Does the intensity of daily walking matter for protecting against the development of a slow gait speed in people with or at high risk of knee osteoarthritis? An observational study.

OBJECTIVE: Knee osteoarthritis (OA) is a risk factor for a decline in gait speed. Daily walking reduces the risk of developing slow gait speed and future persistent functional limitation. However, the protective role of walking intensity is unclear. We investigated the association of substituting time spent not walking, with walking at light and moderate-to-vigorous intensities for incident slow gait over 2-years, among people with or at high risk of knee OA. METHOD: We used baseline and 2-year follow-up data from the Multicenter Osteoarthritis (MOST) study (n = 1731) and the Osteoarthritis Initiative (OAI, n = 1925). Daily walking intensity was objectively assessed using accelerometer-enabled devices, and classified as; not walking (<1 steps/min), very-light (1-49 steps/min), light (50-100 steps/min), and moderate-to-vigorous (>100 steps/min). We defined slow gait during a 20-m walk, as <1 m/s and <1.2 m/s. Isotemporal substitution evaluated time-substitution effects on incident slow gait outcomes at 2-years. RESULTS: Replacing 20 min/day of not walking with walking at a moderate-to-vigorous intensity, demonstrated small to moderate reductions in the risk of developing a gait speed <1.0 m/s (Relative Risk [95% confidence interval (CI)]; MOST = 0.51 [0.27, 0.98], OAI = 0.21 [0.04, 0.98]), and <1.2 m/s (MOST = 0.73 [0.53, 1.00], OAI = 0.65 [0.36, 1.18]). However, only risk reductions for <1.0 m/s met statistical significance. Replacing not walking with very-light or light intensity walking was not associated with the risk of developing slow gait outcomes. CONCLUSION: When possible, walking at a moderate-to-vigorous intensity (>100 steps/min) may be best recommended in order to reduce the risk of developing critical slow gait speed among people with, or at high risk of knee OA.

Accuracy of injection and short-term pain relief following intra-articular corticosteroid injection in knee osteoarthritis - an observational study.

BACKGROUND: Intra-articular corticosteroid injections (IACI) are effective treatments for pain in knee osteoarthritis (KOA) but treatment response varies. There is uncertainty as to whether structural factors such as accurate placement of IACI affect outcome. We examined this question in a pragmatic observational study, using ultrasound (US) to verify accuracy of IACI. METHODS: 105 subjects with KOA (mean age 63.1 years, 59% female) routinely referred for IACI underwent assessment of demographic factors, x-ray and US of the knee before aspiration and IACI (based on clinical landmarks) with 40 mg triamcinolone acetonide with lignocaine plus a small amount of atmospheric air by an independent physician. US demonstration of intra-articular mobile air, i.e. a positive air arthrosonogram, was used to determine accurate placement of injection. Both patients and injecting physicians were blind to the US findings. Pain at baseline, three and nine weeks post injection was assessed using the 500 mm WOMAC pain subscale and response defined as ≥ 40% reduction in pain from baseline. Inter-observer reliability of air-arthrosonogram assessment was good: κ 0.79 (three raters). RESULTS: Sixty-three subjects (60.6%) were responders at three weeks and 43 (45.7%) at nine weeks. Seventy-four subjects (70.5%) had a positive arthrosonogram. A positive air arthrosonogram did not associate with a higher rate of response to treatment (p 0.389 at three weeks, p 0.365 at nine weeks). There was no difference in US effusion depth, power Doppler signal or radiographic grade between responders and non-responders to the injection, but female gender associated with response at 3 weeks and previous injection with non-response at 9 weeks. CONCLUSIONS: Accurate intra-articular injection of corticosteroid results did not result in superior outcome in terms of pain compared to inaccurate injection in symptomatic knee OA.

Distribution of effusion in knee arthritis as measured by high-resolution ultrasound.

Information about the distribution of effusion within the arthritic knee joint should be considered in selecting an anatomical approach for arthrocentesis. We recorded ultrasound measurements of fluid distribution in the knees of patients attending our clinic for knee injections under ultrasound guidance. In a cross-sectional observational study, we used high-resolution ultrasound (US) to record measurements of maximum fluid depth in the medial, midline and lateral regions of the suprapatellar pouch (SPP) in 46 patients with arthritis attending for routine US-guided injection of the knee. Mean fluid depth [in millimetres, (SD)] was significantly greater in the lateral SPP [9.2 (5.1)] than in the medial [6.5 (4.6)] or the midline [5.9 (3.7)] regions with the knee in relaxed full extension (p < 0.001 for comparison of lateral SPP with both midline and medial SPP). Small effusions were more commonly detected in the lateral SPP than elsewhere. In patients with painful knee arthritis, fluid distributes maximally to the lateral SPP in the extended knee. This has implications regarding the anatomical approach to arthrocentesis that clinicians should choose to perform and teach.

Inotropic, vasodilating and preconditioning actions of levosimendan in the heart.

BACKGROUND: Levosimendan improves ventricular function, induces vasodilation and induces myocardial preconditioning. We determined the external efficiency and assessed the effects on arrhythmias. METHODS: In isolated, blood-perfused rabbit hearts, levosimendan (0.75 micromol) or placebo was administered, while hemodynamics were recorded. After no-flow ischemia and reperfusion, data were recorded again. RESULTS: Placebo in normoxic hearts did not affect measurements, while levosimendan increased heart rate (+ 18 %) and improved coronary output (+ 52 %), stroke volume (+ 28 %), maximal left ventricular pressure (+ 30 %), maximal rate of pressure increase (+ 36 %), work (+ 68 %), minimal rate of pressure increase (+ 53 %), coronary blood flow (+ 41 %), coronary resistance (- 19 %) and external efficiency (33 %; P < 0.05). During reperfusion, hemodynamics in the levosimendan group were significantly better preserved compared with the placebo group. Early reperfusion arrhythmias were decreased (levosimendan group: 7 +/- 3 % vs. placebo group: 25 +/- 17 %; P < 0.05). CONCLUSIONS: Levosimendan does not impair diastole, dilates coronary vessels, induces pharmacological preconditioning, improves external efficiency and exerts antiarrhythmic properties during reperfusion. As this drug protects the heart from reperfusion injury, it seems well suited for treating dysfunctional hearts after cardiac surgery.

Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis.

Hypertension (HT) is highly prevalent in rheumatoid arthritis (RA). Serum uric acid (SUA) has been associated with HT in the general population. The mutual exclusion of gout and RA, and the systemic inflammatory component of RA may alter this association in this patient population. We explored a potential association between SUA levels and HT in RA and evaluated whether this association is independent of HT risk factors, RA characteristics and relevant drugs. A total of 400 consecutive RA patients were assessed. SUA and complete biochemical profile were measured. Demographic, HT-related factors, RA characteristics and drugs were assessed as potential covariates. Results were analysed using binary logistic models to test the independence of the association between SUA and HT. SUA levels were higher in hypertensive compared to normotensive RA patients (5.44+/-1.6 mg dl(-1) (323.57+/-95.17 micromol l(-1)) vs 4.56+/-1.1 mg dl(-1) (271.23+/-65.43 micromol l(-1)), P<0.001). When adjusted for HT risk factors, renal function, RA characteristics, non-steroidal anti-inflammatory drugs, oral prednisolone, cyclosporine, leflunomide and low-dose aspirin, the odds of being a hypertensive RA patient per 1 mg dl(-1)(59.48 micromol l(-1)) SUA increase were significantly increased: OR=1.59 (95% CI: 1.21-2.1, P=0.001). This was also significant for the subgroup of patients who were not on diuretics (OR=1.5, 95% CI: 1.1-2.05; P=0.011). This cross-sectional study suggests that SUA levels are independently associated with HT in RA patients. Prospective longitudinal studies are needed to confirm and further explore the causes and implications of this association.

[Treatment of hypertension in daily practice. Current results of a postmarketing surveillance study with telmisartan]. / Die Therapie der Hypertonie in der täglichen Praxis. Aktuelle Ergebnisse einer Postmarketing-Surveillance-Studie mit Telmisartan.

AIM: Evaluation of efficacy and tolerability of telmisartan monotherapy and telmisartan plus hydrochlorothiazide in daily practice. METHODS: Patients with arterial hypertension were included in this non-interventional, observational study. Demographic data, medical history, therapy with telmisartan and telmisartan plus hydrochlorothiazide as well as blood pressure and heart rate at 0, 4, 8, and 12 weeks were recorded by 1211 physicians. Moreover, overall efficacy and tolerability were assessed. Adverse events and adverse drug reactions were documented. RESULTS: Out of 6319 patients 52.9% were male. Mean age was 59.9 years and mean body mass index (BMI) was 27.8 kg/m2. 70% of patients had grade 2 or 3 hypertension, 59% had a high or very high additional cardiovascular risk. In 34.6% of patients hypertension was newly diagnosed, while the remaining 65.4% had been hypertensive for an average of 7.2 years. 3386 patients initially received telmisartan (54%: 40 mg; 45.4%: 80 mg). 2928 patients were given telmisartan plus hydrochlorothiazide (56.9%: 80/12.5 mg; 43.1%: 40/12.5 mg). In 69.8% of the patients the dose remained unchanged throughout the study. The remaining patients were either given a higher dose or changed over to the combination. Under treatment, the systolic and diastolic blood pressures decreased by an average of 28.5 mmHg and 14.1 mmHg, respectively. Mean pulse pressure decreased by 14.4 mmHg. The efficacy of the treatment was assessed "very good" or "good" in 94.2% of all patients, and tolerability in 98.8%. Adverse events occurred in 43 (0.7%) patients, and adverse drug reactions in 28 (0.4%) patients. CONCLUSION: Under daily practice conditions telmisartan monotherapy and telmisartan plus hydrochlorothiazide are very effective and well tolerated. Systolic and diastolic blood pressure as well as pulse pressure are effectively lowered.

Association of serum uric acid with cardiovascular disease in rheumatoid arthritis.

OBJECTIVES: Elevated serum uric acid (SUA) levels have been associated with cardiovascular disease (CVD) in the general population. Rheumatoid arthritis (RA) is not thought to associate with high SUA but is characterized by increased CVD morbidity and mortality. We aimed to explore a potential association of SUA with CVD in RA patients and to evaluate whether such an association is present when the traditional CVD risk factors are taken into account. METHODS: . 400 consecutive RA patients were recruited in this cross-sectional study and had all traditional CVD risk factors and SUA assessed. The association of SUA levels with other variables was assessed using bivariate correlations. Subsequent binary logistic models with appropriate adjustments were used to test the independence of the association between SUA and CVD. RESULTS: SUA levels were significantly higher in RA patients with CVD (RA + CVD) compared with RA patients without CVD (RA - CVD) (5.68 +/- 1.81 mg dl(-1) vs 5.06 +/- 1.41 mg dl(-1), P = 0.001). After adjusting for CVD risk factors, physical function (health assessment questionnaire, HAQ) and use of diuretics and/or statins the association between SUA and CVD in RA patients remained significant [Odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.04-1.79, P = 0.025]. Compared with subjects with SUA levels in the lowest quintile (<3.86 mg dl(-1)), those within the highest quintile (>/=6.38 mg dl(-1)) had a 6-fold increase in the odds of having CVD (adjusted OR 6.46, 95% CI 1.66-25.05, P = 0.007). CONCLUSIONS: This cross-sectional study suggests that SUA may be independently associated with CVD in RA patients. This needs to be confirmed in prospective studies.

Therapeutic angiogenesis for peripheral artery disease: cytokine therapy.

In recent years the importance of circulating bone marrow-derived cells in angiogenesis and collateral growth has been demonstrated in peripheral artery disease (PAD) and other ischaemic diseases. Although the mechanisms by which these cells exert their angiogenetic/arteriogenetic effects are not completely understood, improving the accumulation of bone marrow-derived cells at the site of vascular growth using cytokines has become one aim in some of the regenerative therapies. Interestingly recent data indicate that in addition to effects attributed to such accumulated cells there are also direct effects of cytokines used via their receptors. Several investigations in animal hind limb models of ischaemia have demonstrated the beneficial effect of bone marrow mobilisation using colony-stimulating factors (CSF) on collateral growth and perfusion recovery. Clinical studies in PAD patients, however are still rare and led to inconsistent data, in part due to different application protocols, choice of cytokine and low patient numbers with strong placebo effects. Moreover; the aetiology of the disease in humans differs markedly from the artificial occlusion of the femoral artery in a mostly healthy animal in the preclinical setting. Another approach to enhance arteriogenesis, which has been successful in animal models of hind limb ischaemia, is the local injection of the monocyte chemoattractant protein 1 (MCP-1). This treatment stimulated the invasion of monocytes leading to improved collateral growth and restoration of limb perfusion. Recent reports from animal experiments, in which both treatment strategies were combined (i.e. bone marrow mobilisation and enhancement of cell migration to the site of vascular growth), have shown strong synergistic effects, pointing at the importance to orchestrate the different processes involved in vascular repair in order to achieve maximal therapeutic effects.

Inactivation of xanthine oxidoreductase is associated with increased joint swelling and nitrotyrosine formation in acute antigen-induced arthritis.

OBJECTIVE: Arthritis is associated with increased articular formation of nitrotyrosine, which may contribute to injury. Nitrotyrosine is formed by nitration of tyrosine by reactive nitrogen species such as peroxynitrite, the formation of which may be enhanced by xanthine oxidoreductase (XOR), since it can generate nitric oxide from nitrite/nitrate, and superoxide during xanthine metabolism. We hypothesized that inactivation of XOR would protect against antigen-induced arthritis (AIA) and decrease nitrotyrosine formation. METHODS: AIA was induced with methylated bovine serum albumin (mBSA) in three groups of Wistar rats: animals fed on (1) tungsten-enriched chow (0.7 g/kg) (TG), which inactivates XOR, (2) standard chow (SG), and (3) rats treated with allopurinol (50 mg/kg/day; p.o.) (AG). Nitrotyrosine in patella-synovium was quantified by mass spectrometry three weeks after intra-articular (i.a.) antigen injection. RESULTS: Treatment with tungsten, but not allopurinol, suppressed plasma and articular XOR activity at < or = 0.9% of normal levels. XOR inactivation was associated with increased knee swelling 24-48 hrs post i.a. mBSA, compared with controls (mean increase +/- SEM of knee diameter from baseline of 3.3 +/- 0.5, 2.0 +/- 0.3 and 1.9 +/- 0.2 mm in TG, SG and AG (n = 14 each group), respectively; p < 0.05, TG vs SG, ANOVA). Mean ratio of articular nitrotyrosine-tyrosine (+/- SEM) was increased in the XOR-inactivated group, compared with controls: 12.3 +/- 0.7, 9.6 +/- 0.8 and 10.4 +/- 0.5 pg/microg in TG, SG and AG, respectively; p < 0.05, TG vs SG. CONCLUSION: Contrary to expectation, XOR inactivation was associated with increased joint swelling and articular tyrosine nitration in acute AIA, suggesting a novel, protective role for XOR in inflammatory arthritis.

Constitutive and inducible expression of CYP enzymes in immortal hepatocytes derived from SV40 transgenic mice.

1. The expression of liver-specific transcription factors and cytochrome P450 (CYP) enzymes have been studied in three new hepatocyte-like cell lines derived from SV Delta 202 transgenic mice: AMH-Delta 202 (adult mouse hepatocytes), TAMH-Delta 202 (tumour-derived adult mouse hepatocytes) and NMH-Delta 202 (newborn mouse hepatocytes). 2. mRNA levels of liver-enriched transcription factors such as D-element binding protein (DBP), liver-enriched transcription activating protein (LAP) and the hepatic nuclear factors (HNF) 1, 2 and 3 in all Delta 202 transgenic hepatocyte lines were similar to those in the wild-type liver and in primary mouse hepatocytes. 3. Analysis of basal CYP activities and testosterone metabolism revealed that Delta 202 cells showed higher similarities to mouse hepatocytes than Hepa 1c1c7 hepatoma cells. All three Delta 202 cell lines exhibited substantial active CYP1A1/2, CYP2A4/5 and CYP3A11 activities and lower levels of CYP2B, CYP2C and CYP2E1 activities. 4. The Delta 202 cells also responded to model inducers. 3-Methylcholanthrene induced CYP1A1/2 (7-ethoxyresorufin O-deethylation); phenobarbital induced CYP2B (7-benzoxyresorufin O-debenzylation), CYP2A4/5 (testosterone 7alpha -hydroxylation) and CYP3A11 (testosterone 6beta -hydroxylation); and rifampicin and dexamethasone induced CYP3A11 activities in the three Delta 202 cell lines, whereas only AMH-Delta 202 cells reproduced to a limited extent the response of CYP2E1 to ethanol observed in hepatocytes. 5. The results suggest that generation of hepatocyte lines from transgenic animals constitutes a successful approach to obtain in vitro models alternative to primary hepatocytes for drug metabolism and CYP inducibility studies.

Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular mortality for reasons which are insufficiently understood. Chronic inflammation may impair vascular function and lead to an increase of arterial stiffness, an important determinant of cardiovascular risk. OBJECTIVE: To investigate the augmentation index (AIx) as a measure of arterial stiffness in patients with RA, free of cardiovascular disease or risk factors, by means of a matched cohort pilot study. METHOD: Patients with a diagnosis of RA, aged 50 years or younger, were screened for the absence of clinical cardiovascular disease and risk factors, such as smoking, hypercholesterolaemia, hypertension, and excessive systemic steroid use. Suitable subjects were assessed by non-invasive radial pulse wave analysis to determine their AIx. These data were compared with those from healthy controls, matched closely for sex, age, mean peripheral blood pressure, heart rate, and height. RESULTS: 14 suitable patients (11 female; mean (SD) age 42 (6) years, mean RA duration 11 (6) years; mean C reactive protein 19 (15) mg/l, no clinical systemic rheumatoid vasculitis) and matched controls were identified. The RA group had a higher mean (SD) AIx and mean (SD) central blood pressure (BP) than the control group: AIx 26.2 (6.7) v 18.9 (10.8)%, p=0.028; mean central BP 91.3 (7.8) v 88.2 (8.9) mm Hg, p<0.0001, by two tailed, paired t test. CONCLUSIONS: This preliminary study suggests that RA is associated with increased arterial stiffness and central BP, independently of clinically manifest cardiovascular disease or risk factors. This may contribute to the increased cardiovascular mortality in RA.

Increased susceptibility to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in transgenic mice overexpressing c-myc and epidermal growth factor in alveolar type II cells.

PURPOSE: As previously described, SPC/myc transgenic mice developed bronchioloalveolar adenocarcinomas derived from alveolar type II (AT II) cells within 10-14 months, whereas SPC/IgEGF transgenic mice developed hyperplasias. Our purpose was to determine the potential interplay of environmental and genetic factors in lung tumorigenesis. MATERIALS AND METHODS: Six-week-old SPC/myc and SPC/IgEGF transgenic mice, overexpressing c-myc and a secretable form of the epidermal growth factor (IgEGF) under the control of the surfactant protein C (SPC) promoter, were treated with a single dose of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). As control groups, SPC/myc and SPC/IgEGF transgenic mice were treated with NaCl and non-transgenic littermates were treated with NNK or NaCl, respectively. RESULTS: After 6 months, none of the NaCl-treated transgenic littermates showed bronchioloalveolar hyperplasia and adenocarcinoma formation, whereas 100% of the NNK-treated SPC/myc transgenic mice did. The effect of NNK on SPC/IgEGF transgenic mice was less pronounced, inducing hyperplasia in the lung in only 16.7% of them. In 90% of the NNK-treated non-transgenic littermates no neoplastic changes were detected in the lung. CONCLUSIONS: These results demonstrate that the progression of pulmonary bronchioloalveolar adenocarcinomas, induced by expression of c-myc as a transgene, was accelerated by NNK, suggesting that c-myc cooperates with NNK-induced mutations.

Application of cDNA arrays to monitor mRNA profiles in single preimplantation mouse embryos.

Array technology is a widely used tool for gene expression profiling in various biological systems. However, the application of this method to mammalian preimplantation embryos is limited by the small amount of mRNA that can be extracted from a single embryo, which is not sufficient for array analysis. Here we report a protocolfor the rapid global amplification of embryonic mRNA that permits the generation of expression profiles from single murine blastocysts. The approach combines global PCR and 77 RNA polymerase amplification and allows the preparation of labeled, amplified RNA for array hybridization from single murine blastocysts containing approximately 1.5 pg mRNA in less than 12 h. We demonstrate that this amplification procedure is highly reproducible and does not bias original relative mRNA levels. Signal patterns from various embryonic stages of murine development revealed marked differences in mRNA expression that were in accordance with previously published data. We found genes known to be involved in embryonic apoptosis expressed at different levels in individual murine day 3.5 blastocysts. This technique can thus be used to assess embryonic viability and investigate molecular mechanisms of embryonic development.

Localization of 3-nitrotyrosine to rheumatoid and normal synovium.

OBJECTIVE: To determine the localization of 3-nitrotyrosine (3-NT), a footprint marker of peroxynitrite (ONOO-) and other reactive nitrogen species, to the inflamed human synovium and to compare this with normal synovial and nonsynovial tissue of human and animal origin. METHODS: Monoclonal and polyclonal antibodies were used to investigate for 3-NT, inducible nitric oxide synthase (iNOS), macrophage marker CD68, and the vascular smooth muscle marker alpha-actin by avidin-biotin immunocytochemistry. RESULTS: In the inflamed synovium, 3-NT was found in the vascular smooth muscle and macrophages. In normal human synovium, 3-NT was present in the vascular smooth muscle and some lining cells and was not associated with immunoreactivity for iNOS. Similarly, 3-NT could be demonstrated in the vascular smooth muscle cells of normal rats and iNOS knockout mice. It was not present in the vascular smooth muscle of healthy, nonsynovial tissue. CONCLUSION: The synovial vasculature in histologically normal human and naive rodent synovium was alone among the normal tissues studied in exhibiting iNOS-independent immunoreactivity for 3-NT. These findings suggest a physiologic role for ONOO- in normal synovial vascular function.

The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population.

Reduced pulmonary function is an important predictor of mortality in the general population, and antioxidant vitamins are thought to positively influence pulmonary function. Vitamin C, vitamin E, retinol, and carotenoids are powerful antioxidants but information about the joint relation of serum levels of these antioxidants to pulmonary function is limited. We analyzed the association of FEV(1) and FVC with serum vitamins C and E, retinol, and carotenoids (beta-cryptoxanthin, lutein/zeaxanthin, beta-carotene, and lycopene) in a cross-sectional study. The analysis was carried out in a sample of 1,616 randomly selected residents of Western New York, USA, age 35 to 79 yr and free of respiratory disease. Lung function was adjusted for height, age, sex, and race and expressed as percentage of predicted normal FEV(1) (FEV(1)%) and FVC (FVC%). Participants in the lowest quartile of each of the serum antioxidants had consistently lower FEV(1)% and FVC% than those in higher quartiles. Multiple linear regression analysis revealed significant associations of vitamin C, vitamin E, beta-cryptoxanthin, lutein/zeaxanthin, beta-carotene, and retinol with FEV(1)% when these variables were investigated individually after adjustment for other covariates (smoking status, pack-years of smoking, weight, eosinophil count, and education). When all of these antioxidant vitamins were analyzed simultaneously in a multivariate regression model, the strongest association was seen with vitamin E and beta-cryptoxanthin. Only retinol showed an independent effect on FEV(1)% after controlling for vitamin E and beta-cryptoxanthin. As for FEV(1)%, vitamin E and beta-cryptoxanthin were most strongly related to FVC% when all variables were considered in the multivariate regression model. The differences in FEV(1) associated with a reduction of one standard deviation of serum vitamin E or beta-cryptoxanthin were equivalent to the negative influence of approximately 1 to 2 yr of aging. Our findings support the hypothesis that antioxidant vitamins may play a role in respiratory health and that vitamin E and beta-cryptoxanthin appear to be stronger correlates of lung function than other antioxidant vitamins.

Development of pulmonary bronchiolo-alveolar adenocarcinomas in transgenic mice overexpressing murine c-myc and epidermal growth factor in alveolar type II pneumocytes.

Transgenic mouse models were established to study tumorigenesis of bronchiolo-alveolar adenocarcinomas derived from alveolar type II pneumocytes (AT-II cells). Transgenic lines expressing the murine oncogene c- myc under the control of the lung-specific surfactant protein C promoter developed multifocal bronchiolo-alveolar hyperplasias, adenomas and carcinomas respectively, whereas transgenic lines expressing a secretable form of the epidermal growth factor (IgEGF), a structural and functional homologue of transforming growth factor alpha (TGF alpha), developed hyperplasias of the alveolar epithelium. Since the oncogenes c- myc and TGF alpha are frequently overexpressed in human lung bronchiolo-alveolar adenocarcinomas, these mouse lines are useful as models for human lung bronchiolo-alveolar adenocarcinomas. The average life expectancies of hemizygous and homozygous c- myc transgenics were 14.25 months and 9.2 months, respectively, suggesting that a dosage effect of c- myc caused an accelerated bronchiolo-alveolar adenocarcinoma formation. First analyses of double transgenics, hemizygous for both c- myc and IgEGF, show that these mice develop bronchiolo-alveolar adenocarcinomas at the average age of 9 months, indicating that these oncogenes cooperate during the lung cancer formation. Our results demonstrate that c- myc and EGF are directly involved and cooperate with one another during formation of bronchiolo-alveolar adenocarcinomas in the lung.