Regional disparities in incidence, handling and outcomes of patients with symptomatic and ruptured abdominal aortic aneurysms in Norway.

OBJECTIVES: To study incidence, handling and outcome of patients hospitalised with symptomatic and ruptured abdominal aortic aneurysm in Norway. DESIGN, MATERIAL AND METHODS: Retrospective study of 1291 patients, between January 2008 and August 2010 using the National Patient Registry and a regional vascular surgery registry. We applied a stepwise logistic regression model to detect differences in regional in-hospital mortality. RESULTS: 385/711 (54%) patients hospitalised for aneurysm rupture, rAAA (ICD-10: I71.3), died. The odds of dying varied with a factor 2.3 between the extreme regions. 475/711 (67%) underwent repair, 323 survived, giving an in-hospital mortality rate of 32% after surgery. Older patients were significantly less likely to be transported for surgery. The overall incidence for patients aged >50 was 16.6 rAAA per 100,000 person-years. There was remarkable variation across counties with rates between 7.7 and 26.8. A total of 580 patients were hospitalised with suspected symptomatic aneurysms (ICD-10:I71.4, acute admission); 224 (39%) were treated with aneurysm repair, 356 (61%) were discharged without repair without a significant difference across health regions. CONCLUSIONS: For rAAA, we found substantial geographical variations in incidence, surgery and patient outcome. These results highlight the need for increased awareness about the condition and suggest ways to improve care trajectories to reduce delay to surgery, thereby minimising rupture mortality.

Multiple phospholipase A2 enzymes participate in the inflammatory process in osteoarthritic cartilage.

OBJECTIVE: The aim of this study was to determine the involvement of pro-inflammatory phospholipase A2 (PLA2) enzymes in human chondrocytes from patients with osteoarthritis (OA). METHODS: PLA2 involvement in OA chondrocytes was analysed by (a) arachidonic acid (AA) and oleic acid release, (b) PLA2 mRNA analysis, and (c) prostaglandin E2 (PGE2) production in cultured OA chondrocytes in response to various cytokines and platelet activating factor (PAF). RESULTS: Pro-inflammatory cytokines and PAF stimulation led to increased AA release, interleukin (IL)-1ß and tumour necrosis factor (TNF) being the strongest inducers. The pattern of oleic acid release was similar to but less prominent than AA release, suggesting that predominantly arachidonyl selective enzymes were activated. IL-1ß, TNF, IL-6, and IL-8 upregulated secretory group IIA, IID, and V phospholipase A2 (sPLA2-IIA, -IID, -V) and cytosolic group IVA phospholipase A2 (cPLA2-IVA) expression, where induction of chondrocyte sPLA2-IID is a novel finding. Furthermore, IL-1ß, TNF, and IL-6 also induced COX2 expression. PAF induced expression of group IIA, IID and IVA PLA2, and COX2. In line with its anti-inflammatory properties, IL-4 was unable to induce either AA release or expression of PLA2s or COX2. IL-1ß and TNF strongly increased PGE2 production, with IL-1ß as the most prominent inducer. CONCLUSION: Multiple PLA2 isoforms are expressed and influenced by pro-inflammatory stimuli in OA chondrocytes. Hence, several PLA2 enzymes may contribute to chondrocyte function by their upregulation and activation, and increased AA release and PGE2 production may therefore be important effectors in OA pathophysiology. PLA2 enzymes and cPLA2-IVA in particular are thus possible therapeutic targets in OA.

Transplantation of alginate microcapsules: generation of antibodies against alginates and encapsulated porcine islet-like cell clusters.

BACKGROUND: Microencapsulation of islets of Langherhans in alginate poly-L-lysine capsules provides an effective protection against cell-mediated immune destruction, and ideally should allow the transplantation of islets in the absence of immunosuppression. It has previously been suggested that alginate rich in mannuronic acid (high M) is more immunogenic than alginate rich in guluronic acid (high G). The ability of these alginates to induce an antibody response in the recipient or act as an adjuvant to antibody responses against antigens leaked from the capsule was investigated in the present study. METHODS: Empty capsules made from these different types of alginate were transplanted intraperitoneally to Wistar rats or Balb/c mice. In addition, some animals were also injected with bovine serum albumin to assess the ability of the alginates to act as an adjuvant to this antigen. Antibody responses to intraperitoneally transplanted free and microencapsulated fetal porcine islet like cell clusters (ICC) were also evaluated, in animals treated with or without cyclosporine. RESULTS: Antibodies against high M-alginate capsules were detected in the sera of mice transplanted with this capsule type. However, this response was not seen after the transplantation of high G capsules. When Wistar rats were used as recipients, no antibody responses were detected against any type of alginate capsules. Neither type of capsule acted as an adjuvant. Antibodies against ICC were present, in rats transplanted with both nonencapsulated and encapsulated ICCs. Administration of cyclosporine could abolish this production of antibodies against ICC. CONCLUSIONS: High G-alginate capsules are less immunogenic than high M capsules. Because encapsulation did not protect against the generation of antibodies against ICC, it can be assumed that antigen leakage from the capsules occurs, as no evidence was found for capsules breaking in vivo.

Doctors' use of electronic medical records systems in hospitals: cross sectional survey.

OBJECTIVES: To compare the use of three electronic medical records systems by doctors in Norwegian hospitals for general clinical tasks. DESIGN: Cross sectional questionnaire survey. Semistructured telephone interviews with key staff in information technology in each hospital for details of local implementation of the systems. SETTING: 32 hospital units in 19 Norwegian hospitals with electronic medical records systems. PARTICIPANTS: 227 (72%) of 314 hospital doctors responded, equally distributed between the three electronic medical records systems. MAIN OUTCOME MEASURES: Proportion of respondents who used the electronic system, calculated for each of 23 tasks; difference in proportions of users of different systems when functionality of systems was similar. RESULTS: Most tasks listed in the questionnaire (15/23) were generally covered with implemented functions in the electronic medical records systems. However, the systems were used for only 2-7 of the tasks, mainly associated with reading patient data. Respondents showed significant differences in frequency of use of the different systems for four tasks for which the systems offered equivalent functionality. The respondents scored highly in computer literacy (72.2/100), and computer use showed no correlation with respondents' age, sex, or work position. User satisfaction scores were generally positive (67.2/100), with some difference between the systems. CONCLUSIONS: Doctors used electronic medical records systems for far fewer tasks than the systems supported.

Diffusion of Electronic Health Records and electronic communication in Norway.

OBJECTIVE: To assess the diffusion of Electronic Health Record (EHR) systems over time in Norwegian health care. METHODS: This study was based on a retrospective cross-sectional questionnaire survey. Questionnaires for three groups of responders were based on two validated questionnaires from prior studies, which were further customized through workshops. The questionnaires were sent to a random sample of 180 municipalities and 150 general practices in all 26 hospitals in Norway. RESULTS: The diffusion curves for EHR systems from 1980 to 2008 were established and analyzed. The most striking finding was the length of time from the availability of the first adequate EHR systems until full coverage was achieved in general practice and in hospitals. Diffusion of EHRs into nursing homes and maternal and child health centers started ten years later, and the diffusion for these centers has also been slow. In general practice the diffusion seems to follow the classical s-curve of diffusion. Costs and the increasing complexity of EHR systems were regarded by respondents as the most important challenges and concerns for the future. Resistance among health personnel was seen only as a small problem. CONCLUSION: National strategic processes account for the slow diffusion and complexity of EHR systems in the health sector.

Doctors' concerns of PDAs in the ward round situation. Lessons from a formative simulation study.

