Quality of Life in the First Year of Follow-Up in a Randomized Multicenter Trial Assessing the Role of Imaging after Radical Surgery of Stage IIB-C and III Cutaneous Melanoma (TRIM Study).

The benefit of imaging in the follow-up setting for high-risk melanoma patients is uncertain, and even less is known about the impact of intensive follow-up on the patient´s quality of life. In 2017, a Swedish prospective randomized multicenter study started, in which high-risk melanoma patients are randomly assigned 1:1 to follow-up by physical examinations +/- whole-body imaging. The first-year examinations are scheduled at 0, 6 and 12 months. The aim of this study was to investigate whether the patients´ health-related quality of life (HRQoL) and levels of anxiety and depression were affected at 1 year by imaging. Anxiety/depression and HRQoL were assessed at 0 and 12 months by the questionnaires Hospital Anxiety and Depression (HAD) scale and EORTC QLQ-C30 version 3. Expected baseline QLQ-C30 values for the patients were calculated using data from the general population. In total, 204 patients were analyzed. Mean differences in subscale scores at 1 year were not statistically significant either for HRQoL or for anxiety/depression. Baseline HRQoL did not differ from expected values in the general Swedish population. In conclusion, the patients in general coped well with the situation, and adding whole-body imaging to physical examinations did not affect the melanoma patients' HRQoL or levels of anxiety or depression.

Evaluation of multiple transcriptomic gene risk signatures in male breast cancer.

Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. METHODS: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. DISCUSSION: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. RESULTS: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.

Mindfulness-Based Restoration Skills Training (ReST) in a Natural Setting Compared to Conventional Mindfulness Training: Psychological Functioning After a Five-Week Course.

Restoration skills training (ReST) is a mindfulness-based course that draws on restorative nature experience to facilitate the meditation practice and teach widely applicable adaptation skills. Previous studies comparing ReST to conventional mindfulness training (CMT) showed that ReST has important advantages: it supports beginning meditators in connecting with restorative environmental qualities and in meditating with less effort; it restores their attention regulation capabilities; and it helps them complete the course and establish a regular meditation habit. However, mindfulness theory indicates that effortful training may be necessary to achieve generalized improvements in psychological functioning. Therefore, this study tests whether the less effortful and more acceptable ReST approach is attended by any meaningful disadvantage compared to CMT in terms of its effects on central aspects psychological functioning. We analyze data from four rounds of development of the ReST course, in each of which we compared it to a parallel and formally matched CMT course. Randomly assigned participants (total course starters = 152) provided ratings of dispositional mindfulness, cognitive functioning, and chronic stress before and after the 5-week ReST and CMT courses. Round 4 also included a separately recruited passive control condition. ReST and CMT were attended by similar average improvements in the three outcomes, although the effects on chronic stress were inconsistent. Moderate to large improvements in the three outcomes could also be affirmed in contrasts with the passive controls. Using a reliable change index, we saw that over one third of the ReST and CMT participants enjoyed reliably improved psychological functioning. The risk of experiencing deteriorated functioning was no greater with either ReST or CMT than for passive control group participants. None of the contrasts exceeded our stringent criterion for inferiority of ReST compared with CMT. We conclude that ReST is a promising alternative for otherwise healthy people with stress or concentration problems who would be less likely to complete more effortful CMT. By adapting the meditation practices to draw on restorative setting characteristics, ReST can mitigate the demands otherwise incurred in early stages of mindfulness training without compromising the acquisition of widely applicable mindfulness skills.

Influenza vaccination in breast cancer patients during subcutaneous trastuzumab in adjuvant setting.

BACKGROUND: Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting. METHODS: A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured. RESULTS: Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%, p value = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination. CONCLUSION: Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy.

Vinflunine/gemcitabine versus carboplatin/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM).

BACKGROUND: The present study (VINGEM) is the first randomised trial comparing vinflunine/gemcitabine (VG) to standard carboplatin/gemcitabine (CG) in patients with advanced urothelial carcinoma (aUC) ineligible for treatment with cisplatin. PATIENTS AND METHODS: Patients with aUC, creatinine clearance 30-60 ml/min, performance status ≤1 and no prior chemotherapy for metastatic disease were randomised to the experimental arm (vinflunine 280 or 250 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days) or the control arm (carboplatin AUC 4.5 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days). Primary end-point was progression-free survival (PFS). RESULTS: Sixty-two patients were randomised; a total of 59 patients were treated (29 VG, 30 CG). There was no significant difference in PFS between the treatment arms: median 6.2 months for VG versus 6.3 months for CG (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.44-1.28; P = 0.293). Median overall survival was 12.5 months for VG versus 10.6 months for CG. The overall response rate (ORR) was higher in the VG arm than in the CG arm (63% versus 40%) but was not statistically significant in the intention-to-treat analysis. Furthermore, VG showed a high complete response (CR) rate, 22% versus 3% in CG. In the per-protocol group, both ORR and CR were significantly higher for VG than for CG. The most common adverse events (AEs) were fatigue, haematological toxicities, gastrointestinal disorders and nausea/vomiting. Common grade III/IV AEs were neutropenia (VG 62%, CG 43%), thrombocytopenia (VG 7%, CG 37%) and febrile neutropenia (VG 31%, CG 7%). CONCLUSIONS: The combination of VG did not improve PFS compared with standard treatment with CG in patients unfit for cisplatin due to renal impairment. The response rate of VG indicates, however, an active regimen and warrants further studies. CLINICALTRIALS. GOV NUMBER: NCT02665039.

Migratory flight on the Pacific Flyway: strategies and tendencies of wind drift compensation.

Applications of remote sensing data to monitor bird migration usher a new understanding of magnitude and extent of movements across entire flyways. Millions of birds move through the western USA, yet this region is understudied as a migratory corridor. Characterizing movements in the Pacific Flyway offers a unique opportunity to study complementary patterns to those recently highlighted in the Atlantic and Central Flyways. We use weather surveillance radar data from spring and autumn (1995-2018) to examine migrants' behaviours in relation to winds in the Pacific Flyway. Overall, spring migrants tended to drift on winds, but less so at northern latitudes and farther inland from the Pacific coastline. Relationships between winds and autumn flight behaviours were less striking, with no latitudinal or coastal dependencies. Differences in the preferred direction of movement (PDM) and wind direction predicted drift patterns during spring and autumn, with increased drift when wind direction and PDM differences were high. We also observed greater total flight activity through the Pacific Flyway during the spring when compared with the autumn. Such complex relationships among birds' flight strategies, winds and seasonality highlight the variation within a migration system. Characterizations at these scales complement our understanding of strategies to clarify aerial animal movements.

Projected changes in wind assistance under climate change for nocturnally migrating bird populations.

Current climate models and observations indicate that atmospheric circulation is being affected by global climate change. To assess how these changes may affect nocturnally migrating bird populations, we need to determine how current patterns of wind assistance at migration altitudes will be enhanced or reduced under future atmospheric conditions. Here, we use information compiled from 143 weather surveillance radars stations within the contiguous United States to estimate the daily altitude, density, and direction of nocturnal migration during the spring and autumn. We intersected this information with wind projections to estimate how wind assistance is expected to change during this century at current migration altitudes. The prevailing westerlies at midlatitudes are projected to increase in strength during spring migration and decrease in strength to a lesser degree during autumn migration. Southerly winds will increase in strength across the continent during both spring and autumn migration, with the strongest gains occurring in the center of the continent. Wind assistance is projected to increase across the central (0.44 m/s; 10.1%) and eastern portions of the continent (0.32 m/s; 9.6%) during spring migration, and wind assistance is projected to decrease within the central (0.32 m/s; 19.3%) and eastern portions of the continent (0.17 m/s; 6.6%) during autumn migration. Thus, across a broad portion of the continent where migration intensity is greatest, the efficiency of nocturnal migration is projected to increase in the spring and decrease in the autumn, potentially affecting time and energy expenditures for many migratory bird species. These findings highlight the importance of placing climate change projections within a relevant ecological context informed through empirical observations, and the need to consider the possibility that climate change may generate both positive and negative implications for natural systems.

