Linkage of Emergency Medical Services and Hospital Data: A Necessary Precursor to Improve Understanding of Outcomes of Prehospital Care.

Objective: Linking emergency medical services (EMS) data to hospital outcomes is important for quality assurance and research initiatives. However, non-linkage due to missing or incomplete patient information may increase the risk of bias and distort findings. The purpose of this study was to explore if an optimization strategy, in addition to an existing linkage process, improved the linkage rate and reduced selection and information bias. Methods: 4,150 transported patients in a metropolitan EMS system in Alberta, Canada from 2016/17 were linked to two Emergency Department (ED) databases by a standard strategy using a unique health care number, date/time of ED arrival, and hospital name. An optimized strategy added additional linkage steps incorporating last name, year of birth, and a manual search. The strategies were compared to assess the rate of linkage, and to describe event and patient-level characteristics of unlinked records. Results: The standard strategy resulted in 3,650 out of 4,150 (88.0%) linked records (95% CI 86.9%-88.9%). Of the 500 non-linked records, an additional 381 were linked by the optimized strategy (n = 4,031/4,150 [97.1%; 95% CI: 96.6%-97.6%]). There were no false positive linkages. The highest linkage failure was in 25 to 34 year-old patients (n = 93/478, 19.5%), males (n = 236/1975, 12.0%), Echo level events (n = 15/77, 19.5%), and emergency transport (45/231, 19.5%). The optimized strategy improved linkage in these groups by 68.8% (64/93), 79.2% (187/236), 40.0% (6/15), and 51.1% (23/45) respectively. For dispatch card, the highest linkage failure occurred in Card 24-Pregnancy/Childbirth/Miscarriage (n = 30/44, 68.2%), Card 27-Stab/Gunshot/Penetrating Trauma (n = 6/17, 35.3%), and Card 9-Cardiac/Respiratory Arrest/Death (n = 12/46, 26.1%). The optimized strategy improved linkage by 10.0% (3/30), 83.3% (5/6), and 41.7% (5/12) respectively. For the 119 unlinked records, 71 (59.7%) had sufficient information for linkage, but no appropriately matching records could be found. Conclusion: An optimized sequential deterministic strategy linking EMS data to ED outcomes improved the linkage rate without increasing the number of false positive links, and reduced the potential for bias. Even with adequate information, some records were not linked to their ED visit. This study underscores the importance of understanding how data are linked to hospital outcomes in EMS research and the potential for bias.

Venous Thromboembolism Prophylaxis in Neurocritical Care Patients: Are Current Practices, Best Practices?

BACKGROUND/OBJECTIVES: Venous thromboembolism (VTE) is a leading cause of preventable, in-hospital deaths; critically ill patients have a higher risk. Effective and efficient strategies to prevent VTE exist; however, neurocritical care patients present unique challenges due to competing risk of bleeding. The objective of this study was to examine current VTE prophylaxis practices among neurocritical care patients, concordance with guideline-recommended care, and the association with clinical outcomes. METHODS: This retrospective cohort study of patients admitted to ten adult, medical-surgical and neurological intensive care units (ICUs) in nine hospitals between 2014 and 2017 using administrative and clinical data. Neurocritical care patients were classified based on the primary admission diagnosis. Concordance with guideline-recommended care was evaluated using recommendations from recent guidelines. RESULTS: 20.0% of 23,191 patients were classified as neurocritical care. Among neurocritical care patients, pharmacological VTE prophylaxis was administered on 60.9% of all ICU days, mechanical VTE prophylaxis on 46.9%, and no VTE prophylaxis on 12.2% of all ICU days. Type of VTE prophylaxis was associated with sex, neurological diagnosis, and invasive neurological monitoring. Fifty-six percentage of ICU days were guideline concordant but concordance varied by recommendation (range 6-100%) and by type of VTE prophylaxis recommended (p = 0.05); among patients where guidelines recommended use of pharmacologic prophylaxis, care was concordant 26.6% of ICU days, whereas for mechanical prophylaxis it was concordant 80.5% of ICU days. There was an overall improvement in guideline concordance on 2.3% of ICU days after the publication of the Society of Neurocritical Care guideline (p = 0.005). CONCLUSIONS: Neurocritical care patients commonly receive mechanical VTE prophylaxis despite guidelines recommending the use of pharmacological VTE prophylaxis. Our findings suggest uncertainty around best VTE prophylaxis practices for neurocritical care patients remains.

