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Aim: To ascertain and compare the perspectives of students and lecturers at Edinburgh Napier University and Hanze University of Applied Sciences, the Netherlands, regarding person-centred care., Method: Data were collected using face-to-face, structured interviews and analysed using a person-centred nursing framework., Findings: Participants believed that person-centred care should be incorporated within pre-registration nursing education., Conclusion: The way person-centred care is taught varied between the two universities. With the focus on high quality, compassionate care, it is important to identify how nursing curricula can promote these qualities.

This article discusses athletic injuries of the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and posterolateral corner. Best evidence to date validates that conservative management of ACL ruptures is a reasonable strategy. Current data also seem to advocate nonoperative management of PCL injuries. All isolated MCL injuries, regardless of grade, are usually treated with a brief period of immobilization and symptomatic management. Although the surgical literature often advocates surgical treatment of posterolateral corner injuries, there have been no randomized trials substantiating that these injuries are best treated surgically., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To characterize national physician organizations' efforts to reduce health disparities and identify organizational characteristics associated with such efforts., Method: This cross-sectional study was conducted between September 2009 and June 2010. The authors used two-sample t tests and chi-square tests to compare the proportion of organizations with disparity-reducing activities between different organizational types (e.g., primary care versus subspecialty organizations, small [<1,000 members] versus large [>5,000 members]). Inclusion criteria required physician organizations to be (1) focused on physicians, (2) national in scope, and (3) membership based., Results: The number of activities per organization ranged from 0 to 22. Approximately half (53%) of organizations had 0 or 1 disparity-reducing activities. Organizational characteristics associated with having at least 1 disparity-reducing effort included membership size (88% of large groups versus 58% of small groups had at least 1 activity; P = .004) and the presence of a health disparities committee (95% versus 59%; P < .001). Primary care (versus subspecialty) organizations and racial/ethnic minority physician organizations were more likely to have disparity-reducing efforts, although findings were not statistically significant. Common themes addressed by activities were health care access, health care disparities, workforce diversity, and language barriers. Common strategies included education of physicians/trainees and patients/general public, position statements, and advocacy., Conclusions: Despite the national priority to eliminate health disparities, more than half of national physician organizations are doing little to address this problem. Primary care and minority physician organizations, and those with disparities committees, may provide leadership to extend the scope of disparity-reduction efforts.

The aim of this study was to construct a promoter containing DNA motifs for an endogenous transcription factor associated with inflammation along with motifs for pharmacological regulation factors. We demonstrate in transfected cells that expression of a gene of interest is induced by hypoxic conditions or through pharmacological induction, and also show pharmacological repression. In vivo studies utilised electroporation of plasmid to mouse paws, a delivery method shown to be effective by bioluminescence imaging. For gene therapy, the promoter was used to drive expression of IL-1Ra in a paw inflammation model with therapeutic effect observed which was further enhanced when the promoter was additionally induced with a pharmacological activator. One of the most important observations from this study was that promoter induction by hypoxia or inflammation could be prevented by the pharmacological repressor in the absence of doxycycline. These studies demonstrate that hybrid promoters enable pharmacological adjustment to the pathophysiological level of gene expression and, importantly, that they allow termination of gene expression even in the presence of pathophysiological stimuli.

Objective: To examine the association between physician race/ ethnicity, workplace discrimination, and physician job turnover., Methods: Cross-sectional, national survey conducted in 2006-2007 of practicing physicians (n = 529) randomly identified via the American Medical Association Masterfile and the National Medical Association membership roster. We assessed the relationships between career racial/ethnic discrimination at work and several career-related dependent variables, including 2 measures of physician turnover, career satisfaction, and contemplation of career change. We used standard frequency analyses, odds ratios and chi2 statistics, and multivariate logistic regression modeling to evaluate these associations., Results: Physicians who self-identified as nonmajority were significantly more likely to have left at least 1 job because of workplace discrimination (black, 29%; Asian, 24%; other race, 21%; Hispanic/Latino, 20%; white, 9%). In multivariate models, having experienced racial/ethnic discrimination at work was associated with high job turnover (adjusted odds ratio, 2.7; 95% CI, 1.4-4.9). Among physicians who experienced workplace discrimination, only 45% of physicians were satisfied with their careers (vs 88% among those who had not experienced workplace discrimination, p value < .01), and 40% were contemplating a career change (vs 10% among those who had not experienced workplace discrimination, p value < .001)., Conclusion: Workplace discrimination is associated with physician job turnover, career dissatisfaction, and contemplation of career change. These findings underscore the importance of monitoring for workplace discrimination and responding when opportunities for intervention and retention still exist.

Background: Promoting racial/ethnic diversity within the physician workforce is a national priority. However, the extent of racial/ethnic discrimination reported by physicians from diverse backgrounds in today's health-care workplace is unknown., Objective: To determine the prevalence of physician experiences of perceived racial/ethnic discrimination at work and to explore physician views about race and discussions regarding race/ethnicity in the workplace., Design: Cross-sectional, national survey conducted in 2006-2007., Participants: Practicing physicians (total n = 529) from diverse racial/ethnic backgrounds in the United States., Measurements and Main Results: We examined physicians' experience of racial/ethnic discrimination over their career course, their experience of discrimination in their current work setting, and their views about race/ethnicity and discrimination at work. The proportion of physicians who reported that they had experienced racial/ethnic discrimination "sometimes, often, or very often" during their medical career was substantial among non-majority physicians (71% of black physicians, 45% of Asian physicians, 63% of "other" race physicians, and 27% of Hispanic/Latino(a) physicians, compared with 7% of white physicians, all p < 0.05). Similarly, the proportion of non-majority physicians who reported that they experienced discrimination in their current work setting was substantial (59% of black, 39% of Asian, 35% of "other" race, 24% of Hispanic/Latino(a) physicians, and 21% of white physicians). Physician views about the role of race/ethnicity at work varied significantly by respondent race/ethnicity., Conclusions: Many non-majority physicians report experiencing racial/ethnic discrimination in the workplace. Opportunities exist for health-care organizations and diverse physicians to work together to improve the climate of perceived discrimination where they work.

With the new ISO 9001:2008 quality management system (QMS) superseding ISO 9001:2000, Charles Bright, BSc, MBA, principal quality consultant and medical devices lead auditor at specialist medical devices and healthcare sector consultancy Plasmed, discusses implementation of the latest standard, touching on the experience of a large English NHS acute hospital which achieved certification this March--one of only a handful of UK hospitals to have achieved the distinction to date.

Study Design: A posterolateral lumbar interbody arthrodesis animal model was selected to evaluate the percutaneous delivery of OP-1 plasmid DNA. OBJECTIVE.: To evaluate the feasibility of achieving ectopic bone formation using nonviral gene delivery with a minimally invasive technique, by coinjecting plasmid DNA encoding OP-1 with collagen into the paraspinal muscle., Summary of Background Data: Osteoinductive proteins show great promise for achieving spine fusion but suffer from poor bioavailability. Viral gene transfer can produce therapeutic and sustained levels of osteoinductive proteins to achieve osteogenesis in a variety of animal models. Toxicity and immunogenicity concerns, however, limit the appeal of viral gene therapy for spine fusion., Methods: Single-level posterior lumbar arthrodesis was attempted at L5-L6 in 64 adult Sprague-Dawley rats bilaterally. OP-1 plasmid DNA was injected with and without collagen carrier above the L5 transverse process either percutaneously or after open surgery. Bone formation was evaluated at 2 and 4 weeks by manual palpation, posterolateral radiographs, and nondecalcified histology. Control animals received the rhOP-1 protein., Results: Bone formation was detected histologically after the percutaneous and open surgical delivery of 25 microg or 500 microg, respectively, of OP-1 plasmid DNA (pVR1055-OP1) and collagen (bone formation = 75% and 50%), but was weaker than that observed after injection of 30 microg of rhOP-1 protein and collagen (bone formation = 100%). Single-level spine fusion was only achieved in groups receiving percutaneous OP-1 protein and collagen (30 microg protein, fusion rate = 100%) or high concentrations of OP-1 protein alone (40 microg protein, 100%), as confirmed through manual palpation, histology, and radiography. CONCLUSIONS.: These data confirm that OP-1 plasmid DNA can successfully generate bone formation in vivo.

