Sins of omission: A meta-research study evaluating the omission of operability in published retrospective comparisons of surgery with stereotactic body radiotherapy in patients with early-stage non-small cell lung cancer.

INTRODUCTION: Patients receiving stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) are typically inoperable, in concordance with guidelines that advocate surgical resection as preferred treatment for operable patients. This differential treatment allocation complicates retrospective comparisons of surgery with SBRT by introducing the potential for confounding by operability. METHODS: PubMed was queried for manuscripts reporting primary data from retrospective comparisons of overall survival (OS) between patients undergoing surgery versus SBRT for early-stage NSCLC. Each manuscript was categorized for two outcomes: (1) whether treatment allocation was based on a determination of patient operability, and (2) whether a direct OS comparison between operable SBRT patients and surgically treated patients was included. Associations with variables of interest were measured with statistical significance prespecified at p < 0.10. RESULTS: From 3,072 manuscripts identified in our query, sixty-one analyses met screening criteria. Twenty-one (34 %) reported operability status influencing treatment allocation. These were more likely to be published in journals with a surgical focus (52 vs 20 %) and impact factor < 5 (81 vs 58 %), and to contain cohorts from institutional datasets (81 vs 55 %), and to have a radiation oncologist as first (43 vs 25 %) or senior (43 vs 28 %) author. Seven (11 %) manuscripts featured a direct OS comparison between SBRT and surgery. CONCLUSION: Nearly-two-thirds of peer-reviewed retrospective studies that have compared OS between surgery and SBRT for early-stage NSCLC lack information on patient operability status, and nearly 90% lack a direct comparison between operable SBRT patients and those receiving surgery.

Invasive populations of Spiraea tomentosa (Rosaceae) are genetically diverse but decline during succession in forest habitats.

Population genetic and ecological data may help to control invasive plants, which are considered a major threat to natural habitats. In contrast to expected bottleneck events, genetic diversity of such invasive populations may be high due to extensive propagule pressure or admixture. The ecological impact of invasive species has been broadly evaluated in the field; however, long-term studies on the fate of invasive plants are scarce. We analysed genetic diversity and structure in invasive Spiraea tomentosa populations in eastern Germany and western Poland using Amplified Fragment Length Polymorphism. Potential hybridization between co-occurring diploid Sp. tomentosa and tetraploid Sp. douglasii was investigated using Flow Cytometry. The genetic analyses were complemented by data from a 13-year vegetation study in an area invaded by these Spiraea species. We found no evidence for hybridization between Spiraea species. In populations of Sp. tomentosa both genetic diversity (He = 0.26) and genetic structure (ΦPT = 0.27) were high and comparable to other outcrossing woody plants. Low levels of clonality, presence of seedlings and new patches in sites that had been colonized over the last 13 years imply that populations spread via sexual reproduction. In all habitat types, native species diversity declined following Sp. tomentosa invasion. However, detailed aerial mapping of a forest reserve with ongoing succession revealed that Spiraea spp. populations have declined over a 10-year period. Despite its potential for dispersal and negative effects on native plant communities, invasive Spiraea populations may be controlled by increasing canopy cover in forest habitats.

Does silence speak louder than words? The impact of oncologists' emotion-oriented communication on analogue patients' information recall and emotional stress.

OBJECTIVE: The impact of two types of oncologists' emotion-oriented communication on participants' recall of medical information was investigated, and the potential mediation by a reduction in emotional stress. Additionally, moderation effects by personal characteristics were explored. METHODS: An oncologist's communication in response to a patient's emotional expressions was manipulated during a videotaped, scripted bad-news consultation. Three conditions were created: 1) standard communication, 2) emotion-oriented silence, and 3) emotion-oriented speech. Participants (N = 217) were randomly allocated to one of the three conditions. Measurements included information recall (free recall and recognition), emotional stress (self-reported and physiological), and personal characteristics. RESULTS: Emotion-oriented silence (p = .002) and speech (p = .019) enhanced information recognition compared to standard communication. No differences in free recall were found. Emotional stress did not mediate these relations. Poorer functional health literacy predicted poorer recognition, but this was counteracted by emotion-oriented communication. CONCLUSIONS: By means of acknowledging, exploring, empathic and supportive statements, and attentive silence, the oncologist's communication resulted in better information recognition. How oncologists' communication impacts patients' information recall warrants further investigation, as this could not be explained by reducing emotional stress. PRACTICE IMPLICATIONS: These insights will help educators to validate the relevance of emotion-oriented strategies, and encourage oncologists to adopt them.

