Past intensification trajectories of livestock led to mixed social and environmental services.

Recent studies highlighted the multiple positive and negative contributions of livestock to society. Livestock production, through its direct and indirect impacts on land use, is an important driver of services provision. Although a few studies provide an account on the multiple services in different livestock systems, there is still an important knowledge gap on the drivers that contribute to the differentiation of services provisioning across areas. We investigated the hypothesis that the current level of services has derived from past intensification trajectories of livestock. The objective of this study was to understand the influences of past changes in livestock, land-use and socio-economic variables on the current provision of social, environmental and cultural services by the livestock sector in France. We combined a long-term country-wide database on livestock intensification between 1938 and 2010 and a database on services provisioning in 2010. We used a set of multivariate methods to simultaneously analyse the changes in livestock intensification from 1938 to 2010 and the current level of services provisioning. Our analysis focused on a set of 60 French departments where livestock play a significant economic role in agricultural production. Our study revealed that the provision of services was spatially structured and based on three groups of departments, characterised by different rates of change in intensification variables. In the first group, 'Intensive livestock areas', the high level of employment in the livestock sector was mainly associated with high rates of change in monogastric stocking rates (+1045%) and milk productivity (+451%). In the second group, 'Extensive livestock areas', the high levels of environmental and cultural services were mainly associated with moderate rates of change in herbivores stocking rate (+95%) and the stability of grassland area (+13%). In the third group, 'Transition areas', the low provision of all services was associated with the decline in livestock due to crop expansion. This study provides knowledge to understand how past changes determined the current contribution of livestock areas in providing differentiated bundles of services, which might help steer the development of the current livestock sector towards more sustainable trajectories.

Long-term management of chronic spontaneous urticaria with omalizumab.

BACKGROUND: Clinical trials have shown the efficacy of omalizumabs efficacy in refractory chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), but real-life management strategies are lacking. AIM: To assess the long-term efficacy and safety of omalizumab, and to identify predictive factors and optimum dosage regimens. METHODS: This was a prospective study of 13 patients (11 women, 2 men) with severe CSU [weekly urticaria activity score (UAS7) > 28] resistant to anti-H1 antihistamines. Patients were started on omalizumab 150 mg subcutaneously every 4 weeks. Dose and interval between administrations were adjusted according to clinical response (189 administrations; treatment duration range 2-38 months). RESULTS: Mean UAS7 was 36.3 ± 5.4. Of the 13 patients, all had experienced angio-oedema, while in addition, 7 had delayed pressure urticaria (DPU) and 1 had solar urticaria (SU). After omalizumab treatment, 4 (30.8%) of the 13 patients had complete response (CR), and the remaining 8 (61.5%) had partial response. CR was achieved with a dose of 150 mg every 4 (n = 2 patients) or 5 (n = 2) weeks. One of these patients remained disease-free after stopping treatment. Partial responses were achieved with 150 mg every 4 weeks (n = 4) and with 300 mg (n = 4) at intervals of 5 weeks (n = 1), 4 weeks (n = 2) or 3 weeks (n = 1). Only one patient (7.7%) did not show significant improvement, despite a dose of 300 mg every 4 weeks. There were no significant differences in epidemiological, clinical and laboratory data between the different response groups. Only two adverse events were observed: one was mild headache and the other was severe angio-oedema and aggravation of urticaria within 6 h of omalizumab administration. CONCLUSION: Omalizumab dose and interval between administrations could be individualized for long-term management of CSU.

Patch testing - a valuable tool for investigating non-immediate cutaneous adverse drug reactions to antibiotics.

BACKGROUND: Antibiotics are among the most frequent causes of cutaneous adverse drug reactions (CADR); patch testing may be an important tool in their evaluation and management. We assessed the role of patch testing as a diagnostic tool in non-immediate CADR to antibiotics, and evaluated cross-reactivity among them. METHODS: We reviewed data from all patients with non-immediate CADR attributed to antibiotics, which were patch tested between 2000 and 2014 at our dermatology department. RESULTS: Patch tests were performed in 260 patients, and showed overall reactivity to antibiotics of 21.5%, especially in the context of drug reactions with eosinophilia and systemic symptoms (DRESS) (31.6%), maculopapular exanthema (MPE) (21.8%), Stevens-Johnson syndrome/toxic epidermal necrolysis (20%) and acute generalized exanthematous pustulosis (AGEP) (18.1%). Patch test reactivity was higher for amoxicillin, mainly in DRESS (44.4%) and MPE (25.6%), and dicloxacillin (50% in AGEP and 37.5% in MPE). Reactivity to clindamycin occurred, especially in the setting of MPE (23.2%). In AGEP and DRESS, patch tests were useful in detecting reactivity to quinolones (50-100%). Overall reactivity was lower for vancomycin (9.1%), co-trimoxazole (8.6%), macrolides (4.8%) and cephalosporins (4.4%). Positive patch tests for more than one antibiotic occurred in 29/56 cases (51.8%), mostly explained by cross-reactions. Twenty of 24 cases reacted to both amoxicillin and ampicillin. All five cases reacting to ciprofloxacin cross-reacted with other quinolones. CONCLUSION: Although oral rechallenge is considered the gold standard for confirming drug imputability in CADR, patch testing could be suggested as a first choice in the study of non-immediate reactions, since it is a safe and valuable procedure.

