Sigurd Steinshamn

Effects of preterm birth and fetal growth retardation on cardiovascular risk factors in young adulthood

BACKGROUND The association between low birth weight (LBW) and increased risk of obesity, hypertension and cardiovascular disease later in life is well documented in epidemiological studies. However, clinical follow-up studies of LBW populations have only partly supported this. AIMS Evaluate associations between LBW and body fat, blood pressure (BP), lung and endothelial function, and maximal oxygen uptake (VO(2max)) in 18 year old young adults. SUBJECTS Thirty-seven subjects born prematurely with birth weight <1501 g (VLBW group), 47 born at term with low weight (<10th centile) for gestational age (SGA group) and 63 controls with normal birth weight participated in the study. OUTCOME MEASURES Anthropometric measurements, BP, endothelial function, lung function and VO(2max) were recorded. RESULTS Both LBW groups were shorter, lighter, had smaller head circumference and higher subscapular-to-triceps skinfold-ratio than controls. Systolic and mean arterial BP was higher in the VLBW compared with the control group, whereas there were no differences between the groups in endothelial function. The VLBW group had reduced dynamic lung volumes lower carbon monoxide transfer factor and lower VO(2max) compared with controls. In particular young adults born VLBW who were also growth retarded in utero had higher indices of central body fat, higher BP and lower VO(2max). CONCLUSION We found that very preterm birth, but not growth retardation at term, was associated with higher BP and a less favourable fat distribution. In particular, the young adults born VLBW who were also growth retarded in utero had less favourable outcomes.

Cytokine mediators of septic infections in the normal and granulocytopenic host.

Abstract: Cytokines presently known to be involved in systemic bacterial infection are tumour‐necrosis factor (TNF), interleukin (IL)‐1, IL‐6, IL‐8 and interferon‐gamma (IFN‐γ) and the counterregulatory molecules soluble TNF receptor (sTNFR) and IL‐1 receptor antagonist (IL‐1 Ra). In animal models TNF, IL‐1 and IFN‐γ mediate organ damage, low blood pressure and fatality, whereas IL‐6 is involved in infection‐related manifestations, like the production of acute‐phase protein and fever, and IL‐8 is chemotactic to granulocytes. TNF and IL‐1 increase expression of adhesion molecules on endothelial cells and influence a number of components of the haemostatic system in favour of coagulation. The presence of cytokines in the circulation is characterized by sequential releases of TNF, IL‐1 and IL‐6/IL‐8; however, many variations of this pattern exist during human infection. In experiments as well as in human infection TNF, IL‐1, IL‐6, IL‐8 and IFN‐γ have been detected, and levels of TNF, IL‐6 and IL‐8 have been found to be associated with the severity of the disease. Collectively, TNF, IL‐1 and IFN‐γ emerge as mediators of systemic infection and septic shock whereas IL‐6 and IL‐8 are related to other manifestations of infection. Counteracting molecules like sTNFR are released after somewhat of a delay following TNF and IL‐1Ra is released concomitantly with IL‐1. Probably these factors modulate the cytokine effect although their true potency in natural infection has yet to be clarified. In granulocytopenic infections TNF, IL‐1, IL‐6 and IL‐8 can be detected in scrum, and levels of TNF and IL‐6 are even higher than in the normal situation in experimental animals. Antibodies to TNF inhibit bacteria‐induced fatality in granulocytopenic mice. Altogether, few data related to the granulocytopenic situation are available. However, it is reasonable to believe that the altered development of granulocytopenic infections is due to changes in the cellular constitution and not to changes in cytokine production.

Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial

Background Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β2 agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0–4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV1) (23–24 h postdose; day 29) and wm FEV1 (0–4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV1 per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0–4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI −3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV1 (mean difference 183 ml) and 0–4 h postdose wm FEV1 (mean difference 236 ml). Conclusion FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov—NCT00731822.

Interleukin 8 in serum in granulocytopenic patients with infections.