The association between paramedic service system hospital offload time and response time.

OBJECTIVE: To address an important care issue in Canada, we tested the association between paramedic system hospital offload and response time, while considering the impact of other system-level factors. METHODS: Data from Calgary, Alberta (2014-2017), included median offload (exposure) and response (outcome) time aggregated by hour, with covariates paramedic system episodes of care-dispatch and arrival of a response unit-and hospital transport arrivals (collectively called volume), time of day, and season. Analyses used linear regression and modified Poisson models. RESULTS: 301,105 EMS episodes of care over 26,193 1-h periods were included. For any given 1-h period, the median (IQR) across all episodes of care for offload time, response time, episodes of care, and hospital transport arrivals were 55.3 (45.7, 66.3) min, 8.6 (7.6, 9.8) min, 12 (8, 16) episodes, and 8 (5, 10) hospital arrivals, respectively. Multivariable modelling revealed a complex association differing over levels of exposure and covariates, requiring description using "light stress" and "heavy stress" system scenarios. The light scenario was defined as median offload of 30 min and volume < 10th percentile (six episodes and four hospital arrivals), in the summer, and the heavy scenario as median offload of 90 min and volume > 90th percentile (17 episodes and 13 hospital arrivals), in the winter. An increase is reported in minutes:seconds for median hourly response time between scenarios by time of day: 1:04-4:16 (0000-0559 h.), 0:42-2:05 (0600-1159 h.), 0:57-3:01 (1200-1759 h.), and 0:18-2:21 (1800-2359 h.). CONCLUSIONS: Increasing offload is associated with increased response time; however the relationship is complex, with a greater impact on response time noted in select situations such as high volume in the winter. These observations illustrate the interdependence of paramedic, ED, and inpatient systems and provide high-yield targets for polices to mitigate the risk to community availability of paramedic resources at times of high offload delay/system stress.

ABSTRAIT: OBJECTIF: Afin de régler un problème important de soins au Canada, nous avons testé l'association entre le déchargement du système paramédical et le temps de réponse, tout en tenant compte de l'incidence d'autres facteurs au niveau du système. MéTHODES: Les données de Calgary, en Alberta (2014-2017) incluent le temps médian de déchargement (exposition) et de réponse (résultat) agrégé par heure, qui s'agit co-variables épisodes de soins du système paramédical - répartition et arrivée d'une unité d'intervention - et arrivées de transport hospitalier (collectivement appelé volume), l'heure et la saison. Les analyses ont utilisé la régression linéaire et des modèles de Poisson modifiés. RéSULTATS: 301105 épisodes de soins médicaux d'urgence sur 26193 périodes d'une heure ont été inclus. Pour une période d'une heure donnée, la médiane (QRI) pour tous les épisodes de soins pour le temps de déchargement, le temps de réponse, les épisodes de soins et les arrivées par transport à l'hôpital était de 55,3 (45,7, 66,3) minutes, 8,6 (7,6, 9,8) minutes, 12 (8, 16) épisodes et 8 (5, 10) arrivées à l'hôpital, respectivement. La modélisation multi-variable a révélé une association complexe qui varie selon les niveaux d'exposition et les co-variables, et qui nécessite une description à l'aide de scénarios de systèmes de « stress léger ¼ et de « stress lourd ¼. Le scénario léger a été défini comme un déchargement médian de 30 minutes, volume inférieur au 10e percentile (six épisodes et quatre arrivées à l'hôpital), pendant l'été. Le scénario lourd comme déchargement médian de 90 minutes, volume > 90e percentile (17 épisodes et 13 arrivées à l'hôpital), en hiver. Une augmentation est rapportée en minutes: secondes pour le temps de réponse horaire médian entre des scénarios par heure du jour : 1:04-4:16 (0000-0559 h.), 0:42-2:05 (0600-1159 h.), 0:57-3:01 (1200-1759 h.), et 0:18-2:21 (1800-2359 h.). CONCLUSIONS: L'augmentation du déchargement est associée à une augmentation du temps de réponse, mais la relation est complexe, avec un impact plus important sur le temps de réponse noté dans certaines situations, comme un volume élevé en hiver. Ces observations illustrent l'interdépendance des systèmes paramédicaux, des services d'urgence et des services aux patients hospitalisés et fournissent des cibles à haut rendement pour les politiques afin d'atténuer le risque pour la disponibilité des ressources paramédicales dans la collectivité en période de retard élevé ou de stress systémique.

