Correction to: Economic evaluation of AbobotulinumtoxinA vs OnabotulinumtoxinA in real-life clinical management of cervical dystonia.

[This corrects the article DOI: 10.1186/s40734-020-0083-0.].

Economic evaluation of AbobotulinumtoxinA vs OnabotulinumtoxinA in real-life clinical management of cervical dystonia.

BACKGROUND: Botulinum neurotoxins type A (BoNT-As) are commonly used treatments for cervical dystonia (CD). Clinical trials have demonstrated the benefits of them in these patients, but data from real-life clinical practice as well as comparative data on the cost and outcome of different BoNT-A formulations are limited. The aim of this study was to compare abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) on their clinical outcomes and drug costs in real-life clinical practice. METHODS: This analysis included 356 adult patients with idiopathic CD treated with aboBoNT-A (n = 253) or onaBoNT-A (n = 103) from 38 centres across Europe and Australia (NCT00833196). The clinical outcome measures were treatment responses, changes in TWSTRS scores and changes in health utility scores from baseline to study visit 2 and 3. Health utility score was mapped from the TWSTRS total scale, using a previous publication. Costs included drug cost for France. RESULTS: The aboBoNT-A treated group had 2.06 (95% CI: 1.15 to 3.69) times higher odds of achieving treatment response than the onaBoNT-A treated group. The adjusted mean change in TWSTRS total score from baseline to visit 3 were - 6.42 (95% CI: - 7.52 to - 5.33) for aboBoNT-A and - 3.94 (95% CI: - 5.68 to - 2.2) for onaBoNT-A, with a difference of - 2.48 (95% CI: - 4.57 to - 0.39). The corresponding difference in the adjusted mean change for health utility score was 0.008 (95% CI: 0.001 to 0.014). Mean treatment costs for aboBoNT-A and onaBoNT-A were 314.1 (95% CI: 299.1 to 329.0) and 346.6 (95% CI: 322.9 to 370.4) Euros, respectively. CONCLUSIONS: This comparative analysis indicated that treatment with aboBoNT-A may be less costly and lead to improved clinical outcomes when compared with onaBoNT-A, from a French healthcare system perspective. Additional comparative clinical data from larger patient cohorts, as well as more information about cost consequences of an improvement in clinical outcome would be of value to further confirm the findings.

Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis: a retrospective, observational study, and a meta-analysis.

UNLABELLED: The objectives of this study were to estimate persistence with denosumab and put these results in context by conducting a review of persistence with oral bisphosphonates. Persistence with denosumab was found to be higher than with oral bisphosphonates. PURPOSE: This study had two objectives: to analyse persistence in Swedish women initiating denosumab for treatment of postmenopausal osteoporosis (PMO) and to put these findings in context by conducting a literature review and meta-analysis of persistence data for oral bisphosphonates. METHODS: The study used the Swedish Prescribed Drug Register and included women aged at least 50 years initiating denosumab between May 2010 and July 2012. One injection of denosumab was defined as 6-month persistence. Women were considered persistent for another 6 months if they filled their next prescription within 6 months + 56 days and survival analysis applied to the data. A literature search was conducted in PubMed to identify retrospective studies of persistence with oral bisphosphonates and pooled persistence estimates were calculated using a random-effects model. RESULTS: The study identified 2,315 women who were incident denosumab users. Mean age was 74 years and 61% had been previously treated for PMO. At 12 and 24 months, persistence with denosumab was 83% (95% CI, 81-84%) and 62% (95% CI, 60-65%), respectively. The literature search identified 40 articles for inclusion in the meta-analysis. At 12 and 24 months, persistence with oral bisphosphonates ranged from 10% to 78% and from 16% to 46%, with pooled estimates of 45% and 30%, respectively. CONCLUSION: These data from the Swedish Prescribed Drug Register and literature review suggest that persistence was higher with denosumab than with oral bisphosphonates.

Screening for abdominal aortic aneurysm in 65-year-old men remains cost-effective with contemporary epidemiology and management.