Poly(propyl acrylic acid) (PPAA) is a polymer specifically designed to disrupt lipid bilayer membranes within a sharply defined pH range. The pH sensitivity can be used to enhance the release of endocytosed drugs into the cytoplasmic compartment of the cell. By incorporating this polymer in a polymeric gene carrier, chitosan, the release of plasmid DNA from the endosomal compartment was enhanced. In vitro transfection studies confirmed that the incorporation of PPAA into the chitosan-DNA nanoparticles enhanced gene expression in both HEK293 and HeLa cells compared to chitosan nanoparticles alone. The dose and time at which PPAA was incorporated during the complex formation affected the release of DNA and transfection efficiency. The optimal dose of PPAA incorporated into the chitosan nanoparticles was determined to be 10 microg, corresponding to a PPAA/DNA weight ratio of 1:1. At this dose, the ternary complexes are approx. 400 nm in size with a net negative surface charge of -17.4 mV. Intracellular trafficking studies confirmed the association of PPAA, DNA and chitosan at 24 h post-transfection and the subsequent release of DNA and PPAA from the chitosan at 48 h. The diffuse appearance of the majority of the DNA and the PPAA at later time points suggests that the PPAA triggered membrane disruption resulting in the release of DNA from the endosomal compartment. Finally, the lack of colocalization between PPAA and Lysotracker indicated that the PPAA-loaded nanoparticles were not trafficked through a lysosomal pathway. This study suggests the promising strategy of including PPAA in the formulation of polymer-DNA complexes for non-viral gene delivery.

Tumor necrosis factor (TNF)-alpha is produced by cells of the immune system and is a key mediator in immune and inflammatory reactions. Through interaction with widely expressed receptors (TNF receptor 1 and TNF receptor 2), TNF-alpha is able to orchestrate the expression of a range of downstream proinflammatory molecules. Over the past decade novel biologics that inhibit TNF-alpha have been developed as extremely effective treatments for rheumatoid arthritis. Structurally, these biologics are antibodies, or TNF receptors on an antibody backbone that bind TNF-alpha directly and are delivered to patients by repeated injection. Gene therapy offers an improved approach to delivering biologics as a single administration of their encoding genetic material. In the present study we demonstrate the therapeutic effect of a small molecular weight dimeric TNF receptor 2 (dTNFR) constitutively expressed from plasmid DNA, delivered intramuscularly with electroporation, after disease onset in a collagen-induced arthritis model. Regulated promoters that enable the production of a transgene to be controlled are more suited to the application of gene therapy in the clinic. Regulated expression of dTNFR from the plasmid pGTRTT was also therapeutic in the mouse collagen-induced arthritis model when the inducer doxycycline was also administered, whereas no therapeutic effect was observed in the absence of doxycycline. The therapeutic effect of dTNFR expressed from a constitutive or regulated plasmid was dependent on the degree of disease activity at the time of DNA injection. The observations of this study are considered with regard to the disease model, the magnitude of gene regulation, and the path to clinical application.

The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.

