The process of minimising medicine use through dialogue based animal health and welfare planning, Workshop report FIBL. In: CORE Organic project no. 1903 - ANIPLAN

The process of minimising medicine use through dialogue based animal health and welfare planning. Livestock are important in many organic farming systems, and it is an explicit goal to ensure high levels of animal health and welfare (AHW) through good management. In two previous EU network projects, NAHWOA & SAFO, it was concluded that this is not guaranteed merely by following organic standards. Both networks recommended implementation of individual animal health plans to stimulate organic farmers to improve AHW. These plans should include a systematic evaluation of AHW and be implemented through dialogue with each farmer in order to identify goals and plan improvements. 11 research institutions in 7 European countries have been involved in the ANIPLAN project with the main objective to minimise medicine use in organic dairy herds through active and well planned AHW promotion and disease prevention. The project consisted of 5 work packages, 4 of which comprised research activities building on current research projects, new applications across borders, exchange of knowledge, results and conclusions between participating countries, and adopting them to widely different contexts. International and national workshops have facilitated this exchange. In the project, animal health and welfare planning principles for organic dairy farms under diverse conditions were developed. Animal health and welfare assessments, based on the WelfareQuality parameters, were conducted in different types of organic dairy herds across Europe. Finally, guidelines for communication about animal health and welfare promotion in different settings were also developed relevant to both existing animal health advisory services or farmer groups such as the Danish Stable School system and the Dutch network program. These proceedings contain the presentations at the final workshop, which also included invited external guests. The proceedings also contain three reports which are deliverables of the project. They are focused on the process of planning for better animal health and welfare, and how farmers and facilitators manage this situation. The focus areas are animal health planning, AHW assessment using animal based parameters and development of advisory systems and farmer groups

Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119

AbstractGPR119 is a Gαs-coupled lipid-sensor in the gut, where it mediates release of incretin hormones from the enteroendocrine cells and in pancreatic α-cells, where it releases insulin. Naturally occurring lipids such as monoacylglycerols (MAGs) and N-acylethanolamines (NAEs), like oleoylethanolamide (OEA), activate GPR119, and multiple synthetic ligands have been described. Here, we extend the GPR119 signaling profile to Gαq and Gαi in addition to β-arrestin recruitment and the downstream transcription factors CRE (cAMP response element), SRE (serum response element) and NFAT (nuclear factor of activated T cells). The endogenous OEA and the synthetic AR231453 were full agonists in all pathways except for NFAT, where no ligand-modulation was observed. The potency of AR231453 varied <16-fold (EC50 from 6 to 95nM) across the different signaling pathways, whereas that of OEA varied >175-fold (from 85nM to 15μM) indicating a biased signaling for OEA. The degree of constitutive activity was 1–10%, 10–30% and 30–70% of OEA-induced Emax in Gαi, Gαq and Gαs-driven pathways, respectively. This coincided with the lowest and highest OEA potency observed in Gαi and Gαs-driven pathways, respectively. Incubation for 2h with the 2-MAG-lipase inhibitor JZL84 doubled the constitutive activity, indicating that endogenous lipids contribute to the apparent constitutive activity. Finally, besides being an agonist, AR231453 acted as a positive allosteric modulator of OEA and increased its potency by 54-fold at 100nM AR231453. Our studies uncovering broad and biased signaling, masked constitutive activity by endogenous MAGs, and ago-allosteric properties of synthetic ligands may explain why many GPR119 drug-discovery programs have failed so far

Somatotropinoma Infarction During Octreotide Therapy Leading to Bilateral Cavernous Sinus Syndrome

The cyclic somatostatin analog, octreotide, forms the mainstay of medical treatment for acromegaly. In addition to lowering circulating growth hormone levels and shrinking tumor size, octreotide may provide symptomatic relief of headaches associated with growth hormone secreting tumors. The majority of reported complications of octreotide therapy are gastrointestinal and metabolic. The present case illustrates the development of acute bilateral cavernous sinus syndrome with loss of eye movement bilaterally during octreotide therapy. Serial MRI examination suggest tumor infarction as the etiology. The symptoms resolved over 2 months as the tumor shrunk in size and growth hormone was dramatically reduced.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47491/1/11102_2004_Article_324058.pd

The pseudogap state in superconductors: Extended Hartree approach to time-dependent Ginzburg-Landau Theory

It is well known that conventional pairing fluctuation theory at the Hartree level leads to a normal state pseudogap in the fermionic spectrum. Our goal is to extend this Hartree approximated scheme to arrive at a generalized mean field theory of pseudogapped superconductors for all temperatures $T$. While an equivalent approach to the pseudogap has been derived elsewhere using a more formal Green's function decoupling scheme, in this paper we re-interpret this mean field theory and BCS theory as well, and demonstrate how they naturally relate to ideal Bose gas condensation. Here we recast the Hartree approximated Ginzburg-Landau self consistent equations in a T-matrix form. This recasting makes it possible to consider arbitrarily strong attractive coupling, where bosonic degrees of freedom appear at $T^*$ considerably above $T_c$. The implications for transport both above and below $T_c$ are discussed. Below $T_c$ we find two types of contributions. Those associated with fermionic excitations have the usual BCS functional form. That they depend on the magnitude of the excitation gap, nevertheless, leads to rather atypical transport properties in the strong coupling limit, where this gap (as distinct from the order parameter) is virtually $T$-independent. In addition, there are bosonic terms arising from non-condensed pairs whose transport properties are shown here to be reasonably well described by an effective time-dependent Ginzburg-Landau theory.Comment: 14 pages, 5 figures, REVTeX4, submitted to PRB; clarification of the diagrammatic technique added, one figure update

