The association between education and fear of recurrence among breast cancer patients in follow-up - and the mediating effect of self-efficacy.

BACKGROUND: Major restructuring of surveillance after breast cancer treatment with less follow-up consultations may result in insecurity and fear of recurrence (FCR) among the less resourceful breast cancer patients. We investigate the association between breast cancer patients' education and FCR and if self-efficacy mediates the associations between education and FCR. MATERIAL AND METHODS: A questionnaire survey was conducted from 2017 to 2019, among 1773 breast cancer patients shortly after having their follow-up switched from regular outpatient visits with an oncologist to either nurse-led or patient-initiated follow-up, with a subsequent questionnaire after 12 months. Data on disease and treatment characteristics were extracted from medical records and the Danish Breast Cancer Group Database. Logistic regression analyses were used to examine the association between education and FCR. Separate analyses were conducted for patients ≤ and >5 years since diagnosis and all models were adjusted for age and cohabitation status. To explore potential mediation by self-efficacy, we conducted regression analyses on education and FCR further adjusting for self-efficacy. RESULTS: The participation rate was 57%, and after the exclusion of patients due to missing data, 917 were included in analyses. Patients with long education had significantly less FCR compared to patients with short education (OR (95% CI) 0.71 (0.51;0,99)). When separated by time since diagnosis, there was no association among patients >5 years since diagnosis while the OR was 0.51 (95% CI, 0.30;0.85) for patients ≤5 years since diagnosis. Further adjusting for self-efficacy among patients <5 years since diagnosis resulted in an OR of 0.56 (95% CI, 0.33;0.95) among patients with long compared to short education. CONCLUSION: Up to 5 years after diagnosis, breast cancer patients with long education are less likely to experience FCR than patients with short education. Self-efficacy mediated only a very small part of this association, indicating that other factors play a role in socioeconomic differences in FCR among breast cancer patients.

Endoscopic Anterior Component Separation and Transversus Abdominus Release are not Associated with Increased Wound Morbidity Following Retromuscular Incisional Hernia Repair.

INTRODUCTION: Traditional anterior component separation during incisional hernia repair (IHR) is associated with a high rate of postoperative wound morbidity. Because extensive subcutaneous dissection is avoided by endoscopic anterior component separation (eACS) or open transversus abdominis release (TAR), we hypothesized that these techniques did not increase the incidence of surgical site occurrence (SSO) compared to IHR without component separation (CS). MATERIAL AND METHOD: This was a retrospective single-center cohort study of patients undergoing open retromuscular IHR comparing patients with or without the use of CS. Retromuscular mesh repair was performed in all patients, and CS was obtained by eACS or TAR. The primary outcome was 90-day incidence of postoperative SSO. Secondary outcomes included length of stay (LOS), 90-day readmission, 90-day reoperation rate and 3-year recurrence rate. RESULTS: A total of 321 patients underwent retromuscular repair, 168 (52.3%) of whom received either eACS or TAR. The addition of eACS or TAR was associated neither with development of SSO (odds ratio: 1.80, 95% confidence interval: 0.94-3.46, P = 0.077) nor with hernia recurrence (hazard ratio 0.77, 0.26-2.34, P = 0.648). There was no significant difference between the groups regarding the frequencies of 90-day readmission or 90-day reoperation. CONCLUSION: eACS or TAR as adjuncts to open retromuscular IHR were not associated with increased wound morbidity or hernia recurrence.

MyHealth: specialist nurse-led follow-up in breast cancer. A randomized controlled trial - development and feasibility.

