 expression in arthritic joints. CONCLUSION: ICAM-1 expression is upregulated in experimental arthritis. It appears that the kappa-opioid PD117302, but not the NSAID naproxen, inhibits the upregulation of ICAM-1 in arthritic joints, suggesting these agents act via different mechanisms. The ability of the kappa-agonist, PD117302, to inhibit both the inflammation and upregulation of ICAM-1 in arthritic joints emphasizes the potential of kappa-agonists as antiarthritic agents.

Role of neutrophils and mast cells in acute indomethacin-induced small bowel injury in the rat.

The aim of this study was to determine whether the injury to the rat jejunum during the first 4.5 h exposure to indomethacin is due to an influx of neutrophils or degranulation of resident mast cells. Indomethacin and vehicle both caused changes in villous morphology (length, width, etc.) while only indomethacin injured the small bowel, as indicated by increased histological lesion score and 51Cr-ethylene diamine tetraacetate (EDTA) flux across the intestinal epithelium. Immunohistochemical staining showed the same small increase in neutrophil density (predominantly in the submucosa) following exposure to vehicle as following exposure to indomethacin. Chronic oral administration of indomethacin for 48 h did cause increased tissue neutrophil density compared to that in vehicle-fed controls. Mast cell depletion (using dexamethasone) did not alter either the indomethacin-induced increase in 51Cr-EDTA clearance or the increase in neutrophil density caused by the vehicle and by indomethacin. However, the lesion score following exposure to indomethacin was significantly lower in mast-cell-depleted animals than in control animals. We conclude that the acute phase of indomethacin-induced intestinal injury is not associated with neutrophil influx. Increased neutrophils seen after chronic indomethacin may result from injury rather than be causative. Mast cells appear to exacerbate the initial stages of indomethacin-induced intestinal injury.

Portal hypertension enhances endotoxin-induced intercellular adhesion molecule 1 up-regulation in the rat.

BACKGROUND & AIMS: Liver disease or portosystemic shunting enhances th e sensitivity to endotoxin. The aim of this study was to investigate whether intercellular adhesion molecule 1 (ICAM-1) expression in response to endotoxin may be dysregulated in an animal model of portal hypertension. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated animals served as controls. ICAM-1 expression was measured using radiolabeled antibodies under baseline conditions or 5 hours after treatment with either endotoxin or recombinant tumor necrosis factor (TNF). Immunoreactive plasma TNF was also measured. RESULTS: Under baseline conditions, ICAM-1 expression in all organs studied was similar in portal-hypertensive and sham-operated rats. ICAM-1 up-regulation after a high dose of endotoxin (5 mg/kg) was similar in both groups of animals. However, portal-hypertensive animals showed a significantly higher ICAM-1 expression in response to low doses of endotoxin (0.1-10 microgram/kg). The response to a low (but not a high) dose of recombinant TNF was also significantly enhanced in portal-hypertensive animals. In addition, portal-hypertensive rats had higher plasma TNF levels after treatment with endotoxin or recombinant TNF. CONCLUSIONS: Portal hypertension induces an exaggerated ICAM-1 up-regulation in response to endotoxin, which is related to an increased production and decreased clearance of the cytokine.

Stimulated chemiluminescence in several models of oxidative stress.

It had been suggested that increased chemiluminescence, stimulated by tertiary-butylhydroperoxide (t-BuOOH) resulted from tissues which had undergone previous oxidative stress. Therefore, we tested animals subjected to various conditions generally regarded to cause oxidative stress, then removed relevant target organs and measured t-BuOOH stimulated (and unstimulated) chemiluminescence from biopsy sized samples of these tissues. The conditions chosen included 5000 rads whole body irradiation, hyperoxia, ischaemia-reperfusion and chronic indomethacin (a non-steroidal anti-inflammatory drug) treatment, with determination of chemiluminescence from samples of stomach and thymus after irradiation, brain and lungs after hyperoxia, kidney and stomach following ischaemia-reperfusion, and ileum and jejunum after chronic indomethacin administration. Neutrophils were also measured in the latter model. We cannot substantiate the claim that t-BuOOH stimulated chemiluminescence is a reliable indicator that a tissue has undergone oxidative stress. Large increases in stimulated chemiluminescence occurred only in frankly ulcerated tissue of the gastrointestinal tract and this enhanced chemiluminescence may be associated with increased neutrophils infiltrating the ulcer site.

Regional differences in constitutive and induced ICAM-1 expression in vivo.

The aim of the present study was to characterize and compare the expression of intercellular adhesion molecule 1 (ICAM-1) on unstimulated and endotoxin-challenged endothelial cells in different tissues of the rat. ICAM-1 expression was measured using 125I-labeled anti-rat ICAM-1 monoclonal antibody (MAb) and an isotype-matched control MAb labeled with 131I (to correct for nonspecific accumulation of the binding MAb). Under baseline conditions, ICAM-1 MAb binding was observed in all organs. The binding of 125I-ICAM-1 MAb varied widely among organs, with the largest accumulation (per g tissue) in the lung, followed by heart (1/30th of lung activity), splanchnic organs (1/50th of lung activity), thymus (1/100th of lung activity), testes (1/300th of lung activity), and skeletal muscle (1/800th of lung activity). Endotoxin induced an increase in ICAM-1 MAb binding in all organs except the spleen. Endotoxin-induced upregulation of ICAM-1 was greatest in heart and skeletal muscle (5- to 10-fold), whereas the remaining organs exhibited a two- to fourfold increase in ICAM-1 expression. Maximal upregulation of ICAM-1 occurred at 9-12 h after endotoxin administration. A dose-dependent increase in ICAM-1 expression was elicited by 0.1-10 microgram/kg, with higher doses (up to 5 mg/kg) producing no further increment. Induction of ICAM-1 mRNA after endotoxin was observed in all tissues examined (lung, heart, intestine), peaked at 3 h, and then rapidly returned to control levels. These findings indicate that ICAM-1 is constitutively expressed on vascular endothelium in all organs of the rat and that there are significant regional differences in the magnitude and time course of endotoxin-induced ICAM-1 expression.

Role of leukocytes in indomethacin-induced small bowel injury in the rat.

This study assesses the role of neutrophils in indomethacin-induced small bowel injury and determines the influence of intestinal pH on the magnitude of this injury. Rat jejunum was perfused via the lumen with buffer, and mucosal injury was assessed by blood-to-lumen clearance of 51Cr-EDTA and quantitative histology. Reduction in luminal pH from 7.4 to 6.0 in the presence of indomethacin (1.0 mg/ml) increased 51Cr-EDTA clearance from 2.0 +/- 0.1 to 6.5 +/- 0.3 microliter.min-1.g-1. Indomethacin caused a reduction in villus length, an increase in villus width, and an increase in lesion score. Depletion of neutrophils with antiserum largely prevented the increase in 51Cr-EDTA clearance and morphological changes. Intravenous indomethacin given at a dose to mimic therapeutic plasma levels (1 mg/kg iv) had no significant effect on 51Cr-EDTA clearance but caused similar morphological changes to those observed following intraluminal administration. The data suggest that neutrophils play a role in acute indomethacin injury and that the drug given intravenously can cause morphological changes without necessarily altering mucosal permeability to 51Cr-EDTA.

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin.

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0-0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.