Critical fluctuation conductivity in layered superconductors in strong electric field

The paraconductivity, originating from critical superconducting order-parameter fluctuations in the vicinity of the critical temperature in a layered superconductor is calculated in the frame of the self-consistent Hartree approximation, for an arbitrarily strong electric field and zero magnetic field. The paraconductivity diverges less steep towards the critical temperature in the Hartree approximation than in the Gaussian one and it shows a distinctly enhanced variation with the electric field. Our results indicate that high electric fields can be effectively used to suppress order-parameter fluctuations in high-temperature superconductors.Comment: 11 pages, 2 figures, to be published in Phys. Rev.

Microscopic theory of the pseudogap and Peierls transition in quasi-one-dimensional materials

The problem of deriving from microscopic theory a Ginzburg-Landau free energy functional to describe the Peierls or charge-density-wave transition in quasi-one-dimensional materials is considered. Particular attention is given to how the thermal lattice motion affects the electronic states. Near the transition temperature the thermal lattice motion produces a pseudogap in the density of states at the Fermi level. Perturbation theory diverges and the traditional quasi-particle or Fermi liquid picture breaks down. The pseudogap causes a significant modification of the coefficients in the Ginzburg-Landau functional from their values in the rigid lattice approximation, which neglects the effect of the thermal lattice motion. To appear in Physical Review B.Comment: 21 pages, RevTeX, 5 figures in uuencoded compressed tar fil

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

Follicle-stimulating hormone signal transduction: Role of carbohydrate in aromatase induction in immature rat Sertoli cells

Receptor activated adenylate cyclase acts as a major transmembrane signalling system. It is widely accepted that upon binding to its receptor, follicle-stimulating hormone (FSH) activates the cAMP-dependent pathway which in turn mediates FSH-induced estradiol production in Sertoli cells. Studies utilizing several chemically derived variants of FSH have demonstrated that these variants bind to the FSH receptors with equal avidity but differ in their ability to activate cAMP-dependent pathways. Since cAMP is believed to be the second messenger responsible for FSH signal transduction, we tested two hypotheses: (1) that the effects of different oFSH variants on cAMP production and aromatase induction (as measured by estradiol production) would be in parallel; and (2) that deglycosylated ovine FSH (DG-oFSH) would antagonize the ability of intact oFSH to stimulate aromatase induction, similar to its reported antagonistic effect on cAMP production.Immature rat (7- to 10-day-old) Sertoli cells were cultured and the effects of several different oFSH variants on cAMP production and/or aromatase induction were tested. The variants tested were native oFSH, DG-oFSH, asialo oFSH (AS-oFSH), a recombinant of intact LH[alpha] and FSH[beta] ([alpha] + [beta]) and a recombinant of deglycosylated LH[alpha] and intact FSH[beta] (DG[alpha] + [beta]). Both native oFSH and [alpha] + [beta] recombinant at relatively large doses (10 ng) elicited a significant increase in extracellular cAMP accumulation as well as total cAMP production. In contrast, DG-oFSH did not produce an increase in cAMP even at 10-fold higher doses than native oFSH. Intracellular cAMP concentrations did not increase following stimulation with native oFSH, DG-oFSH or DG[alpha] + [beta].In contrast to the divergent effects of oFSH and DG-oFSH on cAMP production all variants of oFSH stimulated estradiol production from Sertoli cells albeit with varying potencies. The sensitivity (minimal effective dose) and ED50 (dose at which half maximal response is achieved) of the estradiol (E2) response curve to increasing concentrations of native oFSH were 0.025 +/- 0.01 and 0.33 +/- 0.05 ng, respectively. Asialo-oFSH (AS-oFSH) increased E2 production with a potency (comparative dose required for effect) similar to that of native oFSH. In contrast, there was a 10-fold reduction in potency of DG-oFSH (ED50 of 3.27 +/- 1.7 ng). The efficacy (maximum effect on aromatase induction) of native, DG and AS-oFSH were equipotent. Coincubation of DG-oFSH (0.005-100 ng) with oFSH (0.01-0.625 ng) demonstrated the inductive effects to be additive. In contrast to the reduced potency of DG-oFSH, DG[alpha] -- [beta] recombinants (0.156-160 ng) increased E2 production with a potency similar to that of the native oFSH.Our data suggest: (1) the effects of oFSH variants on cAMP production and aromatase induction are not always parallel; (2) DG-oFSH is a weak agonist and not an antagonist of oFSH-mediated aromatase induction; (3) the reduced potency of DG-oFSH must involve oligosaccharides internal to sialic acid; and (4) depleting the carbohydrate moiety on the [alpha] subunit alone may not be adequate to reduce the potency of oFSH to induce aromatase. Since DG-oFSH does not increase cAMP accumulation, but is able to induce aromatase, the FSH-mediated induction of aromatase may be transduced through other signal pathways. Alternatively, the maximal steroidogenic response may be induced by small, but undetectable, increases in intracellular cAMP concentrations or availability of segregated cAMP pools.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29186/1/0000239.pd

ONCOR: design of the Dutch cardio-oncology registry

Background: The relative new subspecialty ‘cardio-oncology’ was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy–related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established. / Aim: The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice. / Methods: Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment. / Discussion: Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy–related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate