Healthy universities: Exploring the relationship between psychosocial needs and work-related health among university employees.

The present study explores psychosocial needs among university employees and the extent to which these needs influence employee perceptions of how work positively or negatively affects their health. Structural equation modeling (SEM) analyses among Norwegian faculty members (N = 11,533) suggest that needs differ in importance to the two work-related health outcomes. Multi-group analyses suggest gender differences in the level of these needs and in their degree of relationship with positive/negative work-related health. Among women, the strongest predictors of positive and negative work-related health are work engagement and autonomy, respectively. Among men, the strongest predictors of positive and negative work-related health are meaning and social community, respectively. Although significant differences were found in the level of the psychosocial needs across different university groups (faculty, PhD students, administrative/technical staff), their predictive value for how work affects their health positively or negatively is basically equivalent across groups. Study findings raise two implications: (1) the mechanisms and characteristics of the work environment that promote versus detract from health in the university setting do not appear to be two sides of the same coin and suggest different sets of interventions for improving employee health, and (2) gender differences should be taken into account in designing interventions to improve health and well-being in universities.

Evaluation of cyclosporine-sparing effects of polyunsaturated fatty acids in the treatment of canine atopic dermatitis.

A randomised, double-blinded, placebo-controlled multicentre trial was conducted in 36 dogs with atopic dermatitis to evaluate the cyclosporine-sparing effect of polyunsaturated fatty acids. Dogs were stable on their individual cyclosporine dosage and received either a mainly omega-3 fatty acid product with a minor omega-6 fatty acid fraction or placebo, orally for 12 weeks. Dogs were examined every 4 weeks and the Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) was determined by a clinician. Pruritus, quality of life, global condition and coat quality were scored by the owner. If the dog's CADESI-03 and/or pruritus score improved by at least 25% compared with the previous visit, the cyclosporine dosage was decreased by approximately 25%. If the scores deteriorated by at least 25%, the cyclosporine dosage was increased by the same percentage. The median daily cyclosporine dosage/kg bodyweight decreased in the active group from 4.1 mg to 2.6 mg and in the placebo group from 3.5 mg to 3.3 mg over the study period. The difference between the two groups was significant (P = 0.009). The improvement in median pruritus score from inclusion to completion was significantly greater in the active group than in the placebo group (P = 0.04). There was no significant difference in CADESI-03 changes between groups (P = 0.38). The results of this study indicate a cyclosporine-sparing effect of a mainly omega-3 fatty acid supplement in dogs with atopic dermatitis.

Increasing response rates from physicians in oncology research: a structured literature review and data from a recent physician survey.

Although the physician survey has become an important tool for oncology-focused health services research, such surveys often achieve low response rates. This mini-review reports the results of a structured review of the literature relating to increasing response rates for physician surveys, as well as our own experience from a survey of physicians as to their referral practices for suspected haematologic malignancy in the United States. PubMed and PsychINFO databases were used to identify methodological articles assessing factors that influence response rates for physician surveys; the results were tabulated and reviewed for trends. We also analysed the impact of a follow-up telephone call by a physician investigator to initial non-responders in our own mailed physician survey, comparing the characteristics of those who responded before vs after the call. The systematic review suggested that monetary incentives and paper (vs web or email) surveys increase response rates. In our own survey, follow-up telephone calls increased the response rate from 43.7% to 70.5%, with little discernible difference in the characteristics of early vs later responders. We conclude that in addition to monetary incentives and paper surveys, physician-to-physician follow-up telephone calls are an effective method to increase response rates in oncology-focused physician surveys.

[Pyoderma in dogs]. / Pyodermie beim Hund.

Bacterial infections associated with cutaneous commensal organisms like Staphylococcus pseudintermedius are frequently encountered in small animal practice. In this review, pathogenesis, clinical signs, and topical and systemic therapeutic options are discussed.

Hydrogen peroxide regulation of bovine endothelin-converting enzyme-1.

Vascular injury leads to the production of reactive oxygen species (ROS), but the mechanisms by which ROS contribute to vascular pathology are not completely understood. We hypothesized that ROS increase endothelin converting enzyme (ECE-1) expression. We found that glucose oxidase (GO) increases ECE-1 mRNA, protein, and activity in bovine aortic endothelial cells. Catalase abolishes this effect. Glucose oxidase treatment of endothelial cells transactivates the ECE-1 promoter. The ECE-1 promoter element that mediates this response to GO is located between -444 and -216 bp. This region contains a STAT response element, and GO activates STAT-3 binding to this STAT response element. Our data suggest that STAT3 mediates hydrogen peroxide induction of ECE-1 expression.