BACKGROUND: Healthcare professionals in hospital care increasingly use small-screen handheld computers. Studies that have investigated doctors' concerns about handheld usage have mainly focused on technical, organizational and performance issues. Very few have looked at the effects of Personal Digital Assistants (PDAs) on the interaction between physician and patient. OBJECTIVE: The aim of this study was to explore the effects of PDA usage on the physicians' prescription work, their concerns about using it in point-of-care situations, and the effects on the patient-physician dialog. METHODS: We used a qualitative and comparative approach where 14 physicians each carried out four simulated ward rounds in which they modified the medication of patient actors using a paper-based medical chart and three versions of a PDA-based system. We analyzed ward round video recordings, semi-structured interviews with the doctors, and focus group using approaches based on ethnomethodology and grounded theory. RESULTS: Physicians used PDA and paper differently. Physicians' actions, as well as their non-verbal communication, were less transparent and clear for the patient when using a PDA. Doctors were worried about distractions from the handheld device and about a negative impact on the physician-patient conversation. In general, physicians were more comfortable with paper, but preferred PDA because it offered an undo function and reduced the need to memorize drug names and dosages by providing concrete alternatives in the user interface. CONCLUSIONS: Despite the many benefits, PDA usage at the point-of-care comes with the increased risk of distractions for physicians and can cause a negative patient experience. Designers of point-of-care systems need to be aware of, and address, the problems with handhelds and learn from the attributes and access capabilities of paper charts.

An immunosuppressive murine leukaemia virus induces a Th1-->Th2 switch and abrogates the IgM antibody response to sheep erythrocytes by suppressing the production of IL-2.

Many retroviruses have tropism for cells in the immune system and have a propensity to induce immunosuppression in the host. Some of the effects of retroviruses on immune cell function are thought to be mediated through cytokines. Friend ImmunoSuppressive virus-2 (FIS-2) is a low oncogenic murine leukaemia virus (MuLV) that induces lymphadenopathy and immunosuppression in NMRI mice. The role of T cell cytokines during the generation of a primary antibody response in healthy and FIS-2-infected mice was studied following the antibody response to sheep erythrocytes by an in vitro immunization (IVI) technique. In cultures from FIS-2-infected mice, the antibody response was reduced compared with cultures from uninfected mice and the production of the Th2 cytokines IL-4 and IL-6 was elevated, whereas the Th1 cytokines IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were reduced. The suppressed anti-sheep erythrocyte antibody response in cultures from mice infected with FIS-2 seemed to be caused by an insufficient production of IL-2, since addition of recombinant IL-2 stimulated the antibody response. This effect was also observed in cultures depleted of T cells, indicating a direct effect of IL-2 on B cells. A switch to a Th2 cell response and suppression of IL-2 production might play a central role in the immune cell dysfunction induced by FIS-2.

Multiple derangements of cytokine homeostasis in mice infected with immunosuppressive retrovirus.

Altered production of various lymphokines is considered an important factor in retrovirus-induced immunosuppression. We have measured the production of interleukin 2 (IL-2), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-beta 1), and tumor necrosis factor alpha (TNF-alpha) in splenocytes of retrovirus-infected NMRI mice. In Con A-stimulated splenocytes from mice infected with the acute transforming retrovirus Friend leukemia complex (FLC), TNF-alpha and IL-6 production was significantly suppressed. We compared cytokine production in infection with Friend-derived murine immunosuppressive virus (Fd-MIV), a low oncogenic retrovirus that induces a immunosuppression of a magnitude similar to that of FLC. In Fd-MIV infection, the ability of lymphoid cells to produce both IL-2 and TNF-alpha was suppressed. The suppression of these cytokines coincided with the suppression of the primary antibody response. In contrast to FLC infection, the production of IL-6 was elevated. Furthermore, increased production of TGF-beta was found in unstimulated splenocytes from Fd-MIV-infected mice. Infection with immunosuppressive retroviruses induces a complex derangement of T-cell cytokine homeostasis and the relative contributions of the various factors to the immunosuppressed state are difficult to assess at present.

Detection of cytokine mRNA in human, articular cartilage from patients with rheumatoid arthritis and osteoarthritis by reverse transcriptase-polymerase chain reaction.