Background: Traditionally, women treated for breast cancer (BC) have been followed up through regular oncologist-led visits in outpatient clinics, focusing on detection of recurrences, new primary BC, symptom management, and psychological support. However, this follow-up routine is expensive and its effectiveness has been questioned. Consequently, alternative follow-up programs have been tested. The Guided Self-Determination method (GSD), which facilitates partnership between health-care provider and patient, has been shown to improve self-management in patients with chronic conditions, including cancer. Patient-reported outcomes (PRO) is another increasingly used tool to improve patient-provider communication, symptom monitoring and control. In combination, GSD and PRO may have the potential to meet the objectives of BC follow-up. To test this, we developed the MyHealth study, a randomized controlled trial comparing a nurse-led follow-up program based on GSD, collection of PRO, and patient navigation with routine oncologist-led follow-up. Here we describe how we developed the intervention and are currently testing the feasibility of the MyHealth protocol in terms of recruitment, adherence to the intervention, collection of PRO, and patient navigation. Material and methods: We have invited the first 25 consecutively enrolled patients to test the MyHealth intervention. This consists of (1) 3-5 initial GSD appointments with a nurse, (2) collection of PRO, and (3) symptom management and patient navigation. The randomized trial was launched in January 2017 and is still recruiting. Results of the feasibility study: Of 32 patients invited, 25 accepted participation. At 18-month follow-up, two patients have withdrawn, 143 PRO questionnaires have been completed (mean 5.7/patient) resulting in 59 nurse contacts (mean 2.4 per patient) and 14 project physician contacts (mean 0.6 per patient). Conclusion: A high recruitment rate and response rate to PRO indicate that follow-up led by specialist nurses, based on collection of PRO is feasible and acceptable for patients treated for early stage BC.

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

AIMS: Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. METHODS: The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. RESULTS: The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. CONCLUSION: The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

In this study, we developed and examined the potential of the novel ASGARD risk score to tailor personalized follow-up intervals for diagnostic heart scans, incorporating updated heart rate and blood marker measurements along with the heart scan data from the previous year. Patients with the ASGARD risk score within the lowest 50% had a low annual risk of aortic valve-related events (less than 5%) for a minimum of 15 months.In clinical settings, the ASGARD score could provide a personalized and safe monitoring alternative to routine heart scans, prioritizing the diagnostic heart scans for high-risk patients.

Nurse-Led Individualized Follow-Up Versus Regular Physician-Led Visits After Early Breast Cancer (MyHealth): A Phase III Randomized, Controlled Trial.

PURPOSE: Follow-up after breast cancer with regular visits has failed to detect recurrences, be cost-effective, and address patient needs. METHODS: MyHealth is a phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT02949167). Patients, who recently completed primary treatment for stage I-II breast cancer, were randomly assigned in variable block sizes and stratified by age and human epidermal growth factor receptor 2 status to intervention or control follow-up. The nurse-led intervention comprised three to five individual self-management sessions, regular reporting of symptoms, and navigation to health care services. The control follow-up comprised regular outpatient visits with the physician. The primary outcome was breast cancer-specific quality of life (QoL) measured by the Trial Outcome Index-Physical/Functional/Breast summary score of the Functional Assessment of Cancer Therapy-Breast 2 years after random assignment. Secondary outcomes were fear of recurrence, anxiety, depression, and health care utilization. Analyses were intention-to-treat and P values were two-sided with 95% confidence level set at 0.005 because of multiple comparisons. RESULTS: Among 1,101 eligible patients, 875 were invited and 503 were randomly assigned to control (n = 252) or intervention (n = 251) follow-up. At 2 years, patients in the intervention group reported a significantly and clinically relevant higher QoL (mean, 75.69 [standard deviation [SD], 12.27]) than patients in the control group (71.26 [SD, 14.08]), with a mean difference of 5.05 (95% CI, 3.30 to 6.79; P < .001). The intervention group reported significantly less fear of recurrence, anxiety, and depression; they had fewer physician consultations but more nurse contacts and an unchanged diagnostic imaging pattern. The effect on all outcomes was stable through a 3-year follow-up. CONCLUSION: The MyHealth study suggested a new strategy for follow-up after early breast cancer as it provided significant improvements in QoL.

Glycocalyx shedding patterns identifies antipsychotic-naïve patients with first-episode psychosis.