Unlabelled: Constant pain could, in principle, counteract mobilization of antianalgesia systems and prevent the development of acute tolerance to the analgesic effects of opioids. We sought to determine whether a tonic nociceptive input caused by inflammation inhibits the development of acute tolerance to alfentanil. The inflammation was induced by injection of carrageenan into the rat hind paw. A threshold of motor response to increasing pressure on the paw was used to determine analgesia. Alfentanil was administered IV with an infusion algorithm designed to maintain a constant plasma level of opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia. The continuous decline of the analgesic effect from its peak at 30 min to the end of the 4-h infusion period was profound, despite the constant-rate infusion of alfentanil. The degrees of decline were very similar in rats with and without carrageenan-induced inflammation (from 242 +/- 31 to 154 +/- 20 g, P < 0.0001; and from 242 +/- 33 to 148 +/- 14 g, P < 0.0001, respectively). The results suggest that inflammatory nociceptive input does not prevent the development of acute tolerance to opioid-induced analgesia measured as an increased reaction threshold to painful pressure. We conclude that acute tolerance to the analgesic effect of opioids is profound and develops very rapidly, even in the presence of constant nociceptive input., Implications: We examined whether inflammatory pain can prevent the rapid decline in analgesic effectiveness (acute tolerance) of alfentanil during its IV infusion. We found that acute tolerance to the analgesic effect of alfentanil, in the presence of constant pain caused by inflammation, develops as rapidly as without it.

Unlabelled: Ketamine administered intraoperatively in very small doses reduces postoperative opioid consumption. We suggest that this effect is the result of attenuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be attenuated by a dose of ketamine that is too small to produce a direct antinociceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. Ketamine (10 mg/kg) did not change the baseline pain threshold and did not increase the peak of alfentanil-induced analgesia. At the same time, it attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion. These effects were similar to those observed with dizocilpine (0.1 mg/kg). The development of acute tolerance to analgesia induced by the infusion of an opioid can be attenuated by ketamine administered in doses that are not large enough to provide a direct antinociceptive effect. Therefore, ketamine has the potential to reduce opioid consumption even in subanalgesic doses., Implications: Ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

Unlabelled: To test the role of cholecystokinin (CCK) and N-methyl-D-aspartate-nitric oxide (NMDA-NO) systems in the development of acute tolerance to analgesia during alfentanil IV infusion, we conducted experiments in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. CCK(B) receptor antagonists (proglumide, CI-988, and L-365,260) and NMDA-NO cascade inhibitors (dizocilpine and NO synthase inhibitor) were administered before the start of alfentanil infusion. Use of 30 mg/kg proglumide, 10 mg/kg CI-988, and 1 mg/kg L-365,260 attenuated acute tolerance at 1 h of alfentanil infusion by approximately 60%, 55%, and 70%, respectively, and by the end of 4-h infusion by 50%, 50%, and 25%, respectively. Use of 0.1 mg/kg dizocilpine and 10 mg/kg N(G)-nitro-L-arginine methyl ester attenuated acute tolerance at 1 h of alfentanil infusion by approximately 65% and 65% and by the end of 4-h infusion by 30% and 0%, respectively. Comparison of the results with CCK(B) receptor antagonists and inhibitors of NMDA-NO cascade demonstrates that both groups of drugs provide more or less similar degrees of attenuation of acute tolerance to the antinociceptive effect of alfentanil, and none of these drugs completely prevents tolerance development., Implications: The mechanism of acute tolerance to the analgesic effect of alfentanil depends on participation of multiple systems of adaptation that include cholecystokinin(B) receptors and N-methyl-D-aspartic acid-nitric oxide cascade. Drugs that inhibit function of these systems attenuate tolerance development.

This study examined barriers and biases in the medical education experience by surveying fourth-year medical students. There were 270 female and 288 male respondents; their racial background was: 21% Asian, 13% underrepresented minorities, and 66% white. Women reported that the careers they were encouraged to pursue were affected by their gender (44% versus 15%) and they were often mistaken for a nonphysician (92% versus 3%). More importantly, women reported that the lack of a mentor of either gender as a large barrier (27% versus 19%). Underrepresented minorities reported that their race caused them to feel that they had to be twice as good to be treated as an equal to other students (52% versus 6%). Underrepresented minorities identified the lack of a same-race mentor (23% versus 4%) and role model (40% versus 1%) as a large barrier. Underrepresented minorities also noted an overall lack of mentors as a large barrier (25% versus 19%). Women and underrepresented minorities from the class of 1996 reported having a medical school experience characterized by similar barriers to their professional development.