Culturing rate and the surveillance of bloodstream infections: a population-based assessment.

OBJECTIVES: Diagnosis of a bloodstream infection (BSI) requires a positive blood culture. However, low culturing rates will underestimate the true incidence of BSI and high rates may increase the risk of false-positive results. We sought to investigate the relationship between culturing rates and the incidence of BSI at the population level. METHODS: Population-based surveillance was conducted in the western interior of British Columbia, Canada, between 1 April 2010 and 31 March 2017. RESULTS: Among 60 243 blood culture sets drawn, 5591 isolates were obtained, of which 2303 were incident, 1929 were repeat positive and 1359 were contaminants. Overall annual rates of culturing, incident, repeat positive and contaminant isolates were 4832, 185, 155 and 109 per 100 000 population, respectively. During the 84-month study, there was an increase in the culturing rate that reached a plateau at 48 months (5403 cultures per 100 000 per year). The rate of both repeat isolates and contaminants increased linearly with an increasing culturing rate. However, the incident isolate rate reached an inflection point at a rate of approximately 5550 per 100 000 annually, at which point the increase in incident isolates per culture sample was diminished. At a culturing rate above 6123 per 100 000 per year, the number of repeat isolates exceeded that of incident isolates. CONCLUSIONS: The determined incidence of BSI will increase with increased culturing in a population. Further studies are needed to explore optimal BSI culturing rates in other populations.

Characterization of the phantom material virtual water in high-energy photon and electron beams.

The material Virtual Water has been characterized in photon and electron beams. Range-scaling factors and fluence correction factors were obtained, the latter with an uncertainty of around 0.2%. This level of uncertainty means that it may be possible to perform dosimetry in a solid phantom with an accuracy approaching that of measurements in water. Two formulations of Virtual Water were investigated with nominally the same elemental composition but differing densities. For photon beams neither formulation showed exact water equivalence-the water/Virtual Water dose ratio varied with the depth of measurement with a difference of over 1% at 10 cm depth. However, by using a density (range) scaling factor very good agreement (<0.2%) between water and Virtual Water at all depths was obtained. In the case of electron beams a range-scaling factor was also required to match the shapes of the depth dose curves in water and Virtual Water. However, there remained a difference in the measured fluence in the two phantoms after this scaling factor had been applied. For measurements around the peak of the depth-dose curve and the reference depth this difference showed some small energy dependence but was in the range 0.1%-0.4%. Perturbation measurements have indicated that small slabs of material upstream of a detector have a small (<0.1% effect) on the chamber reading but material behind the detector can have a larger effect. This has consequences for the design of experiments and in the comparison of measurements and Monte Carlo-derived values.

Pre-irradiation effects on ionization chambers used in radiation therapy.