Clinical characterization and long-term follow-up of Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SchS) is an acquired autoinflammatory disease characterized by chronic urticarial rash in association with monoclonal gammopathy. Patients may progress to lymphoproliferative disorders, but the associated factors and exact risk of progression are still not well defined. AIM: To characterize the clinical findings, laboratory abnormalities and histopathology of patients with SchS and their respective outcomes. METHODS: We retrospectively reviewed the clinical files and the histological specimens of patients with SchS diagnosed from 1988 to 2015. RESULTS: Nine patients (two women, seven men) were diagnosed with SchS. Mean age at diagnosis was 61.1 years (range 29-80), with a mean time to diagnosis of 3.7 years and a mean follow-up period of 10.1 years (range 3-25). Four patients displayed an association of fever and arthralgia, and all nine patients consistently showed laboratory markers of inflammation. Serum values of the monoclonal component, IgMκ in eight patients and IgGλ in one patient, progressively increased over time. During follow-up, carried out in association with the haematology department five patients progressed to lymphoproliferative disease, namely, lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia (n = 4) and diffuse large B-cell lymphoma (n = 1). CONCLUSIONS: SchS is a rare chronic inflammatory disease with a substantial impact on quality of life. Our study highlights the importance of lifelong follow-up for individuals with SchS, owing to the risk of progression to a lymphoproliferative disorder.

Overlap between maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms among cutaneous adverse drug reactions in a dermatology ward.

BACKGROUND: Inpatients with cutaneous adverse drug reactions (CADR) with overlapping features between maculopapular exanthema (MPE) and drug reaction with eosinophilia and systemic symptoms (DRESS) were examined. OBJECTIVES: To characterize patients with exanthema and few systemic symptoms not meeting the criteria for DRESS [overlapping MPE-DRESS (MP/DR)]. METHODS: We undertook a comparative analysis of clinical and laboratory features of patients with MPE, MP/DR and DRESS (2008-12). RESULTS: We identified 132 inpatients (85 women/47 men, mean age 64·0 ± 17·7 years) with CADR, 37 with DRESS, 28 with MPE, 34 with MP/DR and 33 with other patterns. There were no significant differences in sex, age or concomitant diseases. Allopurinol was the main cause of DRESS (40·5%) and MP/DR (29·4%); antimicrobials were the main cause in MPE (35·7%). In MP/DR the latency period (18·06 ± 13·17 days) was significantly longer than in MPE but shorter than in DRESS. Although hospitalization time was similar to DRESS (13·26 ± 7·41 days), duration of therapy and follow-up in MP/DR was shorter. Exanthema/erythroderma were frequently associated with facial oedema in MP/DR (73·5%) and DRESS (89·2%) but only in 42·0% of patients with MPE. MP/DR histopathology showed keratinocyte vacuolization and perivascular and interstitial infiltrate of lymphocytes, eosinophils and neutrophils, similar but milder than in DRESS, with less interface dermatitis, exocytosis and spongiosis. DRESS was associated with liver involvement (78·4%) and eosinophilia (78·4%), but only in 64·7% and 11·8%, respectively, of patients with MP/DR. CONCLUSIONS: An overlapping pattern between MPE and DRESS was identified and characterized. There may be a continuum spectrum between MPE and DRESS.

Lamb Production Costs: Analyses of Composition and Elasticities Analysis of Lamb Production Costs.