Cytokines are signalling glycoproteins mediating acute inflammation, chronic inflammation, and connective tissue destruction. The present study was designed to characterize the profile of cytokine message in normal human articular cartilage and from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), by means of the reverse transcriptase-polymerase chain reaction (RT-PCR). Message RNA (mRNA) was extracted from fresh or frozen cartilage. The results showed expression of mRNA for IL-6, IL-6R, IL-7, IL-8, IL-10, and IL-12 (p35 and p40) exclusively in the RA cartilage. Except for mRNA for IL-8 and IL-10, no other cytokine or cytokine receptor was expressed in OA and control cartilage. mRNA for IL-1beta, IL-4, TNF-alpha, and TNFR-p75, was not detected in any cartilage sample except for one RA specimen expressing IL-1beta mRNA. However, the expression of message for pro-inflammatory cytokines was far more prominent than anti-inflammatory cytokines. This may suggest a disturbed balance of pro- and anti-inflammatory activity in RA cartilage.

Polyclonal activation of B-lymphocytes and induction of autoimmunity in retrovirus infected NMRI mice.

Polyclonal activation of B-lymphocytes accompanies many retroviral infections. Friend derived murine immunosuppressive virus (Fd-MIV) is a non-defective murine retrovirus which was isolated from T-helper cells from mice infected with the acute transforming retrovirus Friend leukaemia complex (FLC). In contrast to FLC, Fd-MIV does not induce acute transformation of lymphoid and erythroid cells but causes immunosuppression and lymphadenopathy in adult NMRI mice. The effect of Fd-MIV infection on B-lymphocytes was studied. Fd-MIV infection led to a persistent hypergammaglobulinemy with a significant increase in the level of circulating IgG, IgM and immune complexes. In the spleen and lymph nodes, B-lymphocyte proliferation was found. Parallel to the development of hypergammaglobulinemy, autoantibodies to a variety of nuclear and other autoantigens was detected. In conclusion, the Fd-MIV infection leads to a B-lymphocyte dysfunction that has many parallels with AIDS. Furthermore, the Fd-MIV infection seems to represent an example of an autoimmune condition caused by an exogenous infectious agent.

Regulation of interleukin-2 and interleukin-6 production from T-cells: involvement of interleukin-1 beta and transforming growth factor-beta.

The effect of recombinant (r) interleukin-1 beta (rIL-1 beta) and transforming growth factor-beta (TGF-beta) on the production of interleukin-2 (IL-2) and interleukin-6 (IL-6) from an antigen-specific (LBRM-33-1A5) and an antigen-nonspecific (EL-4-NOB-1) T-cell line was investigated. rIL-1 beta induced the production of IL-2 and IL-6 from EL-4-NOB-1 cells in a dose-related manner. The LBRM-33-1A5 cells required phytohemagglutinin (PHA) in addition to rIL-1 beta in order to produce IL-2 and IL-6. IL-2 production was found to precede IL-6 production in both cell lines. No IL-2 or IL-6 production was observed by adding r murine tumor necrosis factor-alpha or r murine interferon gamma to the cells. The presence of 1 ng/ml TGF-beta reduced IL-2 and IL-6 production from both T-cell lines by more than 80%. The inhibition of IL-2 and IL-6 production was still evident by a concentration as low as 10 pg/ml of TGF-beta. rIL-1 beta and PHA also stimulated murine thymocytes to produce IL-6 which was inhibited up to 85% in the presence of 1 ng/ml TGF-beta. Taken together these results suggest that TGF-beta may suppress immune responses by inhibiting the endogenous production of IL-2 and IL-6.

[Arthritis after BCG treatment of bladder cancer. A rare complication]. / Artritt etter BCG-behandling av blaerekreft. En sjelden komplikasjon.

Since 1976 intravesical instillation of bacillus Calmette-Guerin (BCG) has been used after surgical treatment of bladder cancer. Local side effects like cystitis are common, but a small share of the patients develop influenza-like symptoms, arthritis and other complications. We describe two patients with arthritis.

A low oncogenic variant of Friend murine leukemia virus with strong immunosuppressive properties.