Dosimetry protocols recommend that ionization chambers used in radiation therapy be pre-irradiated until they 'settle', i.e., until a stable reading is obtained. Previous reports have claimed that a lack of pre-irradiation could result in errors up to several per cent. Recently, data collected for a large number of commonly used ion chambers at the Institute for National Measurement Standards, NRC, Canada, have been collated and analysed, with additional data contributed by the National Physical Laboratory, UK. With this data set, it was possible to relate patterns of ion chamber behaviour to design parameters. While several mechanisms seem to contribute to this behaviour, the most obvious correlations implicate the type of insulator surrounding the central collector electrode, the extent of collector electrode shielding and possibly the area of the insulator exposed at the base of the active air volume. The results show that ion chambers with electrode connections guarded up to the active air volume settle quickly (approximately 9 min) and the change in response is small (less than approximately 0.2%). For ion chambers where the guard connection surrounding the central collector does not extend up to the active air volume, settling times of 15-20 min and an associated change in response of up to 1% are typical. For some models of ion chambers, the irradiation rate may also play a role in settling behaviour. Settling times for the ion chambers studied here were found to be independent of beam quality.

Increased monocyte Fc-dependent chemiluminescence in renal transplant patients.

A luminol-enhanced chemiluminescence (CL) assay was used to study the microbicidal potential of phagocytic cells and the opsonic properties of serum in renal transplant recipients. Thirty-four patients receiving maintenance immunosuppression with prednisone and either cyclosporine or azathioprine and 35 normal controls were studied. Polymorphonuclear leukocytes (PMN) and monocytes were stimulated at the Fc receptor with heat-aggregated IgG (HAIgG) or immunoglobulin-treated zymosan (ITZ), and at the C3b receptor with serum-treated zymosan. Serum opsonic activity was determined by incubating zymosan with normal or patient serum and stimulating the CL response of normal phagocytes. We found that the Fc and C3b-dependent CL of PMN, the C3b-dependent CL of monocytes, and the opsonic properties of serum were identical in transplant recipients and normal controls. In contrast, the Fc-dependent CL of monocytes in renal transplant patients was 3 times greater than normal when stimulated with either soluble (HAIgG) or particulate (ITZ) ligands. These data suggest that some components of the host immune system are not affected by maintenance immunosuppressive medication in renal transplant recipients. The mechanisms and significance of the increased Fc-receptor-dependent CL observed in monocytes of renal transplant patients remain to be determined.

Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis.

The human ovarian surface epithelium (HOSE) is a common site of gynaecological disease including endometriosis and ovarian cancer, probably due to serial injury-repair events associated with successive ovulations. To comprehend the importance of steroid signalling in the regulation of the HOSE, we used a custom microarray to catalogue the expression of over 250 genes involved in the synthesis and reception of steroid hormones, sterols and retinoids. The array included a subset of non-steroidogenic genes commonly involved in pro-/anti-inflammatory signalling. HOSE cells donated by five patients undergoing surgery for non-malignant gynaecological conditions were cultured for 48 h in the presence and absence of 500 pg/ml interleukin-1alpha (IL-1alpha). Total RNA was reverse-transcribed into biotin-labelled cDNA, which was hybridised to the array and visualised by gold-particle resonance light scattering and charge-coupled device (CCD) camera detection. Results for selected genes were verified by quantitative reverse-transcription PCR. In five out of five cases, untreated HOSE cells expressed genes encoding enzymes required for de novo biosynthesis of cholesterol from acetate and subsequent formation of C21-pregnane and C19-androstane steroids. Consistent with the inability of HOSE cells to synthesise glucocorticoids, oestrogens or 5alpha-reduced androgens de novo, CYP21, CYP19 and 5alpha-reductase were not detected. The only steroidogenic gene significantly up-regulated by IL-1alpha was 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Other cytokine-induced genes were IL-6, IL-8, nuclear factor kappaB (NFkappaB) inhibitor alpha, metallothionein-IIA and lysyl oxidase: inflammation-associated genes that respond to glucocorticoids. The only steroidogenic gene significantly suppressed by IL-1alpha was 3betaHSD1. Other genes suppressed by IL-1alpha were aldehyde dehydrogenase (ALDH) 1, ALDH 10, gonadotrophin hormone-releasing hormone receptor, peroxisome proliferation-activated receptor-binding protein (PPAR-bp) and nuclear receptor subfamily 2 group F member 2. These results define a steroidogenic phenotype of cultured HOSE cells and provide a limited expression profile for genes with associated signalling functions. IL-1alpha co-ordinately induces 11betaHSD1 and a panel of glucocorticoid-regulated, inflammation-associated genes in HOSE cells, providing further evidence that cortisol generated by 11betaHSD1 could participate in the local resolution of inflammation associated with ovulation.