Serum levels of interleukin 8 (IL‐8) were examined in eight patients with acute myeloid leukaemia during 16 courses of chemotherapy. The patients experienced 14 episodes of fever which occurred in periods with granulocyte counts <0·5 × 109/l. Febrile episodes were classified as bacteriologically defined infection (n= 6), clinically defined infection (n= 2), and unexplained fever (n= 6). IL‐8 was detected in 18/25 (72%), 2/3 (67%) and 3/7 (43%) of the serum samples in the respective groups. In contrast, IL‐8 was detected in 22/90 (24%) of the samples taken when no fever was present (P<0·00003 versus bacteriologically defined infection). The median concentration of IL‐8 in samples taken during febrile episodes was 194 ng/ml (range 0–6358 ng/ml) and 0 (range 0–5392 ng/ml) on days without fever (not significant). In three patients with infections caused by, respectively, Streptococcus sanguis, Acinetobacter calcoanitratus and Candida albicans, IL‐8 rose to a peak levels and declined during recovery. We conclude that IL‐I is released systemically during infections with gram‐positive and gram‐negative bacteria and Candida albicans in patients with acute myeloid leukaemia and peripheral granulocytopenia due to chemotherapy. However, IL‐8 can also be detected when no sign of infection is present.

High intensity knee extensor training restores skeletal muscle function in copd patients

Improving reduced skeletal muscle function is important for optimising exercise tolerance and quality of life in chronic obstructive pulmonary disease (COPD) patients. By applying high-intensity training to a small muscle group, we hypothesised a normalisation of muscle function. Seven patients with COPD performed 6 weeks (3 days·week−1) of high-intensity interval aerobic knee extensor exercise training. Five age-matched healthy individuals served as a reference group. Muscle oxygen uptake and mitochondrial respiration of the vastus lateralis muscle were measured before and after the 6-week training programme. Initial peak work and maximal mitochondrial respiration were reduced in COPD patients and improved significantly after the training programme. Peak power and maximal mitochondrial respiration in vastus lateralis muscle increased to the level of the control subjects and were mainly mediated via improved complex I respiration. Furthermore, when normalised to citrate synthase activity, no difference in maximal respiration was found either after the intervention or compared to controls, suggesting normal functioning mitochondrial complexes. The present study shows that high-intensity training of a restricted muscle group is highly effective in restoring skeletal muscle function in COPD patients.

A randomised controlled study of the long-term effects of exercise training on mortality in elderly people: study protocol for the Generation 100 study

Introduction Epidemiological studies suggest that exercise has a tremendous preventative effect on morbidity and premature death, but these findings need to be confirmed by randomised trials. Generation 100 is a randomised, controlled study where the primary aim is to evaluate the effects of 5 years of exercise training on mortality in an elderly population. Methods and analysis All men and women born in the years 1936–1942 (n=6966), who were residents of Trondheim, Norway, were invited to participate. Between August 2012 and June 2013, a total of 1567 individuals (790 women) were included and randomised to either 5 years of two weekly sessions of high-intensity training (10 min warm-up followed by 4×4 min intervals at ∼90% of peak heart rate) or, moderate-intensity training (50 min of continuous work at ∼70% of peak heart rate), or to a control group that followed physical activity advice according to national recommendations. Clinical examinations, physical tests and questionnaires will be administered to all participants at baseline, and after 1, 3 and 5 years. Participants will also be followed up by linking to health registries until year 2035. Ethics and dissemination The study has been conducted according to the SPIRIT statement. All participants signed a written consent form, and the study has been approved by the Regional Committee for Medical Research Ethics, Norway. Projects such as this are warranted in the literature, and we expect that data from this study will result in numerous papers published in world-leading clinical journals; we will also present the results at international and national conferences. Trial registration number Clinical trial gov NCT01666340.

Soluble tumour necrosis factor receptors, tumour necrosis factor and interleukin-6 in serum in granulocytopenic patients with fever

Serum levels of TNF, IL‐6 and soluble TNF receptors p55 and p75 (sTNFR‐p55 and sTNFR‐p75) were examined in 14 patients with acute myeloid leukaemia during 43 courses of chemotherapy. The patients experienced 30 episodes of fever which occurred during granulocytopenia (defined as granulocyte counts <0.2×109/1) and six fever episodes when granulocyte counts were >1.0×109/1. Febrile episodes were classified as microbiologically defined infection, clinically defined infection, and unexplained fever. Levels of bioactive IL‐6 and immunoreactive TNF increased in response to fever during granulocytopenia, whereas bioactive TNF was not detected in any sample in this study. During granulocytopenia, both sTNFR rose significantly in microbiologically defined infection (P<0.01 for sTNFR‐p55 and P<0.05 for sTNFR‐p75), but not in the other two categories. The ratio of sTNFR‐p55 to sTNFR‐p75 was higher during febrile periods in granulocytopenia than in a non‐granulocytopenic situation with granulocyte counts >1.0×109/1 (P<0.01). We conclude that granulocytopenia affects release of the two sTNFR differently during febrile periods, and that release of sTNFR‐p75 in response to fever is reduced during granulocytopenia, suggesting a role for the granulocytes in systemic release of sTNFR‐p75.

