Somatization: the under-recognized factor in nonspecific eczema. The Hordaland Health Study (HUSK).

BACKGROUND: Psychodermatology has focused primarily on depression and anxiety in eczema. Skin symptoms are listed among many others for the ICD-10 diagnosis of somatization disorder. Somatization (unexplained somatic symptoms) is highly prevalent in the general population, but its association with eczema is yet to be empirically investigated. OBJECTIVES: We therefore explored the association between somatization and eczema by examining the extent of somatization in eczema compared with allergic rhinitis, and by examining if eczema was more strongly associated with somatization than with anxiety and depression. Finally, we aimed to examine the relationship between the site of eczema and somatization for individual somatic symptoms and for somatic symptoms as a whole. METHODS: For this population-based cross-sectional study we employed data from the Hordaland Health Study (HUSK) with 15,225 participants aged 41-48 years. Information on nonspecific eczema, allergic rhinitis, somatization, anxiety, depression and other covariates was obtained by self-report. RESULTS: The association between nonspecific eczema and somatization was strong and followed a dose-response pattern, as did all somatic symptoms in our index of somatization when analysed separately. The association between nonspecific eczema and somatization was stronger than that between rhinitis and somatization, and also the association between nonspecific eczema and anxiety and depression. In multivariate models, somatization accounted for most of the association between nonspecific eczema and anxiety/depression. In contrast, the association between nonspecific eczema and somatization was robust for adjustment for anxiety/depression. CONCLUSIONS: Somatization was strongly associated with nonspecific eczema. This applies to a whole range of somatic symptoms constituting the construct of somatization. There is hardly any mention of somatization in leading dermatological journals, in contrast to anxiety and depression which are frequently reported in eczema. We speculate that this under-recognition of somatization in the dermatological literature may correspond to under-recognition of this factor also in clinical practice.

Exercise-induced asthma in adolescents: challenges for physical education teachers.

Asthma is the most common chronic medical condition that school-teachers are likely to encounter among their pupils. This study aimed to identify the needs of physical education teachers in dealing with adolescents with exercise-induced asthma, study their self-reported knowledge of asthma and identify future topics for education about exercise-induced asthma. A questionnaire was drawn up on the basis of the requirements that had emerged in the course of interviews with 18 physical education teachers. One hundred and six physical education teachers at secondary schools in the city of Trondheim and colleges in Sør-Trøndelag County in Norway answered the questionnaire (65% response rate). Eighty-two physical education teachers (78.1%) had pupils with asthma in their sports classes, and 89.4% answered positively regarding their need for advice on teaching pupils with asthma. Twenty-seven (25.9%) reported that they had sufficient knowledge to teach adolescents with asthma. Topics about asthma, its management and activities suitable for asthmatics were given high priority by the teachers.

Hyperoxic interval training in chronic obstructive pulmonary disease patients with oxygen desaturation at peak exercise.

High-intensity work might not be preserved in chronic obstructive pulmonary disease (COPD) during whole-body exercise due to ventilatory limitations that exceed metabolic limitations, resulting in reduced training adaptations. The purpose of the present study was to address the hyperoxic effect during training and testing in COPD patients with hypoxemia at peak exercise. Six COPD and eight coronary artery disease (CAD) patients completed 24 aerobic high-intensity interval training sessions, 4x4 min in hyperoxia at 85-95% of the peak heart rate and peak exercise tested in normoxia and hyperoxia pre- and post-training. VO2peak increased in the COPD group by 19% (13-31%) and in the CAD group by 15% (7-29%), [0.98(0.68-1.52)-1.17(0.89-1.78) and 2.11(1.57-2.64)-2.44(1.92-3.39) L/min], respectively. VO2peak was higher in hyperoxia at pre- and post-test (1.22(0.80-1.87) and 1.37(1.01-1.94) L/min) in the COPD group. Work economy improved by 10% in both groups. Quality of life improved in the COPD group in terms of physical and mental health status by 24% and 35%. Hyperoxic aerobic high-intensity interval training in COPD patients with hypoxemia at peak exercise increases VO2peak, peak workload, work economy and quality of life. Acute hyperoxia increases VO2peak, peak workload at pre- and post-test compared with normoxia in the COPD patients, indicating an oxygen supply limitation to VO2peak.

Prevalence, risk factors, and type of sleep apnea in patients with paroxysmal atrial fibrillation.

BACKGROUND: Recent studies have suggested an association between sleep apnea (SA) and atrial fibrillation (AF). We aimed to study the prevalence, characteristics, risk factors and type of sleep apnea (SA) in ablation candidates with paroxysmal AF. METHODS/RESULTS: We prospectively studied 579 patients with paroxysmal AF, including 157 women (27.1%) and 422 men (72.9%). Mean age was 59.9 ± 9.6 years and mean body mass index (BMI) 28.5 ± 4.5 kg/m2. SA was diagnosed using polygraphy for two nights at home. The Epworth Sleepiness Scale (ESS), STOP-Bang Questionnaire, and Berlin Questionnaire (BQ) assessed the degree of SA symptoms. A total of 479 (82.7%) patients had an apnea-hypopnea index (AHI) ≥ 5, whereas moderate-severe SA (AHI ≥ 15) was diagnosed in 244 patients (42.1%). The type of SA was predominantly obstructive, with a median AHI of 12.1 (6.7-20.6) (range 0.4-85.8). The median central apnea index was 0.3 (0.1-0.7). AHI increased with age, BMI, waist and neck circumference, body and visceral fat. Using the Atrial Fibrillation Severity Scale and the SF-36, patients with more severe SA had a higher AF burden, severity and symptom score and a lower Physical-Component Summary score. Age, male gender, BMI, duration of AF, and habitual snoring were independent risk factors in multivariate analysis (AHI ≥ 15). We found no association between ESS and AHI (R2 = 0.003, p = 0.367). CONCLUSIONS: In our AF population, SA was highly prevalent and predominantly obstructive. The high prevalence of SA detected in this study may indicate that SA is under-recognized in patients with AF. None of the screening questionnaires predicted SA reliably.

Aerobic high intensity one-legged interval cycling improves peak oxygen uptake in chronic obstructive pulmonary disease patients; no additional effect from hyperoxia.

The aim of the present study was to investigate whether hyperoxic aerobic high intensity one-legged interval cycling improves peak oxygen uptake (V O (2peak)) compared to normoxic training in patients with severe chronic obstructive pulmonary disease, and to evaluate the acute effect of hyperoxia during one- and two-legged peak exercise testing. Twelve COPD patients were recruited to perform 3 training sessions per week for 8 weeks in hyperoxia (n=7) or normoxia (n=5). Each leg was trained 4x4 min at 85-95% of the one-legged peak heart rate. One-legged V O (2peak) increased in the hyperoxia and normoxia training groups by 24 and 15% (16.1(13.2)-20.0(11.3) and 17.4(15.1)-20.0(6.7) mL.kg (-1).min (-1)) respectively. The corresponding increases in V O (2peak) during two-legged testing were 14% in both groups (20.1(11.5)-22.9(10.6) and 18.8(8.5)-21.4(7.3) mL.kg (-1).min (-1)). There were no differences between groups from pre- to post-training. Nor were there any differences between acute hyperoxia and normoxia at the pre- or post-peak exercise test. One-legged aerobic high intensity interval cycling significantly increases V O (2peak) in COPD patients. However, breathing supplemental oxygen during training or testing does not appear to improve V O (2peak) above the level attained by breathing ambient air.

Monocyte exposure to Saccharomyces cerevisiae cell wall mannan and decreased TNF-alpha production in mild asthma: a role for mannan-binding lectin?