Effect of haemin limitation on the cytochrome complement and glucose metabolism of non-typable Haemophilus influenzae.

Haemophilus influenzae grown to exponential phase or stationary phase in medium with a low initial concentration of haemin (0.25 microgram/ml) was virtually devoid of cytochromes. Compared with bacteria grown in the presence of excess haemin (10 micrograms/ml), the haemin-limited organisms failed to respire formate and succinate and, generally, the respiratory rates with other substrates were reduced. However, growth rates were not affected by the haemin supply. Haemin-limited growth was associated with a reduced efficiency of glucose utilisation, in terms of glucose growth yields, and affected the net levels of excreted organic acids. Haemin limitation resulted in reduced acetate and increased succinate accumulation in the culture medium and the novel presence of D-lactate. These results indicate that, in contrast to the phenotype expressed in vitro during conventional cultivation of H. influenzae, the haemin-limited phenotype, which may be expressed in vivo, is characterised by a lack of cytochromes and a shift towards a more anaerobic type of metabolism.

Phenotypic variation in the outer membrane protein composition of Actinobacillus (Haemophilus) pleuropneumoniae: non-specific effect of exogenous pyridine nucleotide supply.

Actinobacillus pleuropneumoniae, grown in batch culture, was provided with pyridine nucleotides at concentrations that limited the final growth yield (pyridine nucleotide-deficient cultures) or did not determine the final extent of growth (pyridine nucleotide-sufficient cultures). Sarkosyl-extracted outer membranes from stationary phase, pyridine nucleotide-sufficient organisms contained 23,000 Mr and 43,000 Mr polypeptides that were absent (23,000 Mr) or barely detectable (43,000 Mr) in outer membranes from stationary phase, pyridine nucleotide-deficient organisms or exponential phase organisms. When growth ceased due to exhaustion of pyridine nucleotide, the ratio of the major outer membrane polypeptides (31,000, 38,000 and 69,000 Mr) was altered, becoming more like the ratio found with exponential phase organisms. Similar results were obtained when growth ceased due to glucose exhaustion at low biomass concentrations demonstrating that diverse nutrient deprivations can induce similar changes in outer membrane protein profile. All of these polypeptides were recognized by porcine immune sera indicating their production by A. pleuropneumoniae growing in vivo.

Comparative study of iron acquisition by biotype 1 and biotype 2 strains of Actinobacillus pleuropneumoniae.

Four strains of the swine pathogen, Actinobacillus pleuropneumoniae, namely, the type strain (ATCC 27088; biotype 1), the 'reference' strain of biotype 2 (Bertschinger 2008/76), and two additional biotype 1 strains, strain BC181, which is less virulent than the type strain, and strain K17, which was isolated from a lamb, were investigated with respect to iron acquisition. All strains produced iron-repressible outer membrane proteins. However, only the type and biotype 2 strains could acquire iron from porcine transferrin and no organism could utilize human, bovine or ovine transferrin, or ovine or porcine lactoferrin; haemoglobin supported good growth of all strains except strain K17. In all cases, iron acquisition from transferrin and haemoglobin required direct contact between the organisms and the proteins indicating the existence of specific receptors. An affinity isolation technique, using biotinylated porcine transferrin plus streptavidin-agarose, allowed the isolation of the following polypeptides from total membranes of organisms grown under iron-restricted conditions: 99 kDa and 64 kDa from ATCC 27088; 93 kDa from Bertschinger 2008/76; 95 kDa (trace amounts) and 60 kDa from BC181; none from K17. These results indicate that the 93-99 kDa polypeptides are involved in the acquisition of iron from porcine transferrin and that the inability of strain K17 to use transferrin as an iron source is due, probably, to the lack of, or a defect in, an analogous component.