Psychotic disorders have been linked to immune-system abnormalities, increased inflammatory markers, and subtle neuroinflammation. Studies further suggest a dysfunctional blood brain barrier (BBB). The endothelial Glycocalyx (GLX) functions as a protective layer in the BBB, and GLX shedding leads to BBB dysfunction. This study aimed to investigate whether a panel of 11 GLX molecules derived from peripheral blood could differentiate antipsychotic-naïve first-episode psychosis patients (n47) from healthy controls (HC, n49) and whether GLX shedding correlated with symptom severity. Blood samples were collected at baseline and serum was isolated for GLX marker detection. Machine learning models were applied to test whether patterns in GLX markers could classify patient groups. Associations between GLX markers and symptom severity were explored. Patients showed significantly increased levels of three GLX markers compared to HC. Based on the panel of 11 GLX markers, machine learning models achieved a significant mean classification accuracy of 81%. Post hoc analysis revealed associations between increased GLX markers and symptom severity. This study demonstrates the potential of GLX molecules as immuno-neuropsychiatric biomarkers for early diagnosis of psychosis, as well as indicate a compromised BBB. Further research is warranted to explore the role of GLX in the early detection of psychotic disorders.

Effectiveness of a multidisciplinary and transitional nutritional intervention compared with standard care on health-related quality of life among acutely admitted medical patients aged ≥65 years with malnutrition or risk of malnutrition: A randomized controlled trial.

BACKGROUND & AIM: Malnutrition, risk of malnutrition, and risk factors for malnutrition are prevalent among acutely admitted medical patients aged ≥65 years and have significant health-related consequences. Consequently, we aimed to investigate the effectiveness of a multidisciplinary and transitional nutritional intervention on health-related quality of life compared with standard care. METHODS: The study was a block randomized, observer-blinded clinical trial with two parallel arms. The Intervention Group was offered a multidisciplinary transitional nutritional intervention consisting of dietary counselling and six sub-interventions targeting individually assessed risk factors for malnutrition, while the Control Group received standard care. The inclusion criteria were a Mini Nutritional Assessment Short-Form score ≤11, age ≥65 years, and an acute admittance to the Emergency Department. Outcomes were assessed on admission and 8 and 16 weeks after hospital discharge. The primary outcome was the difference between groups in change in health-related quality of life (assessed by the EuroQol-5D-5L) from baseline to 16 weeks after discharge. The secondary outcomes were difference in intake of energy and protein, well-being, muscle strength, and body weight at all timepoints. RESULTS: From October 2018 to April 2021, 130 participants were included. Sixteen weeks after discharge, 29% in the Intervention Group and 19% in the Control Group were lost to follow-up. Compliance varied between the sub-interventions targeting nutritional risk factors and was generally low after discharge, ranging from 0 to 61%. No difference was found between groups on change in health-related quality of life or on well-being, muscle strength, and body weight at any timepoint, neither using the intention-to-treat analysis nor the per-protocol analysis. The protein intake was higher in the Intervention Group during hospitalization (1.1 (Standard Deviation (SD) 0.4) vs 0.8 (SD 0.5) g/kg/day, p = 0.0092) and 8 weeks after discharge (1.2 (SD 0.5) vs 0.9 (0.4) g/kg/day, p = 0.0025). The percentual intake of calculated protein requirements (82% (SD 24) vs 61% (SD 32), p = 0.0021), but not of calculated energy requirements (89% (SD 23) vs 80% (SD 37), p = 0.2), was higher in the Intervention Group than in the Control Group during hospitalization. Additionally, the Intervention Group had a significantly higher percentual intake of calculated protein requirements (94% (SD 41) vs 74% (SD 30), p = 0.015) and calculated energy requirements (115% (SD 37) vs 94% (SD 31), p = 0.0070) 8 weeks after discharge. The intake of energy and protein was comparable between the groups 16 weeks after discharge. CONCLUSION: We found no effect of a multidisciplinary and transitional nutritional intervention for acutely admitted medical patients aged ≥65 years with malnutrition or risk of malnutrition on our primary outcome, health-related quality of life 16 weeks after discharge. Nor did the intervention affect the secondary outcomes, well-being, muscle strength, and body weight from admission to 8 or 16 weeks after discharge. However, the intervention improved energy and protein intake during hospitalization and 8 weeks after discharge. Low compliance with the intervention after discharge may have compromised the effect of the intervention. The study is registered at ClinicalTrials.gov (identifier: NCT03741283).