A correlation between fungal exposure and aggravation of inflammatory symptoms in asthmatic individuals is well documented in the literature. However, the molecular mediators responsible for clinical symptoms due to fungal exposure in individuals with asthma are still not known. The fungal cell wall polysaccharide mannan stimulates production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha in monocytes. Recently, a role for the plasma protein mannan-binding lectin (MBL) has been proposed in individuals with severe asthmatic disease, although little is known about its role in those with mild and untreated asthma. MBL has been reported to modulate inflammatory cytokine production, but the mechanisms are not known. We conducted a pilot study and found that the cell wall mannan preparation used stimulated lower TNF-alpha production by monocytes from asthmatic subjects compared with that from healthy subjects in the presence of autologous plasma. Lipopolysaccharide-induced TNF-alpha production was not significantly different between the groups. Further, plasma MBL levels in individuals with mild asthma were slightly increased compared with those in normal subjects, although the difference was not statistically significant. We speculate that reduced TNF-alpha production in monocytes from asthmatic subjects after fungal cell wall mannan stimulation could partly be influenced by plasma components such as MBL.

Lack of endotoxin tolerance with respect to TNF alpha production in the subarachnoid space.

To study endotoxin tolerance in the subarachnoid space 0.1 mg of endotoxin derived from Neisseria meningitidis was injected intracisternally into rabbits on 2 consecutive days. On day 1 the maximum peak level of TNF alpha was 7 ng/ml 2 h after injection, whereas on day 2 the highest levels were 3.6 ng/ml and 3.7 ng/ml, respectively, 1 and 2 h after injection. Pretreatment with intravenous endotoxin 5 or 21 h before consecutive intracisternal endotoxin did not affect the cerebrospinal fluid (CSF) levels of TNF alpha. In contrast, there was a marked endotoxin tolerance with respect to TNF alpha in the systemic circulation. Cells appearing in the CSF 5, 12 and 20 h after intracisternal injection of endotoxin were harvested, cultured, and then stimulated with 0.1 mg/ml of endotoxin. In 10 experiments a marked TNF alpha production in the range 10-70 ng/ml was detected in the supernatants, whereas unstimulated cells did not produce TNF alpha. We conclude that tolerance to endotoxin does not develop in the subarachnoid space as evaluated by the present experimental design. The pattern of TNF alpha production and endotoxin tolerance is distinctly different in the subarachnoid space and systemic circulation.

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 ß(2) 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 (FEV(1)) (23-24 h postdose; day 29) and wm FEV(1) (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 FEV(1) 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 FEV(1) (mean difference 183 ml) and 0-4 h postdose wm FEV(1) (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.

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 x L(-1) (interquartile range 3.10-5.15)) than both smokers with normal lung function (3.00 nmol x L(-1) (2.50-3.67)) and never-smokers with normal lung function (2.90 nmol x 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.

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

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-gamma) and the counterregulatory molecules soluble TNF receptor (sTNFR) and IL-1 receptor antagonist (IL-1 Ra). In animal models TNF, IL-1 and IFN-gamma 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-gamma 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-gamma 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 serum, 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.

Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice.

We administered a neutralizing monoclonal antibody to tumor necrosis factor (TNF) during infection with Candida albicans in normal and granulocytopenic mice. Mice were rendered granulocytopenic (less than 0.1 x 10(9) granulocytes per liter) with cyclophosphamide. Growth of C. albicans from the kidneys was significantly increased in normal mice treated with the antibody to TNF, compared with that in control mice, after 36 h (3.6 x 10(4) +/- 1.2 x 10(4) CFU per kidney versus 9.1 x 10(3) +/- 6.2 x 10(3) CFU per kidney; P less than 0.05) and after 72 h (3.7 x 10(6) +/- 2.7 x 10(6) CFU per kidney versus 2.3 x 10(4) +/- 1.3 x 10(4) CFU per kidney; P less than 0.01). In granulocytopenic mice, the antibody to TNF had no effect on the growth of C. albicans from the kidneys. Furthermore, our study showed that the cytokines TNF and interleukin-6 (IL-6) were produced in a dose-dependent manner during C. albicans infection. TNF was detectable between 6 and 60 h, with peak levels at 24 h. Both TNF and IL-6 levels were significantly higher in cyclophosphamide-treated mice than in normal mice. Heat-inactivated C. albicans induced a TNF response different from that induced by viable C. albicans, with an early peak occurring at 3 to 4 h and declining to non-detectable levels after 15 to 24 h. Peak levels of TNF obtained with heat-inactivated C. albicans were lower than those obtained with viable C. albicans. Our study demonstrates that TNF and IL-6 are produced systemically during C. albicans infection and suggests that TNF is essential for granulocyte antifungal activity in vivo.

Effects of stem cell factor and granulocyte colony-stimulating factor on granulocyte recovery and Candida albicans infection in granulocytopenic mice.

The combined action of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on granulocyte recovery and infection with Candida albicans was studied. In mice rendered granulocytopenic with 200 mg/kg cyclophosphamide, daily coinjection of SCF (100 micrograms/kg) and G-CSF (10 micrograms/kg) for 5 days synergistically stimulated granulocyte recovery compared with either factor alone. Growth of C. albicans in the kidneys of granulocytopenic mice with experimental C. albicans infection was reduced by the combined regimen to 25% of that in vehicle-treated controls (P = .018), whereas either factor administered alone in the same doses had no effect. The combined regimen also significantly protected against lethal infection with C. albicans (P < .01). Either factor administered alone in the same doses had no effect on lethality compared with vehicle-treated controls. The combination of SCF and G-CSF may be useful in the treatment of infections with C. albicans in the granulocytopenic host.

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 x 10(9)/l) and six fever episodes when granulocyte counts were > 1.0 x 10(9)/l. 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 x 10(9)/l (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.

Granulocytopenia reduces release of soluble TNF receptor p75 in endotoxin-stimulated mice: a possible mechanism of enhanced TNF activity.

This study demonstrates that granulocytopenia alters the TNF response to endotoxin. Significantly higher levels of bioactive TNF were observed in mice rendered granulocytopenic (< 0.05 x 10(9) granulocytes/litre) with cyclophosphamide than in normal mice. Levels of circulating soluble TNF receptor p75 (sTNFR-p75) in response to endotoxin were higher in normal mice than in granulocytopenic mice whereas no difference in levels of circulating soluble TNF receptor p55 (sTNFR-p55) was observed. To investigate further the role of both sTNFR in inactivation of TNF, murine recombinant (r) TNF or human rTNF was injected in to normal and granulocytopenic mice. Higher TNF bioactivity was recovered in granulocytopenic mice than in normal mice after administration of murine rTNF, whereas, no difference in recovered TNF bioactivity was observed after human rTNF. As murine TNFR-p75 does not bind to human TNF, this observation indicates that less sTNFR-p75 available for neutralization of TNF in the circulation in granulocytopenia results in enhanced TNF bioactivity. Furthermore, endotoxin-induced lethality was increased in granulocytopenic mice. In summary, this study shows that endotoxin-induced release of sTNFR-p75 is reduced and TNF bioactivity increased in granulocytopenia. Our data suggest that release of sTNFR-p75 from granulocytes is a mechanism in the regulation of TNF bioactivity.

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 x 10(9)/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.

TNF receptors in murine Candida albicans infection: evidence for an important role of TNF receptor p55 in antifungal defense.

TNF mediates multiple biologic activities through two distinct cell surface receptors, TNFR-p55 and TNFR-p75. TNF plays an important role in nonspecific resistance against the fungus Candida albicans. We used transgenic mice deficient for TNFR-p55 or TNFR-p75 to investigate the role of the TNFR in antifungal defense. Mice deficient for TNFR-p55 have highly impaired ability to clear infection with C. albicans and readily succumb to the infection. Also mice deficient for TNFR-p75 had a significant reduction in their ability to clear the fungus although lethality was not increased. These data demonstrate that TNFR-p55 in particular, but also TNFR-p75, plays a definite role in defense against infection with C. albicans. In NMRI mice, infection with C. albicans resulted in a significant systemic release of soluble (s)TNFR-p75. Cyclophosphamide-induced granulocytopenia led to a reduction of sTNFR-p75 release, whereas levels of bioactive TNF in response to fungal infection were increased. Release of sTNFR-p55 was not affected by induction of granulocytopenia. These observations suggest that granulocytes are a source of sTNFR-p75, possibly contributing to regulation of TNF activity during infection with C. albicans.