Effects of Plagiorchis elegans (Trematoda: Plagiorchiidae) infection on the carbohydrate metabolism of fourth instar Aedes aegypti (Diptera: Culicidae).

Infection of fourth-instar Aedes aegypti (L.) with the entomopathogenic digenean Plagiorchis elegans (Rudolphi) alters the carbohydrate metabolism of the insect. Within 24 h of cercarial penetration, total body extracts of infected fourth instars exhibited decreased trehalase activity, increased trehalose-6-phosphatase activity, and a concomitant accumulation of trehalose when compared with uninfected larvae. The amounts of glucose, glycogen and lipids, and the activity of glycogen phosphorylase a were similar in extracts of infected and control larvae. The predominant fatty acids, in both control and infected larvae, were C 18:0, C 18:1, and C 18:3. There were no significant differences in the types or proportions of fatty acids found in control and infected larvae. Parasitic infection is discussed in terms of impaired trehalose metabolism.

Tryptone-yeast extract broth as a culture medium for Haemophilus pleuropneumoniae and Haemophilus parasuis to be used as challenge inocula.

Haemophilus pleuropneumoniae and Haemophilus parasuis were grown in a liquid medium containing tryptone and yeast extract. Whereas culture turbidity during exponential growth of either organism was proportional to the number of viable cells, continued incubation of stationary phase cultures was accompanied by a dramatic decrease in viability with no corresponding decrease in culture turbidity. It is concluded that the medium described should prove useful for the growth of porcine haemophili for use in experimental infections provided the stage of growth is given due consideration.

When times get tough, what happens to TQM? Case study.

When Mueller Chemical Company's biggest customer, Ameriton, demanded that MCC install a total quality management system five years ago, the effort seemed worth it. Morale improved dramatically at the German company, as did quality and productivity. But now, in this fictional case study, Ameriton has gone bankrupt. As a result, MCC has had to cut its work force, and senior managers are meeting to decide whether TQM should be part of the downsized MCC. Horst Koblitz, director of TQM, and Division Manager Eva Stichen both vote yes. Stichen's division, which never supplied Ameriton, has turned its process-control system into the company's best thanks to TQM. The division is more cost-efficient, product defects are nearly nonexistent, and its safety record is spotless. As Koblitz notes, Ameriton's failure is no reason to abandon all that MCC has built. Furthermore, shareholders and customers would think that MCC was panicking. MCC just needs to tailor its TQM program to a smaller organization. But CFO Georg Becker doesn't think MCC has the time or resources for fine-tuning. And as he sees it, that might be just as well. The distractions that came with TQM took MCC away from its goal of becoming the chemicals market leader in Europe. While the company organized teams, developed measurement systems, and filled out quality reports, its competitors took away much of the market share MCC was after. TQM was a good long-term approach, but it didn't come with a plan for MCC's current situation. And CEO and Chairman Dieter Mueller won't compromise; TQM must either stay or go.(ABSTRACT TRUNCATED AT 250 WORDS)

The case of the hidden harassment.

The past year has seen a growing public awareness of sexual harassment in the workplace. The question of what constitutes sexual harassment and how to recognize it has been debated in the news, the courts, and Congress. This HBR case study is less concerned with defining it than with examining what a manager should do about it. When Filmore Trust manager Jerry Tarkwell found out one of his employees was being sexually harassed on the job, he thought he knew exactly what to do. Following company policy, he immediately notified the bank's equal employment office. Then he called Jill McNair, the employee being harassed. Her response dumbfounded him. "You had no right to call EEO before talking to me," McNair said angrily. Do you have any idea what could happen to me and to my career if people find out about this?" Tarkwell didn't understand; McNair wasn't to blame. He believed the only person who should be worried was the harasser. Tarkwell tried to spell out the procedure for her. "All you have to do is write a letter and ..." McNair cut him off. "If this gets investigated by EEO, everyone in the building could be questioned. I'll probably get transferred, and then I won't have a chance at promotion. And who'd want to work with me? Every man in the company would be afraid I'd report him if he so much as opened a door for me."(ABSTRACT TRUNCATED AT 250 WORDS)

Cost and outcomes of nosocomial bloodstream infections complicating major traumatic injury.

