Tanniferous forage plants with anthelmintic properties: the example of sainfoin (Onobrychis viciifolia)

Introduction: Sainfoin is a high-quality condensed tannin containing forage plant. The knowledge about anthelmintic effects against sheep nematodes and about the influence of plant preservation (e.g. ensiling) on the anthelmintic activity is limited. Method: 36 parasite naïve lambs (6 groups of 6 animals each) were infected with H. contortus (7,000 L3) and C. curticei (15,000 L3). From day 28 until day 44 p.i., groups A1, B1 and C1 received fresh, dried or ensiled sainfoin. Groups A2, B2 and C2 served as respective tannin-free controls. Individual faecal egg counts on a dry matter basis (FECDM) were performed every 3-4 days. On day 44, all animals were slaughtered and adult worm populations were determined. Results: The consumption of sainfoin was associated with a reduction of adult H. contortus (35% (P<0.1), 47% (P<0.05) and 49% (P<0.1) for fresh, dried and ensiled sainfoin, respectively) but had little effect on adult C. curticei. Compared to the controls, H. contortus specific FECDM was reduced by 62% (P<0.05), 58% (P<0.01) and 48% (P<0.1) for fresh, dried and ensiled sainfoin. FECDM specific to C. curticei were decreased by sainfoin hay and silage (hay 81% , silage 74%, both tests P<0.001) but were unchanged when fresh sainfoin was administered. Conclusion: For H. contortus the FECDM decrease seemed to be due to a nematocidal effect towards adult H. contortus. In contrast for C. curticei, the reduction in FECDM appeared to be a result of a reduced per capita fecundity. The use of conserved tanniferous fodder offers promising perspectives as a complementary control approach against nematodes in sheep

Effect of sainfoin (Onobrychis viciifolia) silage and hay against gastrointestinal nematodes in lambs

The objective of the study was to examine the effect of dried and ensiled sainfoin (Onobrychis viciifolia) against two species of gastrointestinal nematodes (Haemonchus contortus, Cooperia curticei) in lambs. Twenty-four days post experimental infection, 24 lambs were allocated to 4 equal groups. Group A and B received sainfoin silage and control silage respectively for 16 days. Groups C and D were fed on sainfoin hay or control hay for the same period. Feeds were administered ad libitum and mean refusals and live weight were regularly recorded. Individual faecal egg counts (FEC) were performed twice weekly. After the feeding period all lambs were slaughtered for post mortem investigation. The consumption of sainfoin hay was associated with a significant reduction of the adult H. contortus burden by 47 % (P < 0.05) whereas no significant difference was seen when feeding sainfoin silage (49 %, P = 0.112). The C. curticei worm burden was not significantly reduced by either sainfoin hay or silage. At slaughter FEC were significantly reduced by sainfoin hay by 64 % (P < 0.001) compared to the control feed. After feeding sainfoin silage FEC decreased by 48 % (P = 0.056). There was a tendency of better live weight gain in sainfoin hay fed animals compared to the control fed ones (P=0.07). These results demonstrate a nematocidal effect of a tanniferous forage legume against gastrointestinal nema¬¬todes, which was more pronounced against H. contortus. The antiparasitic effects were largely preserved when feeding sainfoin silage, suggesting this conservation procedure to be a valuable alternative to hay

Individual administration of three tanniferous forage plants to lambs artificially infected with Haemonchus contortus and Cooperia curticei

We investigated direct anthelmintic effects associated with the feeding of fresh tanniferous forages against established populations of Haemonchus contortus and Cooperia curticei in lambs. Twenty-four parasite naive lambs were inoculated with a single dose of infective larvae of these two parasites 27 days prior to the start of the feeding experiment. Lambs were individually fed with either chicory (Cichorium intybus), birdsfoot trefoil (Lotus corniculatus), sainfoin (Onobrychis viciifolia) or a ryegrass/ lucerne mixture (control) for 17 days. Animals where then united to one flock and subjected to control feeding for another 11 days to test the sustainability of potentially lowered egg excretion generated by tanniferous forage feeding. When compared to the control, administration of all tanniferous forages was associated with significant reductions of total daily faecal egg output specific to H. contortus (chicory: 89%; birdsfoot trefoil: 63%; sainfoin: 63%; all tests P < 0.05) and a tendency of reduced H. contortus worm burden (chicory: 15%; birdsfoot trefoil: 49% and sainfoin: 35% reduction). Irrespective of the condensed tannin (CT) containing fodder, no anthelmintic effects were found against C. curticei. Cessation of CT-feeding followed by non-CT control feeding did not result in a re-emergence of faecal egg counts based on faecal dry matter (FECDM) in any group, suggesting that egg output reductions are sustainable. The moderate to high concentrations of CTs in birdsfoot trefoil (15.2 g CTs kg-1 dry matter (DM)) and sainfoin (26.1 g CTs kg-1 DM) were compatible with the hypothesis that the antiparasitic effect of these forages is caused by their content of CTs. For chicory (3 g CTs kg-1 DM), however, other secondary metabolites need to be considered. Overall, birdsfoot trefoil and in particular sainfoin seem promising candidates in contributing to an integrated control strategy against H. contortus not only by mitigating parasite related health disturbances of the host but also by a sustained reduction of pasture contamination. # 2007 Elsevier B.V. All rights reserved

Zur generalpräventiven Abschreckungswirkung des Strafrechts: Befunde einer Metaanalyse