Aeroecology of a solar eclipse.

Light cues elicit strong responses from nearly all forms of life, perhaps most notably as circadian rhythms entrained by periods of daylight and darkness. Atypical periods of darkness, like solar eclipses, provide rare opportunities to study biological responses to light cues. By using a continental scale radar network, we investigated responses of flying animals to the total solar eclipse of 21 August 2017. We quantified the number of biological targets in the atmosphere at 143 weather radar stations across the continental United States to investigate whether the decrease in light and temperature at an atypical time would initiate a response like that observed at sunset, when activity in the atmosphere usually increases. Overall, biological activity decreased in the period leading to totality, followed by a short low-altitude spike of biological activity during totality in some radars. This pattern suggests that cues associated with the eclipse were insufficient to initiate nocturnal activity comparable to that occurring at sunset but sufficient to suppress diurnal activity.

Ghrelin expression is associated with a favorable outcome in male breast cancer.

Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18-0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17-0.87). HR for obestatin was 0.38 (95% CI 0.11-1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.

Hypothalamic oxidative stress and inflammation, and peripheral glucose homeostasis in Sprague-Dawley rat offspring exposed to maternal and postnatal chocolate and soft drink.

BACKGROUND: Predisposition to obesity and type 2 diabetes can arise during foetal development and in early postnatal life caused by imbalances in maternal nutritional overload. We aimed to investigate the effects of maternal and postnatal intake of chocolate and soft drink on hypothalamic anti-oxidative stress markers, inflammation and peripheral glucose homeostasis. METHODS: Pregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplements (S). At birth, litter size was adjusted into 10 male offspring per dam. After weaning at 3 weeks of age, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. RESULTS: Offspring exposed to maternal S had up-regulated hypothalamic anti-oxidative markers such as SOD2 and catalase at 3 weeks of age as an indication of oxidative stress. However, at 12 weeks of age these anti-oxidative markers tended to decrease while pro-inflammatory markers such as TNF and IL-1ß became up-regulated of all offspring exposed to S diet during some point of their life. Thus, despite an increase in anti-oxidative stress response, offspring exposed to maternal S had a reduced ability to counteract hypothalamic inflammation. At the same time point, postnatal S resulted in increased adiposity, reduced glucose tolerance and insulin sensitivity with no effect on body weight. However, at 25 weeks of age, the impaired glucose tolerance was reversible to the response of the control regardless of increased adiposity and body weight pointing towards a compensatory response of the insulin sensitivity or insulin secretion. CONCLUSION: Indications of hypothalamic oxidative stress was observed prior to the inflammatory response in offspring exposed to maternal S. Both maternal and postnatal S induced hypothalamic inflammation prior to increased weight gain and thus contributing to obese phenotype.

Risk factors for locoregional disease recurrence after breast-conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis.

BACKGROUND: Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast-conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT. METHODS: Individual patient data sets from 9 studies were pooled. The outcomes of interest were the occurrence of LR and/or LRR. A 1-stage meta-analytic approach was used. Cox proportional hazards regression models were applied to identify factors that were predictive of LR and LRR, respectively. RESULTS: A total of 9 studies (4125 patients) provided their data sets. The 10-year LR rate was 6.5%, whereas the 10-year LRR rate was 10.3%. Four factors were found to be associated with a higher risk of LR: 1) estrogen receptor-negative disease; 2) cN + disease; 3) a lack of pathologic complete response in axilla (pN0); and 4) pN2 to pN3 disease. The predictive score for LR determined 3 risk groups: a low-risk, intermediate-risk, and high-risk group with 10-year LR rates of 4.0%, 7.9%, and 20.4%, respectively. Two additional factors were found to be associated with an increased risk of LRR: cT3 to cT4 disease and a lack of pathologic complete response in the breast. The predictive score for LRR determined 3 risk groups; a low-risk, intermediate-risk, and high-risk group with 10-year LRR rates of 3.2%, 10.1%, and 24.1%, respectively. CONCLUSIONS: BCT after NCT appears to be an oncologically safe procedure for a large percentage of patients with breast cancer. Two easy-to-use clinical scores were developed that can help clinicians to identify patients at higher risk of LR and LRR after NCT and BCT and individualize the postoperative treatment plan and follow-up. Cancer 2018;124:2923-30. © 2018 American Cancer Society.