The objective of this study was to assess the incidence, outcomes, and costs of trauma-related nosocomial bloodstream infection (BSI). This was a 3:1 matched cohort study in patients with severe trauma [defined by an injury severity score (ISS)≥12] admitted to adult or paediatric regional trauma centres over a four-year period. Case patients with nosocomial BSI were matched to controls without a BSI based on predetermined criteria. Outcomes of interest included mortality, length of stay (LOS), and cost attributable to nosocomial BSI. Fifty-seven cases were identified, among whom 51 were successfully matched to three controls. The mean ISS among cases was 30.3, and Staphylococcus aureus was the most commonly isolated pathogen (27%). Being a case was accompanied by a 27% relative increase in the hospital LOS (P=0.02). The odds ratio for 30 day mortality associated with being a case was 5.8 (95% confidence interval (CI): 1.1-30.8; P=0.04). Among survivor-matched groups, being a case was associated with 53% relative increase in the geometric mean total hospital cost [$97,993 (95% CI: $70,143-136,899) for cases and $62,297 (95% CI: $52,155-74,411) for controls, P<0.0001]. This is the first study to show that nosocomial BSI complicating severe trauma is associated with a substantial increase in hospital LOS and in total hospital cost. Our data provide justification to support efforts to reduce the adverse impact of BSI in trauma victims.

Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas.

Ovulation is believed to contribute to the development of ovarian cancers that derive from the ovarian surface epithelium (OSE). The process of ovulation is synonymous with inflammation and inflammatory cytokines such as interleukin-1alpha (IL-1alpha) have recently been shown to induce both inflammatory and anti-inflammatory responses in human OSE (HOSE) cells. In this study we directly compared levels of IL-1alpha-induced gene expression by analysing the levels of 11beta-hydroxysteroid dehydrogenase (11betaHSD) types 1 (11betaHSD-1) and 2 (11betaHSD-2), cyclooxygenase-2 (COX-2), IL-1 receptor (IL-1R) and glucocorticoid receptor alpha (GRalpha) mRNA between normal HOSE cells and cell lines derived from poorly differentiated (SKOV-3, BG-1, PEO-4) and well-differentiated (PEO-14) ovarian adenocarcinoma. In HOSE cell cultures, and to a lesser extent PEO-14 cells, the basal mRNA levels of COX-2 and 11betaHSD-1 were relatively high and further shown to be induced in response to IL-1alpha (for HOSE cells; >20-fold, P<0.05 and PEO-14 cells; >3fold, P<0.05). However, whereas HOSE cells expressed a low level of 11betaHSD-2 mRNA that was only mildly responsive to IL-1alpha (1.3-fold, P<0.001), all cell lines exhibited a higher basal level of 11betaHSD-2 mRNA that was in some cases further stimulated in PEO-4 cells (five-fold; P<0.05) or suppressed in SKOV-3 cells (two-fold; P<0.01) in response to IL-1alpha. All cells tested expressed IL-1R and, with the exception of BG-1, GRalpha. These results indicate that cell lines derived from ovarian cancers have lost the ability to respond normally to inflammatory cytokines such as IL-1alpha. The finding that normal OSE cells, in contrast to cell lines derived from patients with ovarian adenocarcinoma, abundantly express 11betaHSD-1 mRNA but are essentially devoid of 11betaHSD-2 mRNA supports the concept that the pattern of 11betaHSD isoform gene expression is a defining feature of neoplastic cellular transformation, which might have particular relevance to the ovary.