Since lamb is a commodity, producers cannot control the price of the product they sell. Therefore, managing production costs is a necessity. We explored the study of elasticities as a tool for basing decision-making in sheep production, and aimed at investigating the composition and elasticities of lamb production costs, and their influence on the performance of the activity. A representative sheep production farm, designed in a panel meeting, was the base for calculation of lamb production cost. We then performed studies of: i) costs composition, and ii) cost elasticities for prices of inputs and for zootechnical indicators. Variable costs represented 64.15% of total cost, while 21.66% were represented by operational fixed costs, and 14.19% by the income of the factors. As for elasticities to input prices, the opportunity cost of land was the item to which production cost was more sensitive: a 1% increase in its price would cause a 0.2666% increase in lamb cost. Meanwhile, the impact of increasing any technical indicator was significantly higher than the impact of rising input prices. A 1% increase in weight at slaughter, for example, would reduce total cost in 0.91%. The greatest obstacle to economic viability of sheep production under the observed conditions is low technical efficiency. Increased production costs are more related to deficient zootechnical indexes than to high expenses.

HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis in a Portuguese population.

BACKGROUND: HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) particularly in Han Chinese, but the risk in European populations has seldom been studied. OBJECTIVE: To study the association of HLA-B*58:01 with allopurinol-induced sCADR in a Portuguese population. METHODS: We studied 25 patients (11 male/14 female, mean age 67·4 years) with sCARD from allopurinol: 19 DRESS (drug reaction eosinophilia and systemic symptoms) and six Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). HLA was genotyped by reverse sequence-specific oligonucleotide-polymerase chain reaction and results compared statistically with a control group of 23 allopurinol-tolerant individuals and the control population. RESULTS: HLA-B*58:01 was present in 16 patients with sCADR (64%) [12 DRESS (63%), four SJS/TEN (67%)], one allopurinol-tolerant individual (4%) and 63 normal controls (1·96%), with a statistically significant difference between sCADR and the two control groups. When compared with the normal population, HLA-B*58:01 was associated with a higher risk of sCADR, both DRESS [odds ratio (OR) 85·36, 95% confidence interval (CI) 32·52-224·04] and SJS/TEN (OR 99·59, 95% CI 17·91-553·72). There was no statistically different risk between these two types of CADR. CONCLUSIONS: Portuguese patients with sCADR from allopurinol, both DRESS and SJS/TEN, have a high frequency of HLA-B*58:01, with an OR similar to European patients with SJS/TEN. This study also extends this association to DRESS in Europeans. The recommendation to genotype systematically before therapy is controversial, particularly when HLA-B*58:01 prevalence in the normal population is low, as in Europe. However it could be an option for patients with other risks factors.

The neurotransmitters glycine and GABA stimulate glucagon-like peptide-1 release from the GLUTag cell line.

The incretin hormone, glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells following food ingestion. Its secretion is triggered by a range of nutrients, including fats, carbohydrates and proteins. We reported previously that Na(+)-dependent glutamine uptake triggered electrical activity and GLP-1 release from the L-cell model line GLUTag. However, whereas alanine also triggered membrane depolarization and GLP-1 secretion, the response was Na+ independent. A range of alanine analogues, including d-alanine, beta-alanine, glycine and l-serine, but not d-serine, triggered similar depolarizing currents and elevation of intracellular [Ca2+], a sensitivity profile suggesting the involvement of glycine receptors. In support of this idea, glycine-induced currents and GLP-1 release were blocked by strychnine, and currents showed a 58.5 mV shift in reversal potential per 10-fold change in [Cl-], consistent with the activation of a Cl(-)-selective current. GABA, an agonist of related Cl- channels, also triggered Cl- currents and secretion, which were sensitive to picrotoxin. GABA-triggered [Ca2+]i increments were abolished by bicuculline and partially impaired by (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), suggesting the involvement of both GABA(A) and GABA(C) receptors. Expression of GABA(A), GABA(C) and glycine receptor subunits was confirmed by RT-PCR. Glycine-triggered GLP-1 secretion was impaired by bumetanide but not bendrofluazide, suggesting that a high intracellular [Cl-] maintained by Na(+)-K(+)-2Cl- cotransporters is necessary for the depolarizing response to glycine receptor ligands. Our results suggest that GABA and glycine stimulate electrical activity and GLP-1 release from GLUTag cells by ligand-gated ion channel activation, a mechanism that might be important in responses to endogenous ligands from the enteric nervous system or dietary sources.

Enantioselectivity in Ni(II) Schiff-base complexes derived from amino-acids and (S)-o-N-(N-benzylprolyl)aminobenzophenone: molecular structure of several chiral Ni(II) Schiff-base complexes, circular dichroism and molecular mechanics studies.