Friend leukemia complex (FLC) is known to induce immunosuppression but the use of FLC in studies of immune cells function is disadvantageous since the immunosuppression always is accompanied by an acute erythroleukemia. To obtain immunosuppressive variants of FLC with reduced leukemogenic potential, we isolated T-helper cells from FLC infected mice, and passed lysates of the cells to recipient uninfected mice. A group of these mice developed a condition distinct from the disease induced by FLC. A viral stock prepared from these mice, designated Fd-MIV for friend derived murine immunodeficiency virus, induced a profound suppression of the primary antibody response without acute transformation in adult NMRI mice. Terminally a wasting disease with weight loss, atrophy of the thymus and lymph nodes and renal disease was observed in some mice. Analysis of viral DNA and RNA from infected NIH 3T3 cells showed that Fd-MIV contained at least two viral components, a 8.4 kb friend murine leukemia virus (F-MuLV) and a 7.4 kb mink cell focus (MCF)/xenotropic virus related genome. The 7.4 kb genome was not detected in Fd-MIV infected, immunocompromised mice indicating that the 8.4 kb genome might be responsible for the disease.

Molecular cloning and characterization of an immunosuppressive and weakly oncogenic variant of Friend murine leukemia virus, FIS-2.

The FIS variant is a weakly leukemogenic, relatively strong immunosuppressive murine retrovirus which was isolated from the T helper cells of adult NMRI mice infected with Friend murine leukemia virus (F-MuLV) complex (FV). Unlike FV, it does not induce acute erythroleukemia but retains the immunosuppressive property of FV and induces suppression of the primary antibody response rapidly and persistently in adult mice. A previous study showed that the FIS variant contains two viral components, a replication-competent virus and a defective virus. In this study, we have biologically purified the FIS variant by end point dilution and we show that the replication-competent virus FIS-2 alone can induce immunosuppression as the parental FIS variant. Most newborn mice infected with FIS-2 developed erythroleukemia, but with an increased latency period compared with that of F-MuLV clone 57. In contrast, FIS-2 induced suppression of the primary antibody response and disease more rapidly than F-MuLV clone 57 in immunocompetent, adult mice. FIS-2 was further molecularly cloned and characterized. Restriction mapping and nucleotide sequence analysis of FIS-2 showed a high degree of homology between FIS-2 and F-MuLV clone 57, suggesting that FIS-2 is a variant of F-MuLV. The striking difference is the deletion of one of the tandem repeats in the FIS-2 long terminal repeat and the single point mutation in the binding sites for core-binding protein and FVa compared with the long terminal repeat of F-MuLV clone 57. Two single point mutations led to the appearance of two extra potential N glycosylation sites in the FIS-2 gag-encoded glycoprotein. Together, the results suggest that FIS-2 represents an interesting murine model to study retrovirus-induced immunosuppression on the basis of its unique combined property of low leukemogenicity and relatively strong and persistent immunosuppressive activity in adult mice.

Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis.

Rheumatic diseases are often associated with changes in bone metabolism. Excessive production and release of cytokines and other growth factors due to inflammation, e.g. tumor necrosis factor-alpha (TNF-alpha), receptor activator of NF-kappaB ligand (RANKL), interleukins such as IL-1 and IL-6, may cause alterations in bone homeostasis leading to bone degradation. Other components such as osteoprotegerin (OPG) and possibly the ligand-receptor pair hepatocyte growth factor (HGF) and c-met may counteract this destruction, we have measured the levels of OPG, and HGF c-met, in serum, synovial fluid (SF), and cartilage from patients with rheumatoid arthritis (RA) and other arthritides. We found a) elevated levels of both OPG and HGF in SF from RA patients relative to arthritides of other causes, b) increased levels of both OPG and HGF in SF from seropositive RA patients (RA+) compared to seronegative RA patients (RA-), c) elevated levels or both OPG and HGF in serum from RA patients compared to healthy controls, d) no correlation between severity of inflammation and levels of OPG or HGF, and e) presence of HGF c-met in both cartilage and synovial tissue. The most significant elevations of OPG and HGF were found in patients with RA, the rheumatic disease most frequently associated with the development of secondary osteoporosis.