Can prediabetes diagnosed using HemoglobinA1c or oral glucose tolerance test predict presence and severity of coronary artery disease in symptomatic patients?

We investigated whether prediabetes diagnosed by hemoglobinA1c (HbA1c) or oral glucose tolerance test (OGTT) could predict presence and severity of coronary artery disease (CAD) in symptomatic patients. The presence of plaque, stenosis, plaque characteristics, and coronary artery calcium (CAC) were evaluated by coronary CT angiography in 702 patients with suspicion of CAD. Patients were classified by glycemic status using the American Diabetes Association criteria for HbA1c and OGTT, and compared to their respective normal ranges. Prediabetes was observed in 24% by HbA1c and 72% by OGTT. Both prediabetes classifications were associated with increased presence of plaque, stenosis, calcified plaques, CAC >400, and a lower frequency of zero CAC compared to their respective normal range (all, p < 0.05). After adjusting for potential confounders, patients with HbA1c-prediabetes had an odds ratio of 2.1 (95% CI: 1.3-3.5) for CAC >400 and 1.5 (95% CI: 1.0-2.4) for plaque presence, while none of the associations for OGTT-prediabetes were significant. The receiver operating characteristic-curve for HbA1c-prediabetes showed an area under the curve of 0.81 for CAC >400 and 0.77 for plaque presence. Prediabetes defined by HbA1c predicts presence and severity of CAD. Although OGTT identified more patients with prediabetes, their risk of CAD were not explained by prediabetes using these diagnostic-criteria.

The unknown third - Hydrogen isotopes in tree-ring cellulose across Europe.

This is the first Europe-wide comprehensive assessment of the climatological and physiological information recorded by hydrogen isotope ratios in tree-ring cellulose (δ2Hc) based on a unique collection of annually resolved 100-year tree-ring records of two genera (Pinus and Quercus) from 17 sites (36°N to 68°N). We observed that the high-frequency climate signals in the δ2Hc chronologies were weaker than those recorded in carbon (δ13Cc) and oxygen isotope signals (δ18Oc) but similar to the tree-ring width ones (TRW). The δ2Hc climate signal strength varied across the continent and was stronger and more consistent for Pinus than for Quercus. For both genera, years with extremely dry summer conditions caused a significant 2H-enrichment in tree-ring cellulose. The δ2Hc inter-annual variability was strongly site-specific, as a result of the imprinting of climate and hydrology, but also physiological mechanisms and tree growth. To differentiate between environmental and physiological signals in δ2Hc, we investigated its relationships with δ18Oc and TRW. We found significant negative relationships between δ2Hc and TRW (7 sites), and positive ones between δ2Hc and δ18Oc (10 sites). The strength of these relationships was nonlinearly related to temperature and precipitation. Mechanistic δ2Hc models performed well for both genera at continental scale simulating average values, but they failed on capturing year-to-year δ2Hc variations. Our results suggest that the information recorded by δ2Hc is significantly different from that of δ18Oc, and has a stronger physiological component independent from climate, possibly related to the use of carbohydrate reserves for growth. Advancements in the understanding of 2H-fractionations and their relationships with climate, physiology, and species-specific traits are needed to improve the modelling and interpretation accuracy of δ2Hc. Such advancements could lead to new insights into trees' carbon allocation mechanisms, and responses to abiotic and biotic stress conditions.

Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients.

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D2/3 receptor (D2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

A novel approach for the homogenization of cellulose to use micro-amounts for stable isotope analyses.

Climate reconstructions using stable isotopes from tree-rings are steadily increasing. The investigations concentrate mostly on cellulose due to its high stability. In recent years the available amount of cellulose has steadily decreased, mainly because micro-structures of plant material have had to be analyzed. Today, the amounts of cellulose being studied are frequently in the milligram and often in the microgram range. Consequently, homogeneity problems with regard to the stable isotopes of carbon and oxygen from cellulose have occurred and these have called for new methods in the preparation of cellulose for reliable isotope analyses. Three different methods were tested for preparing isotopically homogenous cellulose, namely mechanical grinding, freezing by liquid nitrogen with subsequent milling and ultrasonic breaking of cellulose fibres. The best precision of isotope data was achieved by freeze-milling and ultrasonic breaking. However, equipment for freeze-milling is expensive and the procedure is labour-intensive. Mechanical grinding resulted in a rather high loss of material and it is also labour-intensive. The use of ultrasound for breaking cellulose fibres proved to be the best method in terms of rapidity of sample throughput, avoidance of sample loss, precision of isotope results, ease of handling, and cost.