Unraveling mitotic protein networks by 3D multiplexed epitope drug screening.

Three-dimensional protein localization intricately determines the functional coordination of cellular processes. The complex spatial context of protein landscape has been assessed by multiplexed immunofluorescent staining or mass spectrometry, applied to 2D cell culture with limited physiological relevance or tissue sections. Here, we present 3D SPECS, an automated technology for 3D Spatial characterization of Protein Expression Changes by microscopic Screening. This workflow comprises iterative antibody staining, high-content 3D imaging, and machine learning for detection of mitoses. This is followed by mapping of spatial protein localization into a spherical, cellular coordinate system, a basis for model-based prediction of spatially resolved affinities of proteins. As a proof-of-concept, we mapped twelve epitopes in 3D-cultured spheroids and investigated the network effects of twelve mitotic cancer drugs. Our approach reveals novel insights into spindle fragility and chromatin stress, and predicts unknown interactions between proteins in specific mitotic pathways. 3D SPECS's ability to map potential drug targets by multiplexed immunofluorescence in 3D cell culture combined with our automated high-content assay will inspire future functional protein expression and drug assays.

[Criteria for treating MRSA in sputum]. / Kriterien zur Behandlung von MRSA im Sputum?

Methicillin-resistant strains of Staphylococcus aureus (MRSA) are of particular significance for the management of patients with airway infections, since the disease course is often complicated and treatment rendered difficult by multiple resistance. Their prevalence is now slowly declining, but still alarmingly high. Hospital-acquired infections are predominant, but hospital-associated and community-acquired infections do occur, as do rare infections with livestock-acquired strains. Non-nosocomial strains are characterized by different pathogenic factors and a different spectrum of antibacterial resistance; they often have a threatening disease course. Anti-infectives with activity against MRSA are unusual and have particular toxicity profiles. On the other hand, MRSA colonization is eliminated spontaneously in healthy people and acute bronchitis is treatable by common oral antibiotics. However, chronic airway infection in bronchiectasis and other forms of structural airway damage requires a complex systemic and local treatment approach for pathogen elimination.

Are psychophysiological arousal and self-reported emotional stress during an oncological consultation related to memory of medical information? An experimental study.

Patients forget 20-80% of information provided during medical consultations. The emotional stress often experienced by patients during consultations could be one of the mechanisms that lead to limited recall. The current experimental study therefore investigated the associations between (analog) patients' psychophysiological arousal, self-reported emotional stress and their (long term) memory of information provided by the physician. One hundred and eighty one cancer-naïve individuals acted as so-called analog patients (APs), i.e. they were instructed to watch a scripted video-recoding of an oncological bad news consultation while imagining themselves being in the patient's situation. Electrodermal and cardiovascular activity (e.g. skin conductance level and heart rate) were recorded during watching. Self-reported emotional stress was assessed before and after watching, using the STAI-State and seven Visual Analog Scales. Memory, both free recall and recognition, was assessed after 24-28 h. Watching the consultation evoked significant psychophysiological and self-reported stress responses. However, investigating the associations between 24 psychophysiological arousal measures, eight self-reported stress measures and free recall and recognition of information resulted in one significant, small (partial) correlation (r = 0.19). Considering multiple testing, this significant result was probably due to chance. Alternative analytical methods yielded identical results, strengthening our conclusion that no evidence was found for relationships between variables of interest. These null-findings are highly relevant, as they may be considered to refute the long-standing, but yet untested assumption that a relationship between stress and memory exists within this context. Moreover, these findings suggest that lowering patients' stress levels during the consultation would probably not be sufficient to raise memory of information to an optimal level. Alternative explanations for these findings are discussed.

