Burnout in medical students.

Only a small number of studies have examined the relationship between medical students and burnout syndrome. In Salzburg, Paracelsus Private Medical University (PMU) offers a 5­year medical program instead of the regular 6 years of medical studies. Due to the tight schedule and heavy workload, the stress level of students is high. The purpose of this study was to determine whether PMU students show burnout symptoms. Three surveys were conducted: at the beginning of the academic year (T1, December 2009), at the end of the academic year (T2, June 2010), and at the beginning of the following academic year (T3, December 2010). For the assessment of burnout, the Maslach Burnout Inventory (emotional exhaustion, depersonalization or cynicism, and low personal accomplishment) was used, as well as the Six Factors Theory of Burnout (workload, control, reward, community, fairness, and values) and for comparison, the Austrian norms developed by Unterholzer. Burnout rate was calculated by a combined measure of the three components. The results show a significant difference from the norm means in emotional exhaustion, depersonalization/cynicism, and low personal accomplishment. With regard to areas of work life, all values are below the means, indicating high workload, high external control, low reward, low feeling of community, and low fairness-except values, i.e., motivation of the students. The mean overall burnout frequency turned out to be 47.8 ± 11.0%, whereas females have slightly higher burnout rates than males. An increasing linear trend with burnout rates was seen from the youngest to the oldest class. In addition, the estimated burnout rate increased within the academic term, as T2 had the highest rate, followed by T3, and the lowest rate was seen in T1. In conclusion, burnout in medical students is frequent and significantly related to heavy workload and other factors of worklife, necessitating changes of academic and organizational settings of medical curricula.

Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma.

In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4+ regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDO+ PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.

Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control?

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an emerging immunomodulating factor in cancer. IDO expression in tumour-negative sentinel lymph nodes (SLNs) of patients with melanoma has a negative prognostic value. OBJECTIVES: To analyse the expression pattern of IDO and associated immunological changes in corresponding primary melanomas (PMs), SLNs and metastases. METHODS: In 120 patients with melanoma, PMs with corresponding SLNs (n = 85) and metastases (n = 18) were analysed by immunohistochemical staining for IDO and FoxP3. Tumour-infiltrating lymphocytes (TILs) were scored. IDO expression in stimulated peripheral blood mononuclear cells (PBMCs) was analysed in 27 patients. RESULTS: IDO expression in the sentinel node strongly correlated with endothelial IDO expression in the peritumoral stroma of the corresponding primary (P < 0·001) and metastatic melanoma (P < 0·05). Sentinel IDO positivity was inversely correlated with CD8+ lymphocytes (P = 0·01) and TILs (P = 0·05) in PM. Both IDO expression in the sentinel (P < 0·01) and the PM (P = 0·04) had a negative prognostic effect on overall survival, independent of Breslow thickness, sex, age, ulceration and sentinel invasion. IDO expression by PBMCs after stimulation with cytotoxic T-lymphocyte antigen 4 was not correlated with sentinel IDO expression but tended to correlate with disease stage (P = 0·04). CONCLUSIONS: Endothelial IDO expression is highly consistent in primary, sentinel and metastatic tissues of patients with melanoma, indicating that immune suppression in melanoma is determined very early in the disease course. This supports that IDO expression in melanoma is a marker of antitumour immune response with an independent prognostic value.

Incidental radiological finding of a renal tumour leading to the diagnosis of Birt-Hogg-Dube syndrome.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition characterised by benign tumours of the hair follicle, renal cancer, pulmonary cysts and spontaneous pneumothorax. We report the diagnosis of a BHD syndrome achieved after incidental radiological finding of a renal tumour in a 24-year old man. The patient also displayed recurrent pneumothoraces and showed to have cysts in the basis of both lungs. The association of recurrent pneumothoraces and renal neoplastic disease should alert for the possible presence of this syndrome.

Validation of questions on asthma and wheeze in farming and anthroposophic children.

BACKGROUND: In most epidemiological surveys the estimated prevalence of asthma is based on questionnaire responses, which may depend on the individual's perception as well as medical consulting habits in a given population. Therefore, measurement of bronchial hyper-responsiveness as a key feature of asthma has been suggested as an objective parameter for asthma. OBJECTIVE: The aim of the present study was to validate questionnaire responses on asthma and wheeze against bronchial response to hypertonic saline (HS) (4.5%) in populations previously shown to have a lower prevalence of asthma and allergies: farmers' children and children from anthroposophic families. METHODS: Children whose parents had completed a written questionnaire in the cross-sectional PARSIFAL-study were drawn from the following four subgroups: 'farm children' (n=183), 'farm reference children' (n=173), 'Steiner schoolchildren' (n=243) and 'Steiner reference children' (n=179). Overall, 319 children with wheeze in the last 12 months and 459 children without wheeze in the last 12 months performed an HS challenge. RESULTS: Odds ratios, sensitivity, specificity, likelihood ratios and measures of association did not differ significantly between the four subgroups. The correlation between the bronchial response to HS and wheeze and asthma questions was moderate and similar for farm children, farm reference children, Steiner schoolchildren and Steiner reference children (kappa for 'wheeze': 0.25, 0.33, 0.31, 0.35, respectively, P=0.754, kappa for 'doctor's diagnosis of asthma': 0.33, 0.19, 0.33, 032, respectively, P=0.499). CONCLUSION: The findings from this study suggest that the reliabilitiy of questionnaire responses on asthma and wheeze is comparable between farmers' children, children raised in families with anthroposophic lifestyle and their respective peers.

Exposure to pets, and the association with hay fever, asthma, and atopic sensitization in rural children.

BACKGROUND: An increasing number of studies report pet exposure to be associated with lower risk of asthma and allergies. This 'protective pet effect' has been suggested to result from a modified T-helper (Th)2-cell response, or because of increased microbial load in homes where pets are kept. We examined the associations between pet contact and the occurrence of asthma and allergies in children of the rural Allergy and Endotoxin (ALEX) population, taking farm animal contact, endotoxin and cat allergen levels in mattress dust into account. METHODS: Information about contact with pets and farm animals, asthma and allergy were collected for 812 children by a standardized parents' questionnaire and an interview. Mattress dust endotoxin and cat allergen levels as well as specific IgE and IgG4 antibodies to Fel d1 were determined. RESULTS: Current contact with dogs was inversely associated with diagnosed hay fever (OR 0.26, 95% CI 0.11-0.57), diagnosed asthma (OR 0.29, 95% CI 0.12-0.71), sensitization to cat allergen (OR 0.48, 95% CI 0.23-0.99) and to grass pollen (OR 0.55, 95% CI 0.33-0.94), but not with increased IgG4 levels. Early and current contact with cats were associated with reduced risk of wheezing (OR 0.48, 95% CI 0.23-1.00, and OR 0.49, 95% CI 0.26-0.92, respectively) and grass pollen sensitization. Adjustment for farm animal contact but not for endotoxin and cat allergen exposure attenuated these associations and the effect of pet was stronger among farmers' children. CONCLUSION: Although pet exposure was very frequent in this rural population, the inverse relation between current dog contact, asthma and allergy was mostly explained by simultaneously occurring exposure to stable animals or was restricted to farm children. In addition, a subtle form of pet avoidance may contribute to the protective effect of pet.

Determinants of endotoxin levels in living environments of farmers' children and their peers from rural areas.

BACKGROUND: Lower frequencies of asthma and hayfever have been observed in children with contact to livestock. At school age, the amount of endotoxin measured in the dust of children's mattresses is inversely related to the occurrence of atopic asthma, hayfever and atopic sensitization both in children from farming and non-farming households. OBJECTIVE: The aim of the present study was to investigate which home and lifestyle characteristics of farm and non-farm families contribute to endotoxin levels measured in different indoor home environments. METHODS: In the framework of the Allergy and Endotoxin (ALEX) Study, endotoxin was measured in dust samples from the living room floor and the child's mattress of 319 farmers' families and 493 non-farming families, and in settled dust from stables. Endotoxin content of all dust samples was determined by a kinetic Limulus assay (Limulus-Amebocyte-Lysate test). Information about the child's activities on farms, home characteristics and cleaning behaviours was obtained from parental questionnaires. RESULTS: Endotoxin levels in stables did not predict the amount of endotoxin measured in floors or mattresses. However, a dose-dependent association between the child's activity on the farm and indoor home endotoxin levels was observed, both in farm and non-farm children. In non-farm children pet keeping and the frequency of floor cleaning were additionally associated with endotoxin levels, whereas in farm children parental farm activities, study area, time since last cleaning, the mattress type as well as younger age of the children contributed to increased microbial exposure. CONCLUSION: These results demonstrate that regular contact to farm animals increases indoor home endotoxin concentrations, both in farm and non-farm children, and might thus explain the protective effect of contact to livestock on atopic outcomes. To assess children's individual exposure to a microbial environment, measures of mattress dust exposure are needed as stable endotoxin concentrations were not associated with indoor home levels.

Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey.

BACKGROUND: A farming environment protects against development of asthma, hay fever, and atopic sensitisation in children. We aimed to establish whether increased exposure to microbial compounds has to occur early in life to affect maturation of the immune system and thereby reduces risk for development of allergic diseases. METHODS: We did a cross-sectional survey in rural areas of Austria, Germany, and Switzerland. 2618 (75%) of 3504 parents of 6-13-year-old children completed a standardised questionnaire on asthma, hay fever, and atopic eczema. Children from farming families, and a random sample of non-farmers' children, who gave consent for blood samples to be obtained for measurements of specific serum IgE antibodies to common allergens were invited to participate (n=901). FINDINGS: Exposure of children younger than 1 year, compared with those aged 1-5 years, to stables and consumption of farm milk was associated with lower frequencies of asthma (1% [3/218] vs 11% [15/138]), hay fever (3% [7] vs 13% [18]), and atopic sensitisation (12% [27] vs 29% [40]). Protection against development of asthma was independent from effect on atopic sensitisation. Continual long-term exposure to stables until age 5 years was associated with the lowest frequencies of asthma (0.8% [1/122]), hay fever (0.8% [1]), and atopic sensitisation (8.2% [10]). INTERPRETATION: Long-term and early-life exposure to stables and farm milk induces a strong protective effect against development of asthma, hay fever, and atopic sensitisation.

Austrian children living on a farm have less hay fever, asthma and allergic sensitization.

BACKGROUND AND OBJECTIVES: In some studies, the prevalence of hay fever and asthma has been found to be lower in children from rural areas than in children from an urban environment. We hypothesized that living on a farm might be protective against development of allergic sensitization and allergic diseases. METHODS: In a cross-sectional survey, parents of 2283 children aged 8-10 years from a mostly rural area in Austria answered a standardized questionnaire on allergic diseases and environmental factors. 1137 children performed a skin prick test to seven local allergens. RESULTS: The prevalence of hay fever (3.1 vs 10.3%, P = 0.0002), asthma (1.1 vs 3.9%, P = 0.017) and a positive skin prick reactivity to at least one of the common local allergens (18.8 vs 32.7%, P = 0. 001) was significantly lower in children living on a farm than in children from a non-farming environment. In a multivariate logistic regression model, adjusting for genetic background, parent education, living and housing conditions and dietary factors did not change the odds ratio for the association of farming and allergic sensitization. Only after including 'regular contact with livestock and poultry' into the model did the odds ratio change significantly (cOR 0.48 95% CI 0.30-0.75 to aOR 0.75 95% CI 0.37-1.52) indicating an association between regular contact with farm animals and reduced risk of atopic sensitization. CONCLUSION: Possible explanations for the lower prevalence of hay fever, asthma and allergic sensitization in children living on a farm might be the development of immunotolerance or the stimulation of TH1 cells and suppression of TH2 cells by increased exposure of farm children to microbial antigens in the stables or farmhouses.

Lack of a late asthmatic response after hypertonic saline challenge in children.

Hypertonic saline challenge has become a standardized method for measuring airway responsiveness. However, there is still uncertainty about the occurrence of a late asthmatic response. Therefore, the present study was designed to assess a possible late asthmatic response after hypertonic saline challenge in children. Twenty-one children with mild to moderate bronchial hyperresponsiveness were studied. On days 1 and 2, forced expiratory volume in one second (FEV1) was measured hourly from 10:00 h to 22:00 h to assess diurnal variation of lung function. On the third study day, a hypertonic saline challenge was performed and FEV1 was measured as on control days. The possibility of a late asthmatic response was tested by comparing FEV1 levels up to 12 h after the challenge on the intervention day to FEV1 levels on control days. In no subjects were the FEV1 values following the challenge found to be considerably below the individual mean of the control days. Furthermore, a nonparametric approach was applied for each child and the population looked into as a whole. Again, no late asthmatic response was detectable. The results of this study suggest that in children with mild to moderate bronchial hyperresponsiveness a late asthmatic response does not occur 4-12 h after a 4.5% saline challenge.

Effect of 5-bromodeoxyuridine on differentiation. I. Probability distribution of BUdR-containing DNA-strands in subsequent divisions.

The consequences on transcription of BUdR substitution of the normal thymidine in nuclear DNA are analyzed from a probabilistic point of view. The probability that at any stage subsequent to the administration of BUdR, a randomly chosen cell will be able to make good transcripts is calculated both under the assumption that incorporation of BUdR is complete and under the assumption that incorporation is partial. In the latter case both gradually increasing and decreasing incorporation rates are considered. The presented calculations may be of value for the investigation of any type of differentiating cells. Using the example of the sea urchin embryo it is shown how to calculate the probability that a particular group of cells, which in further development differentiate to a certain organ, will inherit as sufficient number of essential genes unaffected by BUdR in order to ensure a normal development. It is shown that the probability that the four macromeres (or micromeres) in the vegetal half of the 16-cell stage of the sea urchin embryo will contain at least one, two or four plus (or minus) strands of DNA uninfluenced by BUdR gradually decreases the earlier BUdR is administered. The theoretical calculations are in agreement with experimental observations on sea urchin embryos (described in part II).