Variations in the intrinsic water-use efficiency of north Patagonian forests under a present climate change scenario: tree age, site conditions and long-term environmental effects.

The carbon isotope composition (δ13C) in tree rings were used to derive the intrinsic water-use efficiency (iWUE) of Araucaria araucana trees of northern Patagonia along a strong precipitation gradient. It is well known that climatic and ontogenetic factors affect growth performance of this species but little is known about their influence in the physiological responses, as iWUE. Thus, the main objective of this study was to assess the physiological reactions of young and adult trees from two open xeric and two moderately dense mesic A. araucana forests to the increases in atmospheric CO2 (Ca) and air temperature during the 20th century, and to relate these responses with radial tree growth. The results indicated that the iWUE and the intercellular CO2 concentration (Ci) increased 33% and 32% in average during the last century, respectively, but carbon isotope discrimination (∆13C) was more variable between sites and age classes. Trees from xeric sites presented greater iWUE and lower ∆13C and Ci values than those from mesic sites. In general, iWUE was strongly related with Ca and was significantly affected by mean summer maximum temperature. ∆13C from mesic sites seemed to be mainly affected by summer maximum temperature, while trees from xeric conditions did not show any influence. Tree age also presented a significant effect on iWUE. Adult trees showed higher iWUE values than young trees, indicating an incidence of the tree age and/or height, mainly in closed mesic forests. Moreover, some trees presented positive relationships between iWUE and radial tree growth, while others presented negative or no relationships, indicating that other factors may negatively influence tree growth. Broadly, the results demonstrate the incidence of climatic, environmental and ontogenetic variability in the tree responses; however, more studies are needed to better understand which forests will be more affected by actual and future climate changes.

Distribution and Prognostic Significance of Left Ventricular Global Longitudinal Strain in Asymptomatic Significant Aortic Stenosis: An Individual Participant Data Meta-Analysis.

OBJECTIVES: In this individual participant data meta-analysis on left ventricular global longitudinal strain (LVGLS), our objective was to: 1) describe its distribution; 2) identify the most predictive cutoff values; and 3) assess its impact on mortality in asymptomatic patients with significant aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF). BACKGROUND: The evidence supporting the prognostic role of LVGLS in asymptomatic patients with AS has been obtained from several relatively small studies. METHODS: A literature search was performed for studies published between 2005 and 2017 without language restriction according to the following criteria: "aortic stenosis" AND "longitudinal strain." The corresponding authors of selected studies were contacted and invited to share their data that we computerized in a specific database. The primary endpoint was all-cause mortality. RESULTS: Among the 10 studies included, 1,067 asymptomatic patients with significant AS and LVEF >50% were analyzed. The median of LVGLS was 16.2% (from 5.6% to 30.1%). There were 91 deaths reported during follow-up with median of 1.8 (0.9 to 2.8) years, resulting in a pooled crude mortality rate of 8.5%. The LVGLS performed well in the prediction of death (area under the curve: 0.68). The best cutoff value identified was LVGLS of 14.7% (sensitivity, 60%; specificity, 70%). Using random effects model, the risk of death for patients with LVGLS <14.7% is multiplied by >2.5 (hazard ratio: 2.62; 95% confidence interval: 1.66 to 4.13; p < 0.0001), without significant heterogeneity between studies (I2 = 18.3%; p = 0.275). The relationship between LVGLS and mortality remained significant in patients with LVEF ≥60% (p = 0.001). CONCLUSIONS: This individual participant data meta-analysis demonstrates that in asymptomatic patients with significant AS and normal LVEF, impaired LVGLS is associated with reduced survival. These data emphasize the potential usefulness of LVGLS for risk stratification and management of these patients.