Analogue patients' self-reported engagement and psychophysiological arousal in a video-vignettes design: Patients versus disease-naïve individuals.

OBJECTIVES: The ecological validity of video-vignettes design investigating patient-provider communication hinges on the engagement of analogue patients (APs) with the vignette. The present study aimed to compare engagement in two commonly utilized groups of APs, patients and disease-naïve individuals. Engagement was assessed by self-report and in the form of physiological arousal. METHODS: Cancer patients (N=22) and disease-naïve individuals (N=24) were recruited as APs. APs completed the Video Engagement Scale after watching a vignette of a oncologic bad news consultation. Electrodermal and cardiovascular activity were assessed continuously during watching the vignette, and cortisol levels were assessed in four saliva samples. RESULTS: Patients reported higher engagement with the vignette than disease-naïve individuals (t=2.46, p<0.05) and showed a larger blood pressure response (systolic: F=5.87, p<0.01 and diastolic: F=4.00, p<0.05). However, these differences disappeared after adjusting for age. No group differences were found on other psychophysiological parameters. CONCLUSIONS: Our results suggest that patients and disease-naïve individuals are equally engaged when viewing video vignettes. When group differences were found, older age turned out to be a more prominent predictor of engagement. PRACTICE IMPLICATIONS: Researchers may consider other arguments besides APs' disease history when selecting an AP group.

Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses.

OBJECTIVE: Norepinephrine (NE) was measured in synovial fluid of trauma patients and sympathetic nerve fibers were detected in healthy and osteoarthritic (OA) joint tissues indicating that cartilage pathophysiology might be influenced by sympathetic neurotransmitters. The aim of this study was to elucidate the mostly unknown role of NE in OA chondrocyte metabolism and inflammatory responses. METHODS: Articular cartilage was received after total knee replacement surgery from OA patients. Expression of adrenergic receptors (AR) and tyrosine hydroxylase (TH) was tested with end point polymerase chain reaction (PCR) and immunohistochemistry. 3-dimensional (3D) cell cultures were employed to analyze effects of NE on chondrocyte cell metabolism and the expression of interleukins (ILs), matrix metalloproteases (MMPs), tissue inhibitor of metalloproteases (TIMPs), glycosaminoglycan (GAG) and collagen II under non- and inflammatory conditions. Chondrocyte monolayer cultures were used to specify AR subtypes, to analyze cell cycle distribution and to determine catecholamines in cell culture supernatants. RESULTS: AR subtypes and TH were detected in chondrocytes, whereas NE was not released in measurable amounts. 10(-6) M NE reversed IL-1ß induced changes in IL-8, MMP-13, GAG and collagen II expression/production indicating for ß-AR signaling. Additionally, NE caused cell cycle slow down and decreased proliferation via ß-AR signaling. 10(-8) M NE increased the number of proliferating cells and induced apoptosis via α1-AR signaling. CONCLUSIONS: NE affects chondrocytes from OA cartilage regarding inflammatory response and its cell metabolism in a dose dependent manner. The sympathetic nervous system (SNS) may have a dual function in OA pathology with preserving a stable chondrocyte phenotype via ß-AR signaling and OA pathogenesis accelerating effects via α-AR signaling.

[Molecular diagnostics in neuropathology]. / Molekulare Diagnostik in der Neuropathologie.

As in only few other areas of oncology, molecular markers in neurooncology have become an integral part of clinical decision-making. This development is driven by a bustling scientific activity exploring the molecular basis and pathogenesis of human brain tumors. In addition, a high percentage of brain tumor patients are included in clinical studies in which molecular markers are assessed and linked with clinical informativeness. First steps towards more differentiated therapeutic strategies against brain tumors have thus been taken. The implementation in the clinical and diagnostic routine requires a detailed knowledge and a close collaboration between all medical disciplines involved.

Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory viruses may be involved. In at-risk patients who have received trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis, filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation. Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, ß-D-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however, most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unrestrictedly provided in patients whose prognosis is not desperate due to other reasons.

Potential lack of "standardized" processing techniques for production of allogeneic and xenogeneic bone blocks for application in humans.

In the present study, the structure of two allogeneic and three xenogeneic bone blocks, which are used in dental and orthopedic surgery, were histologically analyzed. The ultimate goal was to assess whether the components postulated by the manufacturer can be identified after applying conventional histological and histochemical staining techniques. Three samples of each material, i.e. allogeneic material-1 and -2 as well as xenogeneic material-1, -2 and -3, were obtained commercially. After decalcification and standardized embedding processes, conventional histological staining was performed in order to detect inorganic matrix, cellular or organic matrix components. Allogeneic material-1 showed trabecular bone-like structures, which were free of cellular components as well as of organic matrix. The allogeneic material-2 showed trabecular bone structures, in which connective tissue and cellular remnants were embedded. Additionally, some connective tissue, which resembled fat-like tissue, was found within this material. The xenogeneic material-1 showed trabecular bone-like structures and contained organic components comparable to that demonstrated for the allogeneic material-2. The xenogeneic material-2 showed trabecular bone structures with single cells located in lacunae. The xenogeneic material-3 also showed trabecular structures. Neither cellular nor organic matrix components were found within this material. According to the data of the present study, the allogeneic material-1 and the xenogeneic material-3 were the only investigated materials for which the obtained histological data were in accordance with the manufacturers advertised information. The remaining three materials showed discrepancies-although the manufacturers of all five bone substitute materials stated that their blocks were free of organic/cellular remnants. These data are of great clinical and material science interest. It seems that even patented processing techniques are not always able to deliver reproducible materials. Although the manufacturers of all five bone blocks stated that their blocks were free of organic/cellular remnants, our histological analysis revealed that three out of five bone blocks did contain such remnants. Such specimens might be able to induce an immune response within the recipient.

Neonatal outcomes of fetuses diagnosed with life-limiting conditions when individualized comfort measures are proposed.

OBJECTIVE: To describe the neonatal outcomes of a case series of infants who were prenatally diagnosed with potential life-limiting conditions and to whom individualized comfort measures were offered. STUDY DESIGN: This is a retrospective analysis of the postnatal outcomes of a selected population of 49 infants prenatally diagnosed with potential life-limiting conditions whose parents were prenatally referred for counseling to the comfort care team. RESULT: The prenatal diagnosis was confirmed postnatally in 45 infants. The only four survivors had a significant discrepancy between prenatal and postnatal diagnosis. Whether they were treated with individualized comfort measures (n=28) or intensive care (n=17), all the newborns died with similar median age at death (2 days). CONCLUSION: Diagnostic accuracy is the main determinant of outcomes. Provision of intensive care neither prevents the death of infants affected by life-limiting conditions nor prolongs life compared with that of infants treated with individualized comfort measures.

Induction of multinucleated giant cells in response to small sized bovine bone substitute (Bio-Oss™) results in an enhanced early implantation bed vascularization.

PURPOSE: The host tissue reaction to the xenogeneic bone substitute Bio-Oss™ (Geistlich Biomaterials, Wolhousen, Switzerland) was investigated focusing on the participating inflammatory cells and implantation bed vascularization. MATERIALS AND METHODS: Bio-Oss™ was implanted subcutaneously into CD1 mice for up to 60 days and analyzed by means of specialized histological and histomorphometrical techniques after explantation. RESULTS: Bio-Oss™ induced within the first 15 days an early high vascularization combined with a marked presence of multinucleated giant cells. The latter cells were associated mainly with the smaller sized granules within the implantation bed. Toward the end of the study the number of multinucleated giant cells decreased while the tissue reaction to the larger granules was mainly mononuclear. CONCLUSION: The results of the present study showed that smaller xenogeneic bone substitute granules induce multinucleated giant cells, whereas the larger-sized ones became integrated within the implantation bed by means of a mononuclear cell-triggered granulation tissue. Obviously, the presence of multinucleated giant cells within biomaterial implantation beds is not only related to the type of synthetic bone substitute material, but also to the granule size of the natural-based xenogeneic bone substitute material.

Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study.

Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms. Six hundred and thirty-three healthy females (age 14.63±1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 4½ years thereafter. Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time. Higher interferon (IFN)-γ, higher IFN-γ/interleukin (IL)-4 ratio, lower tumor necrosis factor-α and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression. In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints.

Legionella pneumophila-induced IκBζ-dependent expression of interleukin-6 in lung epithelium.

Severe community- and hospital-acquired pneumonia is caused by Legionella pneumophila. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown. Herein, we demonstrate that different L. pneumophila strains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced by Legionella infection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein ß and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at the iκbζ and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reduced Legionella-related IL-6 expression by 41%. Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.

Integration of model-based weighting into an ICP variant to account for measurement errors in intra-operative A-Mode ultrasound-based registration.

This paper addresses error modeling in A-Mode ultrasound- (US-) based registration and integration of model-based weighting into the Random-ICP (R-ICP) algorithm. The R-ICP is a variant of the Iterative Closest Point (ICP) algorithm, and it was suggested for surface-based registration using A-Mode US in the context of skull surgery. In that application area the R-ICP could yield high accuracy even in case of a small number of data points and a very inaccurate user-interactive pre-registration. However, it cannot cope with unequal point uncertainty, which is an important drawback in the context of hip surgery: Uncertainty about the average speed of sound is an error source, whose impact on the registration accuracy increases with the thickness of the scanned soft tissue. It can, therefore, lead to considerable localization errors if a thick soft tissue layer is scanned, and it might vary a lot from data point to data point as the soft tissue thickness is inhomogeneous. The present work investigates how to account for this error source considering also other error sources such as the establishment of point correspondences. Simulation results show that registration accuracy can be substantially improved when model-based weighting is integrated into the R-ICP.

Salivary cortisol and binge eating disorder in obese women after surgery for morbid obesity.

BACKGROUND: Binge eating episodes characterized by loss of control are hypothesized to be accompanied by changes in hypothalamic pituitary adrenal (HPA) axis functioning. Cortisol is an end product of this neuroendocrine stress system. PURPOSE: The aim of this study was to examine the cortisol levels and the awakening cortisol response (ACR) in obese persons showing binge eating after surgery for morbid obesity. METHOD: Sixteen obese women with binge eating disorder (BED) and 18 obese women without BED participated in the study. Means+/-SD: age 43 +/- 15, body mass index 40 +/- 8. Salivary cortisol, anthropometric assessments, and the eating disorder examination interview were taken. RESULTS: Women with BED showed a significantly lower waist-to-hip ratio and cortisol levels during the day than women without BED, whereas the ACR did not differ. CONCLUSION: Our cross-sectional study in a small sample generates the hypothesis that neuroendocrine regulation differs between obese women with and without BED after obesity surgery. This finding needs replication in future studies that should also examine the causal direction of the observed association.

Health and physiological effects of an emotional disclosure intervention adapted for application at home: a randomized clinical trial in rheumatoid arthritis.

BACKGROUND: The efficacy of emotional disclosure in alleviating psychological and physical stress has been well documented in controlled laboratory studies. A next step is to evaluate its clinical utility in 'real world' settings. We adapted the emotional disclosure intervention for use in home-based settings by stimulating the suggested effective ingredients of cognitive-emotional processing, and evaluated its psychological and clinical effectiveness. Reviews indicated the need to examine the physiological changes brought about by emotional disclosure, which may be particularly relevant in immune-mediated diseases. This study was the first to examine neuroendocrine and immune changes after emotional disclosure in patients with rheumatoid arthritis. METHODS: Sixty-eight patients were randomly assigned to four weekly oral emotional disclosure or time management sessions. At baseline and 1 week and 3 months after the sessions, depressed and cheerful mood, joint scores, erythrocyte sedimentation rate, cortisol, noradrenaline, interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and IL-10 were evaluated. Repeated measures analyses of variance were performed. RESULTS: No effect on psychological well-being and clinical outcome was found (p > or = 0.10). Cortisol (p = 0.01) and the serum level of the pro-inflammatory cytokine IFN-gamma (p = 0.05) were differentially affected by the two conditions. The change of IL-6 nearly reached significance (p = 0.07). CONCLUSIONS: The physiological changes are in agreement with theories on the mechanisms underlying emotional disclosure benefits and are suggestive of better disease control after emotional disclosure. General and study-specific reasons for the absence of psychological and clinical effects are discussed. The findings warn against widespread implementation of this home-based emotional disclosure intervention in unselected rheumatoid arthritis samples.

Predictors of persistent and new-onset fatigue in adolescent girls.

OBJECTIVE: The purpose of this study was to investigate the stability of fatigue in adolescents and to explore whether psychological, somatic, and lifestyle factors are involved in the onset and persistence of fatigue during adolescence. METHODS: In this longitudinal study, a total of 653 adolescent girls (aged 14.40 +/- 1.45 years) who previously participated in an epidemiological study filled out questionnaires 6 (T2) and 12 (T3) months after the initial assessment (T1). Fatigue severity, depression, anxiety, and chronic fatigue syndrome-related symptoms were assessed. We determined the prevalence of severely fatigued cases at T2 and T3 and evaluated whether persistently fatigued participants initially differed from nonfatigued participants and participants with transient fatigue. We examined which factors predicted the development of new-onset fatigue and investigated whether changes in fatigue covaried with changes in other complaints and changes in lifestyle. RESULTS: Of all participants who were severely fatigued at T1, 25.7% were persistently fatigued throughout the study. Persistently fatigued participants had higher levels of depression and anxiety at the beginning of the study, were less physically active, and slept shorter. New-onset fatigue was predicted by depression, less physical activity, and more nightlife activities. Interestingly, new onset was not predicted by initial levels of fatigue. Persistently fatigued participants did not differ in initial fatigue severity from short-term fatigued patients. A decrease in fatigue severity was associated with a decrease in depression, anxiety, and chronic fatigue syndrome-related symptoms and, to a lesser extent, with an increase in physical activity and sleep duration. CONCLUSIONS: The stability of severe fatigue among adolescents is substantial. The involvement in the onset and persistence of fatigue suggests that both preventive and therapeutic strategies with respect to fatigue treatment in adolescents should concentrate on emotional well-being. Moreover, adolescents at risk should be stimulated to spend more time on physical activities and to sleep longer.

Glucocorticoid sensitivity of immune cells in severely fatigued adolescent girls: a longitudinal study.

Fatigue during adolescence is associated with somatic and psychological complaints that resemble the pattern of symptoms described for chronic fatigue syndrome (CFS). Studies in CFS and other stress-related syndromes suggested a dysfunction of the interactions between the hypothalamic-pituitary-adrenal axis (HPA-axis) and the immune system, i.e. a changed glucocorticoid (GC) receptor sensitivity of immune cells, to exist. Here we investigated whether severely fatigued girls from a healthy population have altered cortisol production and immune cell sensitivity for the synthetic GC, dexamethasone (DEX). In a longitudinal design, we examined ex vivo DEX sensitivity of monocytes and of T-cell mitogen-induced responses of severely fatigued (N=65) and non-fatigued girls (N=60). Fatigued girls reported more severe comorbid complaints than non-fatigued participants across three measurements during 1 year (T1: spring, T2: autumn, T3: spring) and had higher plasma cortisol levels throughout the study. DEX sensitivity of T-cell mitogen-induced responses showed seasonal variation with increased sensitivity in autumn compared to spring. No systematic variation of monocyte glucocorticoid receptor (GR) sensitivity was observed. Significant rank correlations of DEX sensitivity of T-cell mitogen-induced responses between the three assessments during the year suggest a stable trait of immune function. Groups did not differ in DEX sensitivity on any of the read outs. However, in a persistently fatigued subgroup, sensitivity to DEX was significantly reduced on the level of interferon (IFN)-gamma production. These results show that although fatigued participants had severe (comorbid) complaints, only in the case when symptoms persisted, altered GC sensitivity of immune cells was observed.