Several Ni(II) complexes derived from (S)-o-N-(N-benzylprolyl)aminobenzophenone ((S)-BBP) and amino acids of general formula [Ni((S)-BBP-L-(or D-)-aa)] were prepared. The crystal and molecular structures of [Ni((S)-BBP-Gly)], [Ni((S)-BBP-L-Ser)] and [Ni((S)-BBP-L-aaIm)](aaIm =L-2-amino-3-(imidazol-1-yl)propanoate were determined by X-ray diffraction analysis. In the three complexes the nickel atoms display a square-planar coordination and the overall structure around the metal indicates that the entire Schiff-base ligands form quite rigid frameworks. Molecular mechanics calculations were carried out for complexes [Ni((S)-BBP-Gly)], [Ni((S)-BBP-Ser)] and [Ni((S)-BBP-aaIm)] containing either the L- or D-amino acid forms, and the factors controlling the stereoselectivity are discussed. Several other [Ni((S)-BBP-L-aa)] complexes are also prepared and their circular dichroism spectra in solution and of the solids dispersed in KBr disks are measured and discussed. In agreement with other studies in solution with similar [Ni((S)-BBP-aa)] complexes, the Cotton effects for the bands with lambda(max) at 520--530 nm are positive when the amino acids have the L-configuration at the alpha-carbon. The same is observed in this work for the solid-state CD spectra of all compounds.

Cytotoxic effects of metal complexes of biogenic polyamines. I. Platinum(II) spermidine compounds: prediction of their antitumour activity.

Cytotoxicity and cell growth inhibition studies were performed for three distinct polynuclear platinum(II) complexes of spermidine, which showed to have significant cytotoxic and antiproliferative properties on the HeLa cancer cell line. The chemical environment of the metal centres in the drugs, as well as the coordination pattern of the ligand, were found to be strongly determinant of their cytotoxic ability. In the light of the results gathered, the most effective anticancer compound among the ones tested (IC50=5 microM) was found to be the one displaying three difunctional (PtCl2N2) moieties ((PtCl2)3(spd)2). Both the cytotoxic activity and the antiproliferative properties of the complexes studied showed to be irreversible for all the concentrations tested.

Mechanism-based discovery of ligands that counteract inhibition of the nicotinic acetylcholine receptor by cocaine and MK-801.

Nicotinic acetylcholine receptors (AChR) belong to a family of proteins that form ligand-gated transmembrane ion channels. They are involved in the fast transmission of signals between cells and the control of intercellular communication in the nervous system. A variety of therapeutic agents and abused drugs, including cocaine, inhibit the AChR and monoamine transporters and interfere with nervous system function. Here we describe a mechanism-based approach to prevent this inhibition. We had previously developed presteady-state kinetic (transient kinetic) techniques, with microsecond-to-millisecond time resolutions, for investigations of reactions on cell surfaces that allow one to determine the effects of inhibitors not only on the channel-opening probability but also on the opening and closing rates of the AChR channel. The transient kinetic measurements led to two predictions. (i) Ligands that bind to a regulatory site on the closed-channel conformation of the AChR with higher affinity than to the site on the open-channel form shift the equilibrium toward the closed-channel form, thereby inhibiting the receptor. (ii) Ligands that bind to a regulatory site with an affinity for the open conformation equal to or higher than their affinity for the closed conformations are expected not to inhibit the receptor and to displace inhibitors. The identification of such ligands in a combinatorial library of RNA ligands is reported. The implication of this approach to other protein-mediated reactions in which an inhibitor changes the equilibrium between active and inactive conformations is discussed.

Reduced vulnerability of the hypertrophied rat heart to oxygen-radical injury.

Effects of xanthine--xanthine oxidase produced oxygen radicals were studied in hypertrophied rat hearts in a Langendorff preparation. Heart hypertrophy was produced by banding of the abdominal aorta for 6 weeks. This resulted in a 22% increase in ventricle/body weight ratio compared with that of sham-operated controls. Perfusion with xanthine--xanthine oxidase caused contractile failure and a significant rise in the resting tension. Complete contractile failure in hypertrophied hearts was seen at 25.5 +/- 3.2 min, whereas in control hearts it happened at 14.4 +/- 5.6 min. Contractile failure due to oxygen radicals in both groups was associated with a decline in high energy phosphates, increased lipid peroxidation, and extensive structural damage. Sarcolemma in both groups became permeable to the extracellular tracer lanthanum. As compared with control, in hypertrophied hearts the malondialdehyde content, indicative of lipid peroxidation, was less by 40%; whereas superoxide dismutase, a free radical scavenger, was higher by a similar amount. These data show a greater capacity of the 6-week hypertrophied heart to withstand a free radical induced contractile failure. This delay in oxygen radical effect can be partially explained by the reduced lipid peroxide content and increased superoxide dismutase activity in the hypertrophied hearts.