Continuous monitoring of the bronchial epithelial lining fluid by microdialysis.

BackgroundContents of the epithelial lining fluid (ELF) of the bronchi are of central interest in lung diseases, acute lung injury and pharmacology. The most commonly used technique broncheoalveolar lavage is invasive and may cause lung injury. Microdialysis (MD) is a method for continuous sampling of extracellular molecules in the immediate surroundings of the catheter. Urea is used as an endogenous marker of dilution in samples collected from the ELF. The aim of this study was to evaluate bronchial MD as a continuous monitor of the ELF.MethodsMicrodialysis catheters were introduced into the right main stem bronchus and into the right subclavian artery of five anesthetized and normoventilated pigs. The flowrate was 2 μl/min and the sampling interval was 60 minutes. Lactate and fluorescein-isothiocyanate-dextran 4 kDa (FD-4) infusions were performed to obtain two levels of steady-state concentrations in blood. Accuracy was defined as [bronchial-MD] divided by [arterial-MD] in percent. Data presented as mean ± 95 percent confidence interval.ResultsThe accuracy of bronchial MD was calculated with and without correction by the arteriobronchial urea gradient. The arteriobronchial lactate gradient was 1.2 ± 0.1 and FD-4 gradient was 4.0 ± 1.2. Accuracy of bronchial MD with a continuous lactate infusion was mean 25.5% (range 5.7–59.6%) with a coefficient of variation (CV) of 62.6%. With correction by the arteriobronchial urea gradient accuracy was mean 79.0% (57.3–108.1%) with a CV of 17.0%.ConclusionUrea as a marker of catheter functioning enhances bronchial MD and makes it useful for monitoring substantial changes in the composition of the ELF.

Expression of neuroendocrine markers in non-small cell lung cancer : A biochemical, immunohistochemical and ultrastructural study

Neuroendocrine (NE) differentiation is reported in some cases of non‐small cell lung cancer (NSCLC). The aim of this study was to evaluate the expression of NE markers in NSCLC using novel sensitive methods. 20 cases of NSCLC were examined using immunohistochemical (IHC) and immunoelectron microscopy (IEM) methods. In addition, circulating levels of the NE markers chromogranin A (CgA) and neuron‐specific enolase (NSE) were measured. Using conventional IHC methods, two tumours (10%) showed immunoreactivity for synaptophysin (SYN), one (5%) for Cg and four (20%) for neural cell adhesion molecule (NCAM). Adding the tyramide signal amplification (TSA) technique, the number of immunoreactive tumours for both SYN and CgA increased to five (25%). No increased immunoreactivity was achieved for NCAM. Nine tumours (45%) were immunoreactive for SYN, CgA or NCAM. Using IEM, one of five representative samples that revealed IHC reactivity for CgA showed immunogold labelling of CgA in cytoplasmic vesicles. Elevated levels of circulating CgA or NSE did not correlate with positive IHC findings. In conclusion, using sensitive IHC methods NE differentiation was seen in a greater proportion of NSCLC than previously reported. Sensitive methods may improve our understanding of the tumour biology and represent an important diagnostic tool for future therapeutic modalities.

Increased serum levels of chromogranin A in male smokers with airway obstruction

The neuroendocrine (NE) system may play an important role in smoking-induced airway diseases. The aim of the present study was to examine the relationship between serum levels of the general NE marker chromogranin A (CgA) and smoking habits, respiratory symptoms and lung function. The study population consisted of never-smokers with normal lung function, smokers with normal lung function and smokers with airway obstruction who were randomly selected from the lung study of the Nord-Trøndelag Health Study (HUNT). Serum CgA was determined in 151, 138 and 116 subjects, respectively. All subjects were seronegative for Helicobacter pylori. Male smokers with airway obstruction had significantly higher serum CgA levels (median 3.70 nmol·L-1 (interquartile range 3.10–5.15)) than both smokers with normal lung function (3.00 nmol·L-1 (2.50–3.67)) and never-smokers with normal lung function (2.90 nmol·L-1 (2.57–3.30)). The elevated levels of CgA correlated with the degree of airway obstruction. Moreover, the presence of respiratory symptoms and chronic bronchitis among male smokers were associated with increased serum CgA levels. Females had CgA levels similar to male smokers independent of smoking status and lung function. Elevated serum chromogranin A levels in subjects with airway obstruction and respiratory symptoms may represent neuroendocrine activation in inflammatory or remodelling processes in the lung.