Tree height strongly affects estimates of water-use efficiency responses to climate and CO2 using isotopes.

Various studies report substantial increases in intrinsic water-use efficiency (W i ), estimated using carbon isotopes in tree rings, suggesting trees are gaining increasingly more carbon per unit water lost due to increases in atmospheric CO2. Usually, reconstructions do not, however, correct for the effect of intrinsic developmental changes in W i as trees grow larger. Here we show, by comparing W i across varying tree sizes at one CO2 level, that ignoring such developmental effects can severely affect inferences of trees' W i . W i doubled or even tripled over a trees' lifespan in three broadleaf species due to changes in tree height and light availability alone, and there are also weak trends for Pine trees. Developmental trends in broadleaf species are as large as the trends previously assigned to CO2 and climate. Credible future tree ring isotope studies require explicit accounting for species-specific developmental effects before CO2 and climate effects are inferred.Intrinsic water-use efficiency (W i ) reconstructions using tree rings often disregard developmental changes in W i as trees age. Here, the authors compare W i across varying tree sizes at a fixed CO2 level and show that ignoring developmental changes impacts conclusions on trees' W i responses to CO2 or climate.

Family based association analysis of the IL2 and IL15 genes in allergic disorders.

Allergic diseases affect an increasing number of individuals and are a major global health problem. A substantial genetic contribution in the aetiology of allergic diseases is well documented. We have previously reported linkage of allergic diseases and atopy to the region harbouring the IL2 gene (4q27). IL15 is located approximately 20 Mb distal to IL2. The two genes encode cytokines that are structurally and functionally related, both inducing T-cell activation and proliferation. We screened the two genes for sequence variation and applied the seven single-nucleotide polymorphisms (SNPs) identified in a family based association study of two Danish samples comprising a total of 235 families with allergic diseases. None of the IL15 SNPs showed significant association and the haplotype analysis yielded inconsistent results in the two samples. In contrast, the two IL2 SNPs showed association both separately and in haplotypes with several atopic phenotypes, most significantly with IgE-mediated allergy. (single SNP P-value 0.0005 for positive skin prick test, haplotype P-value 0.019 for positive RAST test). To our knowledge, this is the first study reporting association between IL2 and IgE-mediated allergy, asthma and atopic eczema. The SNP (rs2069762) that showed the most consistent results is located in the promoter and has previously been shown to influence the level of IL2 expression. We suggest that the observed overtransmission of the T allele of this SNP may convey increased susceptibility to allergic disease by skewing the Th1/Th2 balance towards Th2.

Modelling severe Staphylococcus aureus sepsis in conscious pigs: are implications for animal welfare justified?

BACKGROUND: A porcine model of haematogenous Staphylococcus aureus sepsis has previously been established in our research group. In these studies, pigs developed severe sepsis including liver dysfunction during a 48 h study period. As pigs were awake during the study, animal welfare was challenged by the severity of induced disease, which in some cases necessitated humane euthanasia. A pilot study was therefore performed in order to establish the sufficient inoculum concentration and application protocol needed to produce signs of liver dysfunction within limits of our pre-defined humane endpoints. METHODS: Four pigs received 1 × 10(8) cfu/kg BW of S. aureus, and two controls were sham inoculated with saline. A fixed infusion rate of 3 mL/min was used, while the inoculum concentration, i.e., the dose volume, was changed between the pigs. The following dose volumes were used: 10 mL (n = 1), 20 mL (n = 2), and 30 mL (n = 1), corresponding to infusion durations of 3.33, 6.66, and 10 min at dose rates of 3 × 10(7), 1.5 × 10(7), and 1 × 10(7) cfu/min/kg BW, respectively. Blood samples were drawn for complete blood count, clinical chemistry, and inflammatory markers before and every 6 h after inoculation. Prior to euthanasia, a galactose elimination capacity test was performed to assess liver function. Pigs were euthanised 48 h post inoculation for necropsy and histopathological evaluation. RESULTS: While infusion times of 6.66 min, and higher, did not induce liver dysfunction (n = 3), the infusion time of 3.33 min (n = 1) caused alterations in parameters similar to what had been seen in our previous studies, i.e., increasing bilirubin and aspartate aminotransferase, as well as histopathological occurrence of intravascular fibrin split products in the liver. This pig was however euthanised after 30 h, according to humane endpoints. CONCLUSIONS: A usable balance between scientific purpose and animal welfare could not be achieved, and we therefore find it hard to justify further use of this conscious porcine sepsis model. In order to make a model of translational relevance for human sepsis, we suggest that future model versions should use long-term anaesthesia.

Organization and biology of the porcine serum amyloid A (SAA) gene cluster: isoform specific responses to bacterial infection.

Serum amyloid A (SAA) is a prominent acute phase protein. Although its biological functions are debated, the wide species distribution of highly homologous SAA proteins and their uniform behavior in response to injury or inflammation in itself suggests a significant role for this protein. The pig is increasingly being used as a model for the study of inflammatory reactions, yet only little is known about how specific SAA genes are regulated in the pig during acute phase responses and other responses induced by pro-inflammatory host mediators. We designed SAA gene specific primers and quantified the gene expression of porcine SAA1, SAA2, SAA3, and SAA4 by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in liver, spleen, and lung tissue from pigs experimentally infected with the Gram-negative swine specific bacterium Actinobacillus pleuropneumoniae, as well as from pigs experimentally infected with the Gram-positive bacterium Staphylococcus aureus. Our results show that: 1) SAA1 may be a pseudogene in pigs; 2) we were able to detect two previously uncharacterized SAA transcripts, namely SAA2 and SAA4, of which the SAA2 transcript is primarily induced in the liver during acute infection and presumably contributes to circulating SAA in pigs; 3) Porcine SAA3 transcription is induced both hepatically and extrahepatically during acute infection, and may be correlated to local organ affection; 4) Hepatic transcription of SAA4 is markedly induced in pigs infected with A. pleuropneumoniae, but only weakly in pigs infected with S. aureus. These results for the first time establish the infection response patterns of the four porcine SAA genes which will be of importance for the use of the pig as a model for human inflammatory responses, e.g. within sepsis, cancer, and obesity research.

[The agonist-antagonist nalbuphine prolongs gastro-cecal transit time and induces short-term pain following neuroleptanesthesia using fentanyl. A comparative study using a placebo]. / Der Agonist-Antagonist Nalbuphin verlängert die gastro-coekale Transitzeit und induziert kurzfristig Schmerzen nach Neuroleptanaesthesie mit Fentanyl. Eine Vergleichsuntersuchung zu Plazebo.

Little is known about the effects of mixed opioid analgesics on gastrointestinal propulsion. In 20 patients, nalbuphine (0.1 mg/kg) was given after routine neuroleptanesthesia consisting of 70 micrograms/kg droperidol, 7 micrograms/kg fentanyl, and N2O/O2 (3:1) ventilation, to study its effect on gastrointestinal motility in the postoperative period. For comparison, another group of patients (n = 20) undergoing similar interventions received placebo (0.9% NaCl) at the end of the procedure. Gastrointestinal transit time was determined by measuring the exhaled H2 concentration following gastric lactulose administration. As lactulose is degraded only in the cecum, resulting in the release of hydrogen, the arrival of the polysaccharide at the terminal ileum could thus be determined. Compared to placebo, gastrointestinal transit was significantly longer in patients after nalbuphine (mean transit time 270 min vs 380 min). Pain estimation by visual analogue scale (VAS 0-10) suggested an antagonistic effect at the 10th and 20th min postoperatively, as pain scores in the nalbuphine group were higher when compared to placebo (3.5 vs 1.8 and 2.5 vs 1.4). There was a similar pain score in both groups (1.3 vs 1.4) 30 min after drug administration. However, there was significantly better pain relief after nalbuphine (0.7 vs 1.4 and 0.7 vs 1.1) in the late postoperative period (120th and 240th min). When given after potent opioids, it must be borne in mind that the antagonistic effect of nalbuphine is initially apparent. The agonistic potency of the compound will come into effect around the 30th min post-injection. Delayed gastrointestinal transit after nalbuphine is explained by agonist-like effects on peripheral opioid receptors in the gut.