OBJECTIVES: The epidemiology and management of abdominal aortic aneurysms (AAA) has changed significantly, with lower prevalence, increased longevity of patients, increased use of endovascular aneurysm repair (EVAR), and improved outcome. The clinical and health economic effectiveness of one-time screening of 65-year-old men was assessed within this context. METHODS: One-time ultrasound screening of 65-year-old men (invited) versus no screening (control) was analysed in a Markov model. Data on the natural course of AAA (risk of repair and rupture) was based on randomised controlled trials. Screening detected AAA prevalence (1.7%), surgical management (50% EVAR), repair outcome, costs, and long-term survival were based on contemporary population-based data. Incremental cost-efficiency ratios (ICER), absolute and relative risk reduction for death from AAA (ARR, RRR), numbers needed to screen (NNS), and life-years gained were calculated. Annual discounting was 3.5%. RESULTS: In base case at 13-years follow-up the ICER was €14,706 per incremental quality-adjusted life-year (QALY); ARR was 15.1 per 10,000 invited, NNS was 530, and QALYs gained were 56.5 per 10,000 invited. RRR was 42% (from 0.36% in control to 0.21% in invited). In a lifetime analysis the ICER of screening decreased to €7,570/QALY. The parameters with highest impact on the cost-efficiency of screening in the sensitivity analysis were the prevalence of AAA (threshold value <0.5%) and degree of incidental detection in the control cohort. CONCLUSIONS: In the face of recent changes in the management and epidemiology of AAA, screening men for AAA remains cost-effective and delivers significant clinical impact.

Screening for abdominal aortic aneurysm among patients referred to the vascular laboratory is cost-effective.

UNLABELLED: Screening for abdominal aortic aneurysm (AAA) in high-risk groups has been recommended based on a high prevalence of disease, while being questioned due to a high frequency of co-morbidities and inferior life-expectancy. We evaluated the long-term outcome and the cost-effectiveness of selective AAA screening among patients referred to the vascular laboratory for arterial examination. METHODS: A total of 5,924 patients, referred to the vascular laboratory of a university hospital, were screened for AAA with ultrasound (definition: slashed circle>or=30 mm), 1993-2005. Outcome data were gathered through hospital records and the national population registry. A Markov model was used for health-economic evaluation. RESULTS: An AAA was detected in 181 patients (mean age 72.8 years), of whom 21.5% underwent elective repair (perioperative mortality 5.1%) after 7.5 years of follow-up. Four of six patients diagnosed with AAA rupture were operated upon. Relative 5-year survival compared with the general Swedish population, controlled for age and sex, was 80.4% (95% confidence interval (CI): 70.8-88.8). The cost-effectiveness was robust in base-case (11,084 Euro/life year gained) and in sensitivity analyses of prevalence, cost and survival. CONCLUSIONS: Patients in whom AAA was detected at selective screening had inferior long-term survival and were operated on less frequently, compared with AAA patients described in previous studies. Yet, selective screening at the vascular laboratory was cost-effective.

Health care costs for treatment of disseminated breast cancer.

The rapid development of the care makes it important to have relevant cost information for cost-effectiveness assessments. The aim of this study is to estimate the health care cost of a disseminated breast cancer relapse in Sweden. A retrospective cohort study of women with disseminated breast cancer in Sweden was done. The individual case records were reviewed and all data concerning treatments, hospitalisation, examinations and palliative care were collected. The study included 53 patients with a total mean cost of 93,700 euros (95% Confidence Interval (CI): 78,500 euros - euro109,600 euros ). Drugs and hospitalisations were the largest single cost sources. HER2-positive patients had slightly higher mean costs (euro123,300), while triple negative patients had slightly lower mean costs (70,600 euros). The current costs for patients with disseminated breast cancer are considerably higher than those previously shown, which may have important consequences for economic evaluations of interventions aimed at reducing the risk of disseminated breast cancer.

The burden of rheumatoid arthritis and access to treatment: health burden and costs.

As part of the study "The burden of rheumatoid arthritis and patient access to treatment", this paper reviews evidence on the health burden of rheumatoid arthritis (RA) in terms of morbidity (DALYs), mortality (% of deaths attributable to RA) and quality of life (utility and loss of QALYs), as well as the economic impact on society. Based on available literature on the prevalence and the cost of RA, combined with economic indicators, the annual cost per patient as well as the total national cost is estimated for Europe and North America (Canada and the United States), as well as Australia, Turkey, the Russian Federation and South Africa. Total costs to society were estimated at 45.3 billion in Europe and at 41.6 billion in the United States. Utility scores were found to be amongst the lowest compared to other diseases.

Economic evaluation of parathyroid hormone (PTH) in the treatment of osteoporosis in postmenopausal women.

Parathyroid hormone (PTH) is a new treatment for osteoporosis and has been shown to reduce the risks of vertebral and non-vertebral fractures in postmenopausal women in clinical trials. The objective of this study was to estimate the cost-effectiveness of teriparatide in addition to calcium and vitamin D, using a simulation model. The base case analysis was conducted for a cohort of 69-year-old women in Sweden who had at least one previous vertebral fracture and low bone mineral density. The model simulated the course of events in 6-month cycles in individual patients until death or 100 years of age. During each cycle the patients were at risk of experiencing clinical vertebral, hip or wrist fractures, or death. Total accumulated life-time costs and quality-adjusted life years (QALYs) were estimated. Swedish data on fracture costs, utility reductions after fracture, fracture risks and mortality rates were used. The model incorporated new epidemiological evidence that indicates fracture risks and mortality rates are higher in the subsequent years post-fracture. The results showed that the cost-effectiveness of the treatment is highly dependant on the risk profile of the treated patients and the timing of starting treatment relative to previous fractures. The cost per QALY gained for treatment of a population of 69-year-olds with a T-score at the femoral neck of -3 was in the base case estimated to be between EUR (euro) 20,000 and 64,000 for patients with a recent or historic vertebral fracture respectively. The study provides further evidence of the benefit and cost-effectiveness of starting osteoporotic treatments early in patients with a new fracture, and also that teriparatide may provide valuable clinical benefits for these patients and may be considered a cost-effective intervention when targeted to the appropriate patients.

The cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke: results from the Study on COgnition and Prognosis in the Elderly.

Patients who survive a first stroke are often left with permanent disabilities, and have significant needs for rehabilitation and long-term care. Antihypertensive treatment reduces the risk of cardiovascular events such as stroke. The purpose of this study was to investigate the cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke. The cost-effectiveness analysis was based on data from Study on COgnition and Prognosis in the Elderly (SCOPE), where patients were randomly assigned to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive treatment added as needed. The analysis was carried out using a Markov model, which combined clinical and resource utilization data from SCOPE with Swedish retail prices for drugs and unit costs for in-patient stays, and outpatient visits. The cost per patient was 1949 EUR in the candesartan group and 1578 EUR in the control group. The largest share of the cost was attributed to antihypertensive treatment in the candesartan group and to the long-term cost of stroke in the control group. Candesartan-based antihypertensive treatment was associated with 0.0289 additional quality-adjusted life-years (QALYs) per patient and an incremental cost per QALY gained of approximately 13,000 EUR. Sensitivity analyses showed that these results were fairly stable. In conclusion, the cost per QALY gained with candesartan-based antihypertensive treatment lies within the range of society's willingness to pay for health gains. The results indicate that candesartan-based antihypertensive treatment is cost-effective for the prevention of nonfatal stroke.

Pricing and reimbursement of drugs in Sweden.

The Swedish public health care system is financed mainly by taxes. The major part of drug costs is paid by the drug reimbursement system. Sweden has, as most other countries, seen a large increase in the expenditures on drugs in recent years. The responsibility for the cost of drugs in Sweden has recently been decentralized to the county council level. The reimbursement system of drugs currently covers all drugs with a price approved by the National Social Insurance Board, unless the government specifically decides against such coverage. Two groups of drugs were recently excluded from coverage: drugs for obesity and impotence. The price level of drugs in Sweden is close to the average of the European countries. Economic evaluations are currently not mandatory in Swedish price and reimbursement negotiations but are nonetheless important, particularly in negotiations for drugs expected to command large price premiums. The Swedish pricing and reimbursement system has recently been under investigation, and new reforms are expected in the near future.

Notch and the birth of glial cells.

Notch receptors play crucial roles in many cellular differentiation programs. In addition to a more classical role for Notch in keeping cells in an undifferentiated state, a recent paper has provided clear evidence that Notch signaling is a powerful means of turning adult CNS precursor cells into astrocytes. This work, combined with other reports from the developing CNS, retina and the PNS, demonstrates a role for Notch in gliogenesis. These findings can also be linked to novel insights into the function of proneural basic helix-loop-helix proteins in astrocytic differentiation.

The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity.

Notch signal transduction is mediated by proteolysis of the receptor and translocation of the intracellular domain (IC) into the nucleus, where it functions as a regulator of HES gene expression after binding to the DNA-binding protein RBP-J kappa. The mammalian Notch receptors are structurally very similar, but have distinct functions. Most notably, Notch 1 IC is a potent activator of the HES promoter, while Notch 3 IC is a much weaker activator and can repress Notch 1 IC-mediated HES activation in certain contexts. In this report we explore the molecular basis for this functional difference between Notch 1 and Notch 3 IC. We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins. Furthermore, both Notch 1 and Notch 3 ICs displace the co-repressor SMRT from the DNA-binding protein RBP-J kappa on the HES promoter. The latter observation suggests that both Notch 3 IC and Notch 1 IC can access RBP-J kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ICs when positioned on RBP-J kappa. We show that two distinct regions in the Notch IC are critical for the difference between the Notch 1 and Notch 3 IC. First, the origin of the ankyrin repeat region is important, i.e. only chimeric ICs containing a Notch 1-derived ankyrin repeat region are potent activators. Second, we identify a novel important region in the Notch IC. This region, named the RE/AC region (for repression/activation), is located immediately C-terminal to the ankyrin repeat region, and is required for Notch 1 IC's ability to activate and for Notch 3 IC's ability to repress a HES promoter. The interplay between the RE/AC region and the ankyrin repeat region provides a basis to understand the difference in HES activation between structurally similar Notch receptors.

Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal.

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype.

Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice.

IL-1beta and its endogenous receptor antagonist (IL-1Ra) are rapidly induced by seizures in the rodent hippocampus. Exogenously applied IL-1beta prolongs seizures in an IL-1R type I-mediated manner. This effect depends on N-methyl-d-aspartate receptor activation. We report here that intrahippocampal application of recombinant IL-1Ra or its selective endogenous overexpression in astrocytes under the control of glial acidic fibrillary protein promoter potently inhibits motor and electroencephalographic seizures induced by bicuculline methiodide in mice. Accordingly, transgenic mice show a reduced seizure-related c-fos mRNA expression in various forebrain areas compared with their wild-type littermates. Recombinant IL-1Ra was ineffective in mice deficient in IL-1R type I, having per se a delayed onset to generalized convulsions. These results demonstrate that IL-1Ra mediates potent anticonvulsant effects acting on IL-1R type I and suggest that the balance between brain IL-1beta and IL-1Ra represents a crucial mechanism to control seizure generalization.

The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters.

The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.

Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist.

The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous antagonist that blocks the effects of the proinflammatory cytokines IL-1alpha and IL-1beta by occupying the type I IL-1 receptor. Here we describe transgenic mice with astrocyte-directed overexpression of the human secreted IL-1ra (hsIL-1ra) under the control of the murine glial fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains have been generated and characterized further: GILRA2 and GILRA4. These strains show a brain-specific expression of the hsIL-1ra at the mRNA and protein levels. The hsIL-1ra protein was approximated to approximately 50 ng/brain in cytosolic fractions of whole brain homogenates, with no differences between male and female mice or between the two strains. Furthermore, the protein is secreted, inasmuch as the concentration of hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4) times higher in the transgenic mice than in the control animals. To characterize the transgenic phenotype, GILRA mice and nontransgenic controls were injected with recombinant human IL-1beta (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response elicited by IL-1beta (50 ng/mouse icv) was abolished in hsIL-1ra-overexpressing animals, suggesting that the central IL-1 receptors were occupied by antagonist. The peripheral LPS injection (25 micrograms/kg ip) triggered a fever in overexpressing and control animals. Moreover, no differences were found in LPS-induced (100 and 1,000 micrograms/kg ip; 1 and 6 h after injection) IL-1beta and IL-6 serum levels between GILRA and wild-type mice. On the basis of these results, we suggest that binding of central IL-1 to central IL-1 receptors is not important in LPS-induced fever or LPS-induced IL-1beta and IL-6 plasma levels.

Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta.

IL-1alpha and IL-1beta have potent effects on the central nervous system resulting in fever, activation of the hypothalamic-pituitary-adrenal axis and behavioural depression. These effects have mainly been studied in rats, using recombinant human and mouse IL-1. Because IL-1alpha and IL-1beta show some species specificity in the potency of their biological activities, the objective of the present work was to directly compare the effects of recombinant rat IL-1alpha and IL-1beta in the rat system as a first step to dissect out the mechanisms that are involved in these effects. In vitro, recombinant rat IL-1alpha and IL-1beta bound with the same affinity as human IL-1 to the rat insulinoma Rin m5F cell line that mainly expresses type I IL-1 receptors. This binding activated IL-1 receptors, as shown by induction of the synthesis of TNF-alpha mRNA. In vivo, recombinant rat IL-1alpha and IL-1beta enhanced body temperature, increased plasma levels of corticosterone and ACTH, and depressed social behaviour. All these effects were obtained at doses 100-1,000 fold lower when IL-1 was injected centrally than when it was administered peripherally, indicating that they are centrally mediated. The relative potencies of recombinant rat IL-1alpha and IL-1beta were not the same depending on the endpoint and the route of injection, indicating that different mechanisms are likely to be involved in the various effects of IL-1 on the brain.

Interleukin-1-mediated febrile responses in mice and interleukin-1 beta activation of NFkappaB in mouse primary astrocytes, involves the interleukin-1 receptor accessory protein.

The endogenous pyrogen interleukin-1 (IL-1) is considered as one of the key molecules in orchestrating the host response of injury and inflammation. IL-1 exerts its effects upon binding to the type I IL-1 receptor (IL-1RI). The IL-1-IL-1RI complex is further thought to associate with the IL-1 receptor accessory protein (IL-1RAcP), which is suggested to be important for most IL-1 signal transduction pathways. With the aim of investigating the importance of the IL-1RAcP in IL-1 signalling, IL-1alpha and IL-1beta induced febrile responses and IL-1beta-mediated activation of NFkappaB in primary astrocyte cultures were examined using IL-1RAcP-deficient (IL-1RAcP KO) and wild type mice, respectively. It was shown that neither recombinant rat IL-1alpha (rrIL-1alpha, 25 microg/kg), recombinant rat IL-1beta (rrIL-1beta, 40 microg/kg) nor recombinant human IL-1beta (rhIL-1beta, 50 microg/kg) injected i.p. could elicit febrile responses in the IL-1RAcP-deficient mice, while the same doses of rrIL-1alpha/beta or rhIL-1beta injected into wild type mice caused normal fever responses. A febrile response could be induced in the IL-1RAcP-deficient mice by i.p. administration of E. coli lipopolysaccharide (LPS, 50 microg/kg) and this response was similar to that obtained in wild type mice. Furthermore, it was shown that rhIL-1beta activated, in a concentration-dependent manner, nuclear translocation of the transcriptional nuclear factor kappa B (NFkappaB) in primary astrocyte cultures prepared from wild type mice, whereas no IL-1beta-induced translocation of NFkappaB could be detected in cultures prepared from IL-1RAcP-deficient mice, as revealed by electrophoretic mobility shift assay (EMSA). The rhIL-1beta-induced NFkappaB complexes were shown to contain p50 but no, or very little, p65 and cRel immunoreactive proteins.

Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor.

Stably transfected HEK-293 cells express on their surface the murine type II IL-1 receptor (mIL-1RII) as demonstrated by FACS analysis using the mAb 4E2, however binding of [125I]-hrIL-1beta to these cells is nearly absent. Saturable high affinity binding of [125I]-hrIL-1beta is observed when the murine IL-1 receptor accessory protein (mIL-1RAcP) is coexpressed with mIL-1RII. Binding of [125I]-hrIL-1beta to mIL-1RII-mIL-1RAcP complex can be inhibited either with antibodies to mIL-1RII (mAb 4E2), or by antibodies to mIL-1RAcP (mAb 4C5). The number of high affinity binding sites in cells stably transfected with the cDNA for mIL-1RII is dependent on the dose of cDNA for mIL-1RAcP used to transfect the cells. The high affinity complex between mIL-1RII and mIL-1RAcP is not preformed by interaction between the intracellular domains of these two transmembrane proteins, rather it appears to require the extracellular portions of mIL-1RII and mIL-1RAcP and the presence of a ligand. We suggest that in addition to its earlier described decoy receptor role, IL-1RII may modulate the responsiveness of cells to IL-1 by binding the IL-1RAcP in unproductive/non-signalling complexes and thus reducing the number of signalling IL-1RI-IL-1RAcP-agonist complexes when IL-1 is bound.

Human/mouse interleukin-1 receptor/receptor accessory protein interactions in IL-1beta-induced NFkappaB activation.

We examined whether functional heterologous complexes between human IL-1RI (hIL-1RI) and murine IL-1R accessory protein (mIL-1RAcP) can be formed, utilizing human fibroblast HEK 293 cells and murine fibroblast C127 cells, nontransfected or stably transfected with hIL-1RI (C127-hIL-1RI), respectively. In non-transfected C127 cells, IL-1beta signalled through the mIL-1RI-mIL-1RAcP complex and activated NFkappaB p50/p65 heterodimers. In C127-hIL-1RI cells, IL-1beta signalled through the hIL-1RI and activated both p65/p65 and p50/p65 NFkappaB complexes, where only the activation of NFkappaB p65/p65 was dependent on mIL-1RAcP. Thus, clearly both homologous and heterologous IL-1RI-IL-1RAcP interactions support NFkappaB translocation, but with differences in signalling pattern.