[Establishing a screening programme in Denmark for foetal and neonatal alloimmune thrombocytopenia].

Foetal and neonatal alloimmune thrombocytopenia (FNAIT) can cause cerebral haemorrhage in newborns. FNAIT occurs in women, who do not have the thrombocyte type human platelet antigen (HPA)-1a and are carrying an HPA-1a positive foetus. Maternal antibodies can cause thrombocytopenia in the foetus or newborn. Antenatal screening for FNAIT can easily be integrated in the already existing national screening programme for rhesus immunisation. Prophylactic treatment with immunoglobulines for pregnancies at risk can prevent neonatal complications. We argue, that the WHO criteria for a screening programme for FNAIT are met.

Development and evaluation of an endoscopic surgery course for medical students.

INTRODUCTION: Surgical training has changed with the introduction of endoscopic surgery. However, a gap in undergraduate medical training has become evident regarding theoretical principles of and basic skills training in endoscopic surgery. The objective of this study was to develop and evaluate a course in endoscopic surgery for medical students. METHODS: Kern's six-step approach in curriculum development was used. A course including interactive, faculty-led didactic sessions (14 hours, distributed over three days) and simulation-based basic skills training in endoscopic surgery (nine hours, distributed over four sessions) was developed. Knowledge was tested using a 35-item test before and after the course, and finally the course was evaluated electronically. The project group in cooperation with the faculty -developed the goals and objectives, the test and the evaluation questionnaire. RESULTS: The test-scores significantly improved after the course, p < 0.0001, with a mean difference of 12.95 (95% confidence interval: 11.47-14.44). A total of 74% (14/19) responded that the course increased their interest in a career in a surgical specialty and 58% (11/19) were considering specialising in a surgical specialty. CONCLUSIONS: A course in endoscopic surgery was developed based on Kern's six-step approach. The course was positively perceived by the students in terms of contents as well as structure and relevance. FUNDING: University of Copenhagen, Aase og Ejner Danielsen Fonden, The Juliane Marie Centre for Children, Women and Reproduction, Rigshospitalet. TRIAL REGISTRATION: not relevant.

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

Simulation-based camera navigation training in laparoscopy-a randomized trial.

BACKGROUND: Inexperienced operating assistants are often tasked with the important role of handling camera navigation during laparoscopic surgery. Incorrect handling can lead to poor visualization, increased operating time, and frustration for the operating surgeon-all of which can compromise patient safety. The objectives of this trial were to examine how to train laparoscopic camera navigation and to explore the transfer of skills to the operating room. MATERIALS AND METHODS: A randomized, single-center superiority trial with three groups: The first group practiced simulation-based camera navigation tasks (camera group), the second group practiced performing a simulation-based cholecystectomy (procedure group), and the third group received no training (control group). Participants were surgical novices without prior laparoscopic experience. The primary outcome was assessment of camera navigation skills during a laparoscopic cholecystectomy. The secondary outcome was technical skills after training, using a previously developed model for testing camera navigational skills. The exploratory outcome measured participants' motivation toward the task as an operating assistant. RESULTS: Thirty-six participants were randomized. No significant difference was found in the primary outcome between the three groups (p = 0.279). The secondary outcome showed no significant difference between the interventions groups, total time 167 s (95% CI, 118-217) and 194 s (95% CI, 152-236) for the camera group and the procedure group, respectively (p = 0.369). Both interventions groups were significantly faster than the control group, 307 s (95% CI, 202-412), p = 0.018 and p = 0.045, respectively. On the exploratory outcome, the control group for two dimensions, interest/enjoyment (p = 0.030) and perceived choice (p = 0.033), had a higher score. CONCLUSIONS: Simulation-based training improves the technical skills required for camera navigation, regardless of practicing camera navigation or the procedure itself. Transfer to the clinical setting could, however, not be demonstrated. The control group demonstrated higher interest/enjoyment and perceived choice than the camera group.