The New York Organization of Nurse Executives and the American Organization of Nurse Executives held an Open Space meeting to examine issues to be addressed by nursing leaders in the development of integrated delivery systems. Participants identified issues related to the role of the RN, clarifying the value nursing adds to health care delivery, and how to articulate nursing's contribution toward patient care quality and outcomes. Action plans were developed for two major goals: operationalizing nursing across multiple settings and within multidisciplinary teams and standardizing measurement in integrated networks.

RP 64477 (N-butyl-3-(p-decyloxybenzamido)-4-(methylthio)benzamide) has been shown to be a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) in intestinal, hepatic, adrenal, and arterial tissue preparations obtained from a range of animal species. Drug concentrations producing 50% inhibition of enzyme activity (IC50 values) ranged from 14-283 nM. Inhibition by RP 64477 in a rabbit intestinal enzyme preparation was shown to be non-competitive with respect to the substrate oleoyl-CoA. In whole cell assays using human intestinal (CaCo-2), hepatic HepG2) and monocytic (THP-1) cell lines, RP 64477 inhibited ACAT activity with IC50s of 113, 503, and 180 nM, respectively. RP 64477 (0.03% w/w by diet) reduced significantly cholesterol absorption in cholesterol/cholic acid-fed rats from 94+/- 8% to 65 +/- 4%. In cholesterol-fed rabbits, cholesterol absorption was reduced from 72 +/- 5% to 50 +/-5% and 44 +/- 5% at dose levels of 10 and 30 mg kg-1 b.i.d., respectively. Plasma cholesterol levels were reduced dose-dependently in both cholesterol/cholic-acid-fed rats and cholesterol-fed rabbits. Neither cholesterol absorption nor plasma cholesterol levels were reduced significantly in animals maintained on standard laboratory diets. Pharmacokinetic studies indicated that RP 64477 were very poorly absorbed following oral administration to rats. Plasma levels of drug were < 2 ng mL-1 following a dose of 2000 mg kg-1 p.o.. When radiolabelled RP 64477 was administered orally, limited absorption was indicated by the overwhelming elimination of radioactivity in the faces (96.4% of administered material) coupled with low renal clearance (0.6% of dose) and biliary excretion (0.05% of dose). In conclusion, this work shows that RP 64477 is a potent inhibitor of ACAT obtained from a range of animal species and man. Inhibition of cholesterol absorption and hypocholesterolaemic activity has been demonstrated in rats and rabbits maintained on diets supplemented with cholesterol. Pharmacokinetic studies indicate low systemic exposure to RP 64477 as a result of limited absorption of this drug.

The changes of intracellular pH (pHi) produced by hypoxia in sheep heart Purkinje fibres were studied using liquid ion exchanger-filled microelectrodes. A decrease of temperature from 35 degrees C to 22 degrees C caused an alkalinization of 0.3 pH units. Hypoxia (partial pressure of oxygen < 10 mm Hg) for 20 min induced an acidification of 0.26 +/- 0.18 units (n = 14) at 35 degrees C. The hypoxia-induced acidification at 22 degrees C was smaller than that at 35 degrees C by approximately 65%. Increasing the buffering capacity of the cells decreased the hypoxic acidification. This could be achieved either by use of high extracellular HEPES concentrations (40 mM) or by the use of bicarbonate buffers. Sodium cinnamate (5 mM) increased the hypoxic acidification and slowed the pHi recovery on reintroduction of oxygen, implying an importance role for lactate flux in pH regulation during hypoxia.