'Vielfach wird angenommen, dass Strafdrohungen potentielle Täter von der Tatbegehung abschrecken. Die Richtigkeit dieser Theorie wird jedoch bezweifelt. Zahlreiche empirische Untersuchungen haben unterschiedliche Ergebnisse erzielt. In dem vorliegenden Artikel wird eine Metaanalyse beschrieben, die versucht, die Gründe für die unterschiedlichen Befunde zu ermitteln. Erste Auswertungen deuten darauf hin, dass die Untersuchungsmethoden die Ergebnisse beeinflussen und eine mögliche Abschreckungswirkung des Strafrechts nur mit einem differenzierten Modell angemessen erfasst werden kann.' (Autorenreferat)'It is supposed that threats of punishment deter potential criminals from committing crimes. The correctness of this theory is, however, questionable. Numerous empirical investigations have come to different results. In this article a meta-analysis is described which tries to find out the reasons for the different results. First evaluations indicate that the methods of research have an influence on the results and that a possible deterring effect of the penal law can only be covered reasonably with a very differentiating model.' (author's abstract)

Cholesterol Synthesis Is Associated with Hepatic Lipid Content and Dependent on Fructose/Glucose Intake in Healthy Humans

Visceral obesity and fatty liver have been related to high synthesis and low absorption of cholesterol. This study aimed to investigate the associations of cholesterol metabolism with liver and visceral fat content in healthy humans. Another objective was to explore the effects of very-high-fructose and very-high-glucose diets on cholesterol homeostasis. We report on a cohort of 20 people (12 males, 8 females; age 30.5 ± 2.0 years; body mass index 25.9 ± 0.5 kg/m2) who completed a four-week dietary intervention study. Between the baseline and the followup examination the study participants in addition to a balanced weight-maintaining diet received 150 g of either fructose or glucose per day. Visceral and liver fat were measured with magnetic resonance (MR) imaging and 1H-MR spectroscopy, respectively. Cholesterol absorption and synthesis were estimated from the serum noncholesterol sterol concentrations. Performing cross-sectional analyses the lanosterol and desmosterol to cholesterol ratios were positively correlated with visceral and liver fat content (all P < .03). The lathosterol to cholesterol ratio decreased in response to high-fructose diet (P = .006) but not in response to high-glucose diet. To conclude, visceral and liver fat content are associated with cholesterol synthesis in healthy humans. Furthermore, cholesterol synthesis appears to be dependent on fructose/glucose intake

Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): age is a key contributor to presentation

Background: The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set. Objective: The objective of this study is to describe the Novartis–Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes. Methods: We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients’ baseline age, using phase III study data (≈8000 patients). Results: NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%–75%) in older, disabled or progressive MS patients. Young patients benefit most from treatment. Conclusion: NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity

Serum Neurofilament Light Trajectories and Their Relation to Subclinical Radiological Disease Activity in Relapsing Multiple Sclerosis Patients in the APLIOS Trial

Introduction: Several studies have described prognostic value of serum neurofilament light chain (sNfL) at the group level in relapsing multiple sclerosis (RMS) patients. Here, we aimed to explore the temporal association between sNfL and development of subclinical disease activity as assessed by magnetic resonance imaging (MRI) at the group level and evaluate the potential of sNfL as a biomarker for capturing subclinical disease activity in individual RMS patients. Methods: In the 12-week APLIOS study, patients (N = 284) received subcutaneous ofatumumab 20 mg. Frequent sNfL sampling (14 time points over 12 weeks) and monthly MRI scans enabled key analyses including assessment of the group-level temporal relationship of sNfL levels with on-study subclinical development of gadolinium-enhancing (Gd +)T1 lesions. Prognostic value of baseline sNfL ("high" vs. "low") level for subsequent on-study clinical relapse or Gd + T1 activity was assessed. Individual patient-level development of on-study Gd + T1 lesions wascompared across three predictors: baseline Gd + T1 lesion number, baseline sNfL ("high" vs. "low"), and time-matched sNfL. Results: In patients developing Gd + T1 lesions at week 4 (absent at baseline), sNfL levels increased during the month preceding the week-4 MRI scan and then gradually decreased back to baseline. High versus low baseline sNfL conferred increased risk of subsequent on-study clinical relapse or Gd + T1 activity (HR, 2.81; p < 0.0001) in the overall population and, notably, also in the patients without baseline Gd + T1 lesions (HR, 2.48; p = 0.0213). Individual patient trajectories revealed a marked difference in Gd + T1 lesions between patients with the ten highest vs. lowest baseline sNfL levels (119 vs. 19 lesions). Prognostic value of baseline or time-matched sNfL for on-study Gd + T1 lesions was comparable to that of the number of baseline MRI Gd + T1 lesions. Conclusions: sNfL measurement may have utility in capturing and monitoring subclinical disease activity in RMS patients. sNfL assessments could complement regular MRI scans and may provide an alternative when MRI assessment is not feasible. ClinicalTrials.gov: NCT03560739. Classification of Evidence: This study provides class I evidence that serum neurofilament light may be used as a biomarker for monitoring subclinical disease activity in relapsing multiple sclerosis patients, as shown by its elevation in the weeks preceding the development of new gadolinium-enhancing T1 lesion activity

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis : APLIOS, a randomized phase-2 study

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion

Variance of the SGK1 Gene Is Associated with Insulin Secretion in Different European Populations: Results from the TUEF, EUGENE2, and METSIM Studies

HYPOTHESIS:Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans. METHODS:Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals. RESULTS:Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC(C-Peptide)/AUC(Glc) ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMIxrs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI< or =25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (TT: 226+/-7, XG: 246+/-9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers. CONCLUSIONS:The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk