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Background: Chronic obstructive pulmonary disease (COPD) and asthma can be treated with inhaled corticosteroids (ICS) delivered by low climate impact inhalers (dry powder inhalers) or high climate impact inhalers (pressurized metered-dose inhalers containing potent greenhouse gasses). ICS delivered with greenhouse gasses is prescribed ubiquitously and frequent despite limited evidence of superior effect. Our aim was to examine the beneficial and harmful events of ICS delivered by low and high climate impact inhalers in patients with asthma and COPD., Methods: Nationwide retrospective cohort study of Danish outpatients with asthma and COPD treated with ICS delivered by low and high climate impact inhalers. Patients were propensity score matched by the following variables; age, gender, tobacco exposure, exacerbations, dyspnoea, body mass index, pulmonary function, ICS dose and entry year. The primary outcome was a composite of hospitalisation with exacerbations and all-cause mortality analysed by Cox proportional hazards regression., Results: Of the 10,947 patients with asthma and COPD who collected ICS by low or high climate impact inhalers, 2,535 + 2,535 patients were propensity score matched to form the population for the primary analysis. We found no association between high climate impact inhalers and risk of exacerbations requiring hospitalization and all-cause mortality (HR 1.02, CI 0.92-1.12, p = 0.77), nor on pneumonia, exacerbations requiring hospitalization, all-cause mortality, or all-cause admissions. Delivery with high climate impact inhalers was associated with a slightly increased risk of exacerbations not requiring hospitalization (HR 1.10, CI 1.01-1.21, p = 0.03). Even with low lung function there was no sign of a superior effect of high climate impact inhalers., Conclusion: Low climate impact inhalers were not inferior to high climate impact inhalers for any risk analysed in patients with asthma and COPD., (© 2024. The Author(s).)

This review highlights key aspects of treating chronic obstructive pulmonary disease (COPD) exacerbation, focusing on the optimisation of systemic corticosteroid and antibiotic use through personalised treatment using biomarkers. Eosinophil-guided therapy reduces corticosteroid usage which might reduce side effects, while procalcitonin-guided therapy contributes to reduced antibiotic consumption. These approaches, documented through well-conducted randomized controlled trials, suggest the possibility of enhancing COPD exacerbation management, reducing potential side effects, and addressing concerns related to antibiotic resistance., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: Sedating antihistamines such as promethazine are used as anxiolytics and hypnotic agents for patients with chronic obstructive pulmonary disease (COPD) with and without asthma despite limited knowledge of its effects and side effects. We evaluated if treatment with promethazine had a lower risk of harmful outcome., Methods: Nationwide retrospective cohort study of Danish specialist diagnosed outpatients with COPD treated with promethazine or an active comparator (melatonin). Patients with collection of promethazine or melatonin were propensity score matched 1:1. The primary outcome was a composite of severe COPD exacerbations and death from all causes analyzed by Cox proportional hazards regression. We performed an interaction analysis for comorbid asthma., Results: In our registry of 56,523 patients with COPD, 5,661 collected promethazine ( n  = 3,723) or melatonin ( n  = 1,938). A cohort of 3,290 promethazine- or melatonin-treated patients matched 1:1 was available for the primary analysis.Within 1-year patients treated with promethazine were at higher risk of the primary outcome than matched controls with a Hazard Ratio (HR) of 1.42 (CI 1.27-1.58, p  < 0.0001). Similarly, the risk of death was higher for promethazine-treated patients (HR 1.53, CI 1.32-1.77, p  < 0.0001). An interaction analysis for comorbid asthma showed no interaction between comorbid asthma and the likelihood of a primary outcome when collecting promethazine ( p  = 0.19). Adjusted Cox analysis on the entire population indicated a further increased risk with more promethazine (HR for primary outcome among patients collecting ≥ 400 promethazine tablets/year=2.15, CI 1.94-2.38, p <0.0001)., Conclusions: Promethazine-treated patients with COPD had a concerning excess risk of a composite outcome of severe exacerbations and death from all causes compared to melatonin., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Inhaled corticosteroids (ICSs) are associated with an increased risk of pneumonia among patients with chronic obstructive pulmonary disease (COPD). The introduction of extrafine particle ICS has aimed to improve the distribution of medicine in the airways by altering deposition within the lungs, potentially affecting efficacy and side effects. It remains unclear if extrafine particle ICS administration alters the risk of pneumonia compared with standard particle size ICS., Methods: An observational cohort study including all Danish COPD outpatients receiving ICS from 2010 to 2017. The primary outcome was pneumonia hospitalisation in the different ICS particle dosing regimens. The primary analysis was an adjusted Cox proportional hazards model. For sensitivity analysis, a subgroup analysis of patients receiving spray devices was done. Further, we created a propensity score matched cohort, in which we matched for the same covariates as adjusted for in the main analysis., Results: A total of 35 691 patients were included of whom 1471 received extrafine particle ICS. Among these patients, 4657 were hospitalised due to pneumonia. Patients with COPD receiving extrafine particle ICS had a lower risk of hospitalisation due to pneumonia compared with patients receiving standard particle size ICS in our primary analysis (HR 0.75; 95% CI 0.63 to 0.89; p=0.002), subgroup analysis (HR 0.54; 95% CI 0.45 to 0.65; p<0.0001) and the propensity-matched population (HR 0.72; 95% CI 0.60 to 0.87; p=0.0006)., Interpretation: The use of extrafine particle ICS administration was associated with a lower risk of pneumonia hospitalisation in patients with COPD compared with those who received standard size treatment., Competing Interests: Competing interests: The authors declare that there are no conflicts of interest regarding this article. However, to ensure full transparency, we disclose the following potential conflicts of interest. ASJ, BB, CKH, CR, HKJ, JE, JGH, TW, J-USJ, PS and ZBH declare no potential conflicts of interest. RS has received support for congress fees and travel expenses from Abbort. TSIngebrigtsen is a member of the Danish Society of Anesthesiology’s scientific advisory board. TSItenov is involved in Astra Zenica’s advisory board for biological treatment of severe asthma. TB-S has received consulting fees from GSK and Sanofi Pasteur. Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Sanofi Pasteur and GSK. Received support for attending meetings and/or travel by Astra Zeneca. Participation on Data Safety Monitoring Board or Advisory Board for GSK and Sanofi Pasteur. Receipt of equipment, materials, drugs, medical writing, gifts or other services from GE., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: International guidelines only advocate the use of inhaled corticosteroids (ICSs) in patients with chronic obstructive pulmonary disease (COPD) experiencing recurring exacerbations and eosinophilic inflammation. However, ICSs are commonly used in patients with COPD and without exacerbations and signs of eosinophilic inflammation, thus possibly increasing the risk of hospitalization for pneumonia. Thus, we aimed to determine the risk of hospitalization for pneumonia associated with increasing cumulated ICS doses among patients with COPD to establish whether there is dose dependency., Methods: A retrospective cohort study included all patients with COPD treated at a respiratory outpatient clinic in Denmark. The patients were divided into four groups based on their average daily ICS exposure. The dose-response relationship was investigated using a multivariable Cox proportional hazard regression analysis., Results: In total, 52 100 patients were included, who were divided into the no-use (n = 15 755), low-dose (n = 12 050), moderate-dose (n = 12 488), and high-dose (n = 11 807) groups. ICS use was strongly associated with hospitalization for pneumonia (hazard ratio [HR], 1.3; CI, 1.2-1.3) (ICS vs. no ICS). The risk of hospitalization for pneumonia increased with every dosing group step: low dose: HR, 1.1 (CI, 1.0-1.2); moderate dose: HR, 1.2 (CI, 1.1-1.3), and high dose: HR, 1.5 (CI, 1.4-1.6); "no use" was the reference. Sensitivity analyses confirmed these findings., Conclusions: In the dose-response relationship analysis, ICS dose were associated with a substantially increased risk of hospitalization for pneumonia of up to 50%. Our data support that ICSs should be administered at the lowest possible dose and only to patients with COPD who have a documented need., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic low-grade inflammation as in asthma may lead to a higher risk of cardiovascular events. We evaluated whether patients with COPD and asthma have a higher risk of acute cardiovascular events than patients with COPD without asthma., Methods: Nationwide multicentre retrospective cohort study of Danish outpatients with a specialist diagnosis of COPD with or without asthma. Patients with both COPD and asthma were propensity-score matched 1:2 to patients with COPD without asthma. The primary end-point was severe major adverse cardiac events (MACE), defined as mortal cardiovascular events and events requiring revascularisation or hospitalisation., Results: A total of 52 386 Danish patients with COPD were included; 34.7% had pre-existing cardiovascular disease, and 20.1% had asthma in addition to their COPD. Patients with pre-existing cardiovascular disease were then propensity-score matched: 3690 patients with COPD and asthma versus 7236 patients with COPD without asthma, and similarly, for patients without pre-existing cardiovascular disease (6775 matched with 13 205). The risk of MACE was higher among patients with asthma and COPD versus COPD without asthma: hazard ratio (HR) 1.25 (95% CI 1.13-1.39, p<0.0001) for patients with pre-existing cardiovascular disease and HR 1.22 (95% CI 1.06-1.41, p=0.005) for patients without pre-existing cardiovascular disease., Conclusion: Among patients with COPD, asthma as a comorbid condition is associated with substantially increased risk of cardiovascular events. The signal was an increased risk of 20-25%. Based on our study and other smaller studies, asthma can be considered a risk factor for cardiovascular events among COPD patients., Competing Interests: Conflict of interest: B. Bonnesen has nothing to disclose. Conflict of interest: P. Sivapalan has nothing to disclose. Conflict of interest: A.K. Kristensen has nothing to disclose. Conflict of interest: M.C.H. Lassen has nothing to disclose. Conflict of interest: K.G. Skaarup has nothing to disclose. Conflict of interest: E. Rastoder has nothing to disclose. Conflict of interest: R. Sørensen has nothing to disclose. Conflict of interest: J. Eklöf has nothing to disclose. Conflict of interest: T. Biering-Sørensen has nothing to disclose. Conflict of interest: J-U. Stæhr Jensen has nothing to disclose., (Copyright ©The authors 2022.)

Background: Social distancing measures introduced during the coronavirus disease 2019 pandemic have reduced admission rates for various infectious and noninfectious respiratory diseases. We hypothesized that rates of asthma exacerbations would decline following the national lockdown in Denmark., Objective: To determine weekly rates of in- and out-of-hospital asthma exacerbations before and during the social distancing intervention implemented on March 12, 2020., Methods: All individuals older than 18 years with at least 1 outpatient hospital contact with asthma as the main diagnosis from January 1, 2013, to December 31, 2017, were included. Weekly asthma exacerbation rates from January 1, 2018, to May 22, 2020, were calculated. An interrupted time-series model with the lockdown on March 12, 2020, as the point of interruption was used., Results: A total of 38,225 patients with asthma were identified. The interrupted time-series model showed no immediate fall in exacerbation rates during the first week after March 12, 2020. However, there was a significant decline in weekly exacerbation rates in the following 10 weeks (change in trend for exacerbations requiring hospitalization: -0.75 [95% CI, -1.39 to -0.12]; P < .02 and in all asthma exacerbations: -12.2 [95% CI, -19.1 to -5.4; P < .001), amounting to a reduction of approximately 1 and 16.5 exacerbations per year per 100 patients in the cohort, respectively., Conclusions: The introduction of the social distancing measures in Denmark did not lead to an immediate reduction in asthma exacerbation rates; however, a gradual decline in exacerbation rates during the following 10-week period was observed., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation such as asthma may lead to higher risks of malignancy, which may be inhibited by anti-inflammatory medicine such as inhaled corticosteroids (ICS). The aim of this study was to evaluate if patients with asthma-Chronic Obstructive Pulmonary Disease (COPD) overlap have a higher risk of malignancy than patients with COPD without asthma, and, secondarily, if inhaled corticosteroids modify such a risk in a nationwide multi-center retrospective cohort study of Danish COPD-outpatients with or without asthma. Patients with asthma-COPD overlap were propensity score matched (PSM) 1:2 to patients with COPD without asthma. The endpoint was cancer diagnosis within 2 years. Patients were stratified depending on prior malignancy within 5 years. ICS was explored as a possible risk modifier. We included 50,897 outpatients with COPD; 88% without prior malignancy and 20% with asthma. In the PSM cohorts, 26,003 patients without prior malignancy and 3331 patients with prior malignancy were analyzed. There was no association between asthma-COPD overlap and cancer with hazard ratio (HR) = 0.92, CI = 0.78-1.08, p = 0.31 (no prior malignancy) and HR = 1.04, CI = 0.85-1.26, and p = 0.74 (prior malignancy) as compared to patients with COPD without asthma. ICS did not seem to modify the risk of cancer. In conclusion, in our study, asthma-COPD overlap was not associated with an increased risk of cancer events.