The effects were studied of hypoxia on intracellular ion activities in sheep heart Purkinje fibres. The intracellular pH (pHi), surface pH (pHs), intracellular potassium activity (aki), and intracellular sodium activity (aNai) of the cells were recorded using liquid ion exchanger-filled microelectrodes. Various methods of inhibiting oxidative phosphorylation were compared for their effect on pHi. These methods were the use of hypoxia, anoxia or NaCN (2 mM). Hypoxia was produced by degassing solutions under reduced pressure then bubbling with 100% nitrogen gas. Anoxia was produced in a similar manner but with the addition of the reducing agent sodium dithionite (0.5 mM) to remove all traces of oxygen from the solutions. Anoxia caused the most marked changes. Concentration of sodium dithionite between 0.1 and 1 mM produced similar maximum rates of acidification. High concentrations (5 or 20 mM) could produce larger intracellular acidifications apparently unrelated to anoxia. The effects of hypoxia and NaCN were similar. Inhibition of Na(+)-H+ exchange with amiloride (1 mM) had little effect on the pH changes produced by hypoxia. Periods of hypoxia exceeding 1 h still resulted in rapid, readily reversible changes in pHi. Hypoxia caused a rise in aNai, the effect being larger in anoxic conditions. The intracellular K+ activity decreased in hypoxia with further decreases in anoxic conditions. The intracellular ion changes produced during hypoxia are discussed in terms of the production of lactic acid by the cells and changes in the ATP supply to the Na(+)-K+ pump.

We have investigated the growth promoting activities of two potent vasoactive substances, serotonin and angiotensin II (AII), on cultured porcine aortic smooth muscle cells (ASMC), using a defined serum-free medium. Serotonin (30 nM to 30 microM) stimulated ASMC DNA synthesis both alone and in combination with platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). Serotonin-induced DNA synthesis was significantly inhibited by ketanserin (5-hydroxytryptamine-2 (5HT-2) receptor antagonist). AII (3-10 nM) failed to stimulate ASMC DNA synthesis directly, either alone or in combination with PDGF or EGF. Since both serotonin and AII were found to activate phosphatidylinositol turnover and are reported to mobilise intracellular calcium, it is apparent that these events alone are insufficient to stimulate ASMC mitogenesis.

Clinic-initiated topical treatment of recurrent genital herpes with foscarnet cream (concentration, 0.3% in men and 1% in women) was compared with a placebo in a Canadian multicenter trial involving 309 patients. Culture-positive episodes of herpes took significantly longer to heal than did the others. Lesions in men were larger and lasted longer but were less symptomatic than those in women. Foscarnet did not statistically improve the times to healing or the loss of symptoms overall but did result in a higher proportion of symptom-free individuals after one day of treatment. Foscarnet-treated patients had a reduced duration of shedding of virus, and this was significant for men. These clinical benefits do not, however, warrant general use of this agent for established lesions. Earlier, prodromal treatment might have been more effective, but patient-initiated studies include a greater proportion of culture-negative (shorter) episodes that often make results difficult to interpret.

The effects of the glycoside saponin on ferret ventricular muscle have been investigated. Saponin produced a positive inotropic effect, the extent of which was determined by the bathing calcium concentration. If the bathing calcium concentration is reduced to levels equivalent to those found intracellularly then similar saponin concentrations are able to "skin" the cardiac cells. The effects were further investigated in sheep heart Purkinje fibres. In the presence of normal extracellular calcium concentrations (to prevent skinning), saponin produced increases in sodium activity, decreases in potassium activity but little change in intracellular pH. The decreases of potassium activity were compared to the effects of strophanthidin. The changes in intracellular ion levels were accompanied by the development of a contracture. The effects of saponin could be explained by its interaction with cholesterol in the cell membrane resulting in an increase in membrane permeability to sodium which may be part of a nonspecific increase in membrane permeability.