Inducible nitric oxide synthase inhibition of weibel-palade body release in cardiac transplant rejection.

BACKGROUND: Inducible nitric oxide synthase (iNOS, or NOS2) reduces the severity of accelerated graft arteriosclerosis (AGA) in transplanted organs, although the precise mechanism is unclear. METHODS AND RESULTS: We transplanted wild-type murine hearts into either wild-type or NOS2-null recipient mice; we then measured cardiac allograft survival and analyzed tissue sections by immunohistochemistry. We have confirmed that NOS2 increases cardiac allograft survival. We now show that there is less inflammation of cardiac allografts in wild-type hosts than in NOS2-null hosts. Furthermore, staining for von Willebrand factor reveals that the presence of NOS2 is correlated with the presence of Weibel-Palade bodies inside endothelial cells, whereas the absence of NOS2 is correlated with the release of Weibel-Palade bodies. CONCLUSIONS: Weibel-Palade bodies contain mediators that promote thrombosis and inflammation. Therefore, nitric oxide (NO) may stabilize the vessel wall and prevent endothelial activation in part by inhibiting the release of the contents of Weibel-Palade bodies. Prevention of Weibel-Palade body release might be a mechanism by which NO protects the vessel wall from inflammatory disorders such as atherosclerosis or graft arteriosclerosis.

Intersection of interferon and hypoxia signal transduction pathways in nitric oxide-induced tumor apoptosis.

Activated macrophages play a central role in antitumor immunity. However, the stimuli that activate macrophages to kill tumor cells are not completely understood. Because the center of solid tumors can be hypoxic, we hypothesized that hypoxia may be an important signal in activating macrophages to kill tumor cells. Hypoxia stimulates IFN-primed macrophages to express the inducible nitric oxide synthase (NOS2) and to synthesize nitric oxide (NO). We show that this synergy between IFN and hypoxia is mediated by the direct interaction of the hypoxia inducible factor-1 (HIF-1) and IFN regulatory factor-1 (IRF-1), which are both required for the hypoxic transcription of NOS2. This interaction between HIF-1 and IRF-1 may explain the mechanism by which macrophages infiltrating into tumors are activated to express NOS2 and to produce NO, a mediator of tumor apoptosis.

Activation of NF kappa B and expression of ICAM-1 in ischemic-reperfused canine myocardium.

Although redox-sensitive transcription factors, including nuclear factor kappa B (NF kappa B) and activator protein-1 (AP-1), have been shown to induce intercellular adhesion molecule-1 (ICAM-1) gene transcription in isolated cells, little is known about their involvement in the regulation of the ICAM-1 gene in vivo during ischemia-reperfusion. Anesthetized closed-chest dogs underwent 90 min coronary artery occlusion, followed by reperfusion for 0, 15, 30, 60, 180, or 360 min. Blood flow (fluorescent or radioactive microspheres), ICAM-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), and nuclear DNA-binding activity of NF kappa B and AP-1 (electrophoretic mobility shift assays) were assessed in myocardial tissue samples. ICAM-1 protein was expressed constitutively on vascular endothelium, but expression levels decreased markedly during ischemia. Within 15 min reperfusion, endothelial ICAM-1 protein increased, associated with a rapid appearance of ICAM-1 mRNA. Activation of both NF kappa B and AP-1 occurred following ischemia-reperfusion, but did not coincide temporally with early post-reperfusion ICAM-1 gene induction. NF kappa B was activated during ischemia, when ICAM-1 mRNA was undetectable, and did not increase further until 60 min reperfusion, well after the increase in ICAM-1 mRNA had begun. Similarly, AP-1 did not increase until 60 min reperfusion. In non-ischemic myocardium, NF kappa B and AP-1 were both activated, but ICAM-1 mRNA did not appear until 6 h later. By immunohistology, NF kappa B (p65 subunit) and the c-Fos subunit of AP-1 were localized primarily in vascular endothelium. Reperfusion of ischemic myocardium is associated with very rapid ICAM-1 gene induction in the context of prior NF kappa B activation, without new activation of NF kappa B. In non-ischemic myocardium, ICAM-1 transcription begins hours after NF kappa B is activated. These findings support a role for NF kappa B in ICAM-1 induction in vivo, but suggest that other processes, such as oxygen-radical generation, may combine with NF kappa B to trigger an accelerated transcription of ICAM-1 following ischemia-reperfusion.

Effect of azithromycin on murine arteriosclerosis exacerbated by Chlamydia pneumoniae.

Chlamydia pneumoniae infection can exacerbate atherosclerosis in animals. To test the hypothesis that antibiotic therapy inhibits the atherogenic effects of C. pneumoniae infection, 10-week-old apolipoprotein E (ApoE) null mice were infected with C. pneumoniae or placebo, were treated for 2 weeks after infection with azithromycin or placebo, and were killed at 20 weeks of age. Infection did not affect the size of the aortic lesion, and antibiotic treatment had no effect. Another group of mice, 12-week-old ApoE mice, were infected with C. pneumoniae or placebo, were treated for 2 weeks after infection with azithromycin or placebo, and were killed at 26 weeks of age. C. pneumoniae infection increased the size of the lesion in infected mice, but azithromycin did not reduce the size of the aortic lesion in infected mice. Therefore, immediate therapy of acute infection may be necessary to prevent the proatherogenic effects of C. pneumoniae infection.

Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages.

Pulmonary inflammation and fibrosis are characterized by increased turnover and production of the extracellular matrix as well as an impairment of lung fibrinolytic activity. Although fragments of the extracellular matrix component hyaluronan induce macrophage production of inflammatory mediators, the effect of hyaluronan on the fibrinolytic mediators plasminogen activator inhibitor (PAI)-1 and urokinase-type plasminogen activator (uPA) is unknown. This study demonstrates that hyaluronan fragments augment steady-state mRNA, protein, and inhibitory activity of PAI-1 as well as diminish the baseline levels of uPA mRNA and inhibit uPA activity in an alveolar macrophage cell line. Hyaluronan fragments alter macrophage expression of PAI-1 and uPA at the level of gene transcription. Similarly, hyaluronan fragments augment PAI-1 and diminish uPA mRNA levels in freshly isolated inflammatory alveolar macrophages from bleomycin-treated rats. These data suggest that hyaluronan fragments influence alveolar macrophage expression of PAI-1 and uPA and may be a mechanism for regulating fibrinolytic activity during lung inflammation.

Superoxide regulation of endothelin-converting enzyme.

Reactive oxygen species (ROS) act as signaling molecules in the cardiovascular system, regulating cellular proliferation and migration. However, an excess of ROS can damage cells and alter endothelial cell function. We hypothesized that endogenous mechanisms protect the vasculature from excess levels of ROS. We now show that superoxide can inhibit endothelin-converting enzyme activity (ECE) and decrease endothelin-1 synthesis. Superoxide inhibits ECE but hydrogen peroxide and nitric oxide do not. Superoxide inhibits ECE by ejecting zinc from the enzyme, and the addition of exogenous zinc restores enzymatic activity. Superoxide may inhibit other zinc metalloproteinases by a similar mechanism and may thus play an important role in regulating the biology of blood vessels.

Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium.

Nitric oxide (NO) plays an important role in airway function, and endothelial NO synthase (eNOS) is expressed in airway epithelium. To determine the basis of cell-specific eNOS expression in airway epithelium, studies were performed in NCI-H441 human bronchiolar epithelial cells transfected with the human eNOS promoter fused to luciferase. Transfection with 1624 base pairs of sequence 5' to the initiation ATG (position -1624) yielded a 19-fold increase in promoter activity versus vector alone. No activity was found in lung fibroblasts, which do not express eNOS. 5' deletions from -1624 to -279 had modest effects on promoter activity in H441 cells. Further deletion to -248 reduced activity by 65%, and activity was lost with deletion to -79. Point mutations revealed that the GATA binding motif at -254 is mandatory for promoter activity and that the positive regulatory element between -248 and -79 is the Sp1 binding motif at -125. Electrophoretic mobility shift assays yielded two complexes with the GATA site and three with the Sp1 site. Immunodepletion with antiserum to GATA-2 prevented formation of the slowest migrating GATA complex, and antiserum to Sp1 supershifted the slowest migrating Sp1 complex. An electrophoretic mobility shift assay with H441 versus fibroblast nuclei revealed that the slowest migrating GATA complex is unique to airway epithelium. Thus, cell-specific eNOS expression in airway epithelium is dependent on the interaction of GATA-2 with the core eNOS promoter, and the proximal Sp1 binding site is also an important positive regulatory element.

Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo.

Reperfusion of ischemic tissue results in the generation of reactive oxygen species that contribute to tissue injury. The sources of reactive oxygen species in reperfused tissue are not fully characterized. We hypothesized that the small GTPase Rac1 mediates the oxidative burst in reperfused tissue and thereby contributes to reperfusion injury. In an in vivo model of mouse hepatic ischemia/reperfusion injury, recombinant adenoviral expression of a dominant negative Rac1 (Rac1N17) completely suppressed the ischemia/reperfusion-induced production of reactive oxygen species and lipid peroxides, activation of nuclear factor-kappa B, and resulted in a significant reduction of acute liver necrosis. Expression of Rac1N17 also suppressed ischemia/reperfusion-induced acute apoptosis. The protection offered by Rac1N17 was also evident in knockout mice deficient for the gp91phox component of the phagocyte NADPH oxidase. This work demonstrates the crucial role of a Rac1-regulated oxidase in mediating the production of injurious reactive oxygen species, which contribute to acute necrotic and apoptotic cell death induced by ischemia/reperfusion in vivo. Targeted inhibition of this oxidase, which is distinct from the phagocyte NADPH oxidase, should provide a new avenue for in vivo therapy aimed at protecting organs at risk from ischemia/reperfusion injury.-Ozaki, M., Deshpande, S. S., Angkeow, P., Bellan, J., Lowenstein, C. J., Dinauer, M. C., Goldschmidt-Clermont, P. J., Irani, K. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo.

Inducible nitric oxide synthase protection against coxsackievirus pancreatitis.

Coxsackievirus infection causes myocarditis and pancreatitis in humans. In certain strains of mice, Coxsackievirus causes a severe pancreatitis. We explored the role of NO in the host immune response to viral pancreatitis. Coxsackievirus replicates to higher titers in mice lacking NO synthase 2 (NOS2) than in wild-type mice, with particularly high viral titers and viral RNA levels in the pancreas. Mice lacking NOS have a severe, necrotizing pancreatitis, with elevated pancreatic enzymes in the blood and necrotic acinar cells. Lack of NOS2 leads to a rapid increase in the mortality of infected mice. Thus, NOS2 is a critical component in the immune response to Coxsackievirus infection.

C6 produced by macrophages contributes to cardiac allograft rejection.

The terminal components of complement C5b-C9 can cause significant injury to cardiac allografts. Using C6-deficient rats, we have found that the rejection of major histocompatibility (MHC) class I-incompatible PVG.R8 (RT1.A(a)B(u)) cardiac allografts by PVG.1U (RT1.A(u)B(u)) recipients is particularly dependent on C6. This model was selected to determine whether tissue injury results from C6 produced by macrophages, which are a conspicuous component of infiltrates in rejecting transplants. We demonstrated that high levels of C6 mRNA are expressed in isolated populations of macrophages. The relevance of macrophage-produced C6 to cardiac allograft injury was investigated by transplanting hearts from PVG. R8 (C6-) donors to PVG.1U (C6-) rats which had been reconstituted with bone marrow from PVG.1U (C6+) rats as the sole source of C6. Hearts grafted to hosts after C6 reconstitution by bone marrow transplantation underwent rejection characterized by deposition of IgG and complement on the vascular endothelium together with extensive intravascular aggregates of P-selectin-positive platelets. At the time of acute rejection, the cardiac allografts contained extensive perivascular and interstitial macrophage infiltrates. RT-PCR and in situ hybridization demonstrated high levels of C6 mRNA in the macrophage-laden transplants. C6 protein levels were also increased in the circulation during rejection. To determine the relative contribution to cardiac allograft rejection of the low levels of circulating C6 produced systemically by macrophages, C6 containing serum was passively transferred to PVG.1U (C6-) recipients of PVG.R8 (C6-) hearts. This reconstituted the C6 levels to about 3 to 6% of normal values, but failed to induce allograft rejection. In control PVG.1U (C6-) recipients that were reconstituted with bone marrow from PVG.1U (C6-) donors, C6 levels remained undetectable and PVG.R8 cardiac allografts were not rejected. These results indicate that C6 produced by macrophages can cause significant tissue damage.

An inducible nitric-oxide synthase (NOS)-associated protein inhibits NOS dimerization and activity.

A variety of transcriptional and post-transcriptional mechanisms regulate the expression of the inducible nitric-oxide synthase (iNOS, or NOS2). Although neurons and endothelial cells express proteins that interact with and inhibit neuronal NOS and endothelial NOS, macrophage proteins that inhibit NOS2 have not been identified. We show that murine macrophages express a 110-kDa protein that interacts with NOS2, which we call NOS-associated protein-110 kDa (NAP110). NAP110 directly interacts with the amino terminus of NOS2, and inhibits NOS catalytic activity by preventing formation of NOS2 homodimers. Expression of NAP110 may be a mechanism by which macrophages expressing NOS2 protect themselves from cytotoxic levels of nitric oxide.