Long acting analogue of the calcitonin gene-related peptide induces positive metabolic effects and secretion of the glucagon-like peptide-1.

The pharmacological potential of Calcitonin gene-related peptide (CGRP) beyond vasodilation is not completely understood and studies are limited by the potent vasodilatory effect and the short half-life of CGRP. In particular, the effects of CGRP on metabolic diseases are not clarified. A peptide analogue of the α form of CGRP (αAnalogue) with prolonged half-life (10.2 ± 0.9h) in rodents was synthesised and used to determine specific metabolic effects in 3 rodent models; normal rats, diet-induced obese rats and the Leptin deficient mouse model (ob/ob mice). The αAnalogue (100 nmol/kg) induced elevated energy expenditure and reduced food intake after single dosing in normal rats. In addition, the αAnalogue increased levels of circulating Glucagon-Like Peptide-1 (GLP-1) by >60% and a specific concentration dependent CGRP-induced GLP-1 secretion was verified in a murine L-cell line. Two weeks treatment of the type 2 diabetic ob/ob mice with the αAnalogue caused reduction in fasting insulin levels (199 ± 36 pM vs 332 ± 68 pM) and a tendency to reduce fasting blood glucose (11.2 ± 1.1mM vs 9.5 ± 0.5mM) and % glycosylated haemoglobin (HbA1c) (5.88 ± 0.17 vs 5.12 ± 0.24), demonstrating a potential anti-diabetic effect. Furthermore, two weeks treatment of diet-induced obese rats with the αAnalogue caused reduction in food intake and a significant decline in body weight (3.6 ± 1.9 gvs. -36 ± 1.1g). We have demonstrated that long-acting CGRP analogues may have a therapeutic potential for the treatment of type 2 diabetes through positive metabolic effects and effect on GLP-1 secretion.

Adaptive strategies in nocturnally migrating insects and songbirds: contrasting responses to wind.

Animals that use flight as their mode of transportation must cope with the fact that their migration and orientation performance is strongly affected by the flow of the medium they are moving in, that is by the winds. Different strategies can be used to mitigate the negative effects and benefit from the positive effects of a moving flow. The strategies an animal can use will be constrained by the relationship between the speed of the flow and the speed of the animal's own propulsion in relation to the surrounding air. Here we analyse entomological and ornithological radar data from north-western Europe to investigate how two different nocturnal migrant taxa, the noctuid moth Autographa gamma and songbirds, deal with wind by analysing variation in resulting flight directions in relation to the wind-dependent angle between the animal's heading and track direction. Our results, from fixed locations along the migratory journey, reveal different global strategies used by moths and songbirds during their migratory journeys. As expected, nocturnally migrating moths experienced a greater degree of wind drift than nocturnally migrating songbirds, but both groups were more affected by wind in autumn than in spring. The songbirds' strategies involve elements of both drift and compensation, providing some benefits from wind in combination with destination and time control. In contrast, moths expose themselves to a significantly higher degree of drift in order to obtain strong wind assistance, surpassing the songbirds in mean ground speed, at the cost of a comparatively lower spatiotemporal migratory precision. Moths and songbirds show contrasting but adaptive responses to migrating through a moving flow, which are fine-tuned to the respective flight capabilities of each group in relation to the wind currents they travel within.

Detection of flow direction in high-flying insect and songbird migrants.

Goal-oriented migrants travelling through the sea or air must cope with the effect of cross-flows during their journeys if they are to reach their destination. In order to counteract flow-induced drift from their preferred course, migrants must detect the mean flow direction, and integrate this information with output from their internal compass, to compensate for the deflection. Animals can potentially sense flow direction by two nonexclusive mechanisms: either indirectly, by visually assessing the effect of the current on their movement direction relative to the ground; or directly, via intrinsic properties of the current. Here, we report the first evidence that nocturnal compass-guided insect migrants use a turbulence-mediated mechanism for directly assessing the wind direction hundreds of metres above the ground. By comparison, we find that nocturnally-migrating songbirds do not use turbulence to detect the flow; instead they rely on visual assessment of wind-induced drift to indirectly infer the flow direction.