Patients admitted to hospital with coronavirus disease 2019 (COVID-19) may develop acute respiratory failure (ARF) with compromised gas exchange. These patients require oxygen and possibly ventilatory support, which can be delivered via different devices. Initially, oxygen therapy will often be administered through a conventional binasal oxygen catheter or air-entrainment mask. However, when higher rates of oxygen flow are needed, patients are often stepped up to high-flow nasal cannula oxygen therapy (HFNC), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or invasive mechanical ventilation (IMV). BiPAP, CPAP, and HFNC may be beneficial alternatives to IMV for COVID-19-associated ARF. Current evidence suggests that when nasal catheter oxygen therapy is insufficient for adequate oxygenation of patients with COVID-19-associated ARF, CPAP should be provided for prolonged periods. Subsequent escalation to IMV may be implemented if necessary.

Species (spp.) belonging to the genus Fusobacterium are anaerobic commensals colonizing the upper respiratory tract, the gastrointestinal tract, and the genitals. Infections with Fusobacterium spp. have been reported at many anatomical sites, including pneumonias and pleural empyemas; however, there are very few published cases of Fusobacterium spp. causing spondylodiscitis or fistulas. Bone infections with Fusobacterium can spread directly to surrounding muscular tissue or by hematogenous transmission to any other tissue including pleurae and lungs. Similarly, pleural infections can spread Fusobacterium spp. to any other tissue including fistulas and bone. Concomitant pleural empyema and spondylodiscitis are rare; however, there are a few published cases with concomitant disease, although none caused by Fusobacterium spp. A 77-year-old female patient was assessed using computed tomography (CT) scanning of the thorax and abdomen, as well as analyses of fluid drained from the region affected by the pleural empyema. A diagnosis of Fusobacterium empyema, fistula, bacteremia, and spondylodiscitis was made, and the patient's condition improved significantly after drainage of the pleural empyema and relevant long-term antibiotic treatment. We describe the first confirmed case with concomitant infection with Fusobacterium nucleatum as spondylodiscitis and pleural empyema connected by a fistula., (© 2021 APMIS. Published by John Wiley & Sons Ltd.)

Acute respiratory distress syndrome (ARDS) is an acute inflammation of the lung resulting from damage to the alveolar-capillary membrane, and it is diagnosed using a combination of clinical and physiological variables. ARDS develops in approximately 10% of hospitalised patients with pneumonia and has a mortality rate of approximately 40%. Recent research has identified several biomarkers associated with ARDS pathophysiology, and these may be useful for diagnosing and monitoring ARDS. They may also highlight potential therapeutic targets. This review summarises our current understanding of those clinical biomarkers: (1) biomarkers of alveolar and bronchiolar injury, (2) biomarkers of endothelial damage and coagulation, and (3) biomarkers for treatment responses.

Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has presented health-care systems worldwide with novel challenges and experiences and evidence is emerging during the pandemic. Patients requiring hospitalization frequently suffer from respiratory failure of different severities., Aim: The aim of this guideline is the treatment of patients with SARS CoV-2 (COVID-19) in hospital; in particular, it addresses the treatment of respiratory failure treated in general Internal Medical- and Pulmonary Medical wards., Results: Elderly patients and patients with chronic disease are particularly vulnerable to COVID-19. Target oxygen saturation should be between 92% and 96% in patients without chronic lung diseases. Treatment with >5 L oxygen/min should be in close collaboration with intensive care colleagues and >15 l/min preferably in intensive care units. High-flow nasal canula (HFNC) and long-term Continuous Positive Airway Pressure (CPAP) are recommended for patients not responding to conventional oxygen therapy. Non-invasive ventilation (NIV) is only recommended for selected patients, such as those with a ceiling of treatment or patients presenting with hypercapnic failure. With the use of humidification protective equipment as FFP2-3 masks should be used. Nebulized medication should be avoided, and spacers should be used instead., Conclusion: Respiratory failure is frequently the cause of hospitalization in patients with COVID-19 and should be monitored closely., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: It is still a matter of debate whether the outcome of community acquired pneumonia is more severe in patients with chronic obstructive pulmonary disease. We aimed to determine whether chronic obstructive pulmonary disease was associated with increased mortality and to identify risk-factors for mortality in patients with community acquired pneumonia and chronic obstructive pulmonary disease., Methods: Retrospective cohort study comparing patients with community acquired pneumonia and chronic obstructive pulmonary disease to patients without chronic obstructive pulmonary disease. We included 1309 patients with community acquired pneumonia admitted from 2011 until 2012 (243 patients with chronic obstructive pulmonary disease and 1066 without chronic obstructive pulmonary disease)., Results: At admission patients with community acquired pneumonia and chronic obstructive pulmonary disease presented with more severe pneumonia as measured by CURB-65 score compared to patients without chronic obstructive pulmonary disease. Mortality on day 30 was generally high, and higher among patients with community acquired pneumonia and chronic obstructive pulmonary disease compared to those without chronic obstructive pulmonary disease (16.0% versus 11.3%, p = .04). In an adjusted analysis, however, chronic obstructive pulmonary disease was not independently associated with 30-d mortality (odds ratio 0.94, confidence interval 95% 0.59-1.50). Factors related to mortality in patients with community acquired pneumonia and chronic obstructive pulmonary disease were age, premorbid condition, severity of pneumonia as determined by CURB-65 score, and pleural effusion and multi-lobular infiltrate on chest X-ray., Conclusions: Chronic obstructive pulmonary disease was not independently associated with 30-d mortality in patients with community acquired pneumonia.

Introduction: Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case-control studies., Material and Methods: This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self-reported and ultrasound examination-based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self-reported and ultrasound examination-based gestational age were compared with women with a deviation of 7 days or less., Results: Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001)., Conclusion: Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

We describe characteristics and risk factors regarding pregnancy outcome in women with a preconception body mass index (BMI) >50 kg/m² compared with women with BMI ≤50 kg/m² in a retrospective population cohort study in singleton pregnancies from the Danish Medical Birth Registry. Results were analyzed as relative risks by a two-proportion z-test. Women with preconception BMI >50 kg/m² smoked, developed gestational diabetes and pre-eclampsia, and needed induction of labor more frequently than mothers with BMI ≤50 kg/m². Examination of the case records showed that many attempted vaginal delivery without epidural analgesia, 21% needed an emergency cesarean section (compared with 12% among women with BMI ≤50 kg/m²), and 25% underwent general anesthesia in this context. Many neonates were macrosomic and 34% needed neonatal intensive care and early feeding compared with 6% of neonates from women with BMI ≤50 kg/m². Women with an extremely high preconception BMI develop more pregnancy complications and their neonates appear affected by this as well., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: The majority of patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced inoperable disease. While treatment with conventional chemotherapy has improved during the last decade the 5 years survival is still modest. Novel drugs, which selectively target aberrant elements in neoplastic cells and their microenvironment have recently been and are continuously developed including drugs inhibiting the angiogenic system. Angiogenic factor vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) seem to play key roles in tumour-induced angiogenesis. Previous studies have been inconclusive on the topic of a role for VEGF and its receptor as prognostic factors in NSCLC., Methods: Paraffin-embedded histological material from 102 patients operated for NSCLC was included and a representative block with lung cancer tissue was selected from each patient for immunohistochemical studies. The sections were incubated with primary monoclonal antibodies to VEGF-A and VEGFR2. The expression of the immunohistochemical staining was assessed semi-quantitatively by estimating the percentage and the intensity of tumour cells stained on whole tumour slides. Kaplan-Meier survival curves were generated to evaluate the significance of immunohistochemical VEGF-A and VEGFR2 expression for the prognosis., Results: VEGF-A and VEGFR2 expression was observed in the majority of NSCLC patients. VEGF-A expression showed a correlation to histological type with increased expression in adenocarcinomas as compared to squamous cell carcinomas. There was no statistically significant correlation between VEGF-A and VEGFR2 expression and age, gender or stage at diagnosis. Finally there was no relation between expression of VEGF-A and VEGFR2, nor an effect of high expression of both VEGF-A and VEGFR2 on survival., Conclusion: In conclusion VEGF-A and VEGFR2 are expressed in NSCLC, but the immunohistochemical expression of VEGF-A and VEGFR2 has no prognostic impact in NSCLC. We show that the histological subgroups of NSCLC express VEGF-A differently, with adenocarcinomas having the highest amount. Whether these markers might be useful as clinically reliable predictive markers remains to be solved.

MEK kinase 1 (MEKK1) is a potent JNK-activating kinase, a regulator of T helper cell differentiation, cytokine production and proliferation in vitro. Using mice deficient for MEKK1 activity (Mekk1(DeltaKD)) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus-specific immune response. Mekk1(DeltaKD) mice challenged with vesicular stomatitis virus (VSV) showed a fourfold increase in splenic CD8(+) T cell numbers. In contrast, the number of splenic T cells in infected WT mice was only marginally increased. The CD8(+) T cell expansion in Mekk1(DeltaKD) mice following VSV infection is virus-specific and the frequency of virus-specific T cells is significantly higher (more than threefold) in Mekk1(DeltaKD) as compared to WT animals. Moreover, the hyper-expansion of T cells seen in Mekk1(DeltaKD) mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus-specific Mekk1(DeltaKD) CD8(+) T cells incorporated BrdU as compared to virus-specific WT CD8(+) T cells. In contrast, similar levels of apoptosis were detected in Mekk1(DeltaKD) and WT T cells following VSV infection. These results strongly suggest that MEKK1 plays a negative regulatory role in the expansion of virus-specific CD8(+) T cells in vivo.

Mitogen-activated protein kinase/extracellular signal to regulated kinase (MEK) kinase 1 (MEKK1) is a c-Jun N-terminal kinase (JNK) activating kinase known to be implicated in proinflammatory responses and cell motility. Using mice deficient for MEKK1 kinase activity (Mekk1(DeltaKD)) we show a role for MEKK1 in definitive mouse erythropoiesis. Although Mekk1(DeltaKD) mice are alive and fertile on a 129 x C57/BL6 background, the frequency of Mekk1(DeltaKD) embryos that develop past embryonic day (E) 14.5 is dramatically reduced when backcrossed into the C57/BL6 background. At E13.5, Mekk1(DeltaKD) embryos have normal morphology but are anemic due to failure of definitive erythropoiesis. When Mekk1(DeltaKD) fetal liver cells were transferred to lethally irradiated wild-type hosts, mature red blood cells were generated from the mutant cells, suggesting that MEKK1 functions in a non-cell-autonomous manner. Based on immunohistochemical and hemoglobin chain transcription analysis, we propose that the failure of definitive erythropoiesis is due to a deficiency in enucleation activity caused by insufficient macrophage-mediated nuclear DNA destruction.