Field efficacy and safety of an oral formulation of the novel combination anthelmintic, derquantel-abamectin, in sheep in New Zealand

AIM: To evaluate the efficacy and safety of the novel anthelmintic combination, derquantel-abamectin, against gastrointestinal nematode populations in sheep, under field-use conditions

Differences in efficacy of monepantel, derquantel and abamectin against multi-resistant nematodes of sheep

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%)

Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate

Anthelmintic resistance has become a global phenomenon in gastro-intestinal nematodes of farm animals, including multi-drug resistance against the three major classes of anthelmintics. There is an urgent need for an anthelmintic with a new mode of action. The recently discovered amino-acetonitrile derivatives (AADs) offer a new class of synthetic chemicals with anthelmintic activity. The evaluation of AADs was pursued applying in vitro assays and efficacy and tolerability studies in rodents, sheep, and cattle. Amongst various suitable compounds, AAD 1566 eliminated many tested pathogenic nematode species, both at larval and adult stages, at a dose of 2.5 mg/kg bodyweight in sheep and 5.0 mg/kg bodyweight in cattle. The same doses were sufficient to cure animals infected with resistant or multi-drug-resistant nematode isolates. These findings, complemented by the good tolerability and low toxicity to mammals, suggest that AAD 1566, monepantel, would be a suitable anthelmintic drug development candidate

Triceps Surae Short Latency Stretch Reflexes Contribute to Ankle Stiffness Regulation during Human Running

During human running, short latency stretch reflexes (SLRs) are elicited in the triceps surae muscles, but the function of these responses is still a matter of controversy. As the SLR is primarily mediated by Ia afferent nerve fibres, various methods have been used to examine SLR function by selectively blocking the Ia pathway in seated, standing and walking paradigms, but stretch reflex function has not been examined in detail during running. The purpose of this study was to examine triceps surae SLR function at different running speeds using Achilles tendon vibration to modify SLR size. Ten healthy participants ran on an instrumented treadmill at speeds between 7 and 15 km/h under 2 Achilles tendon vibration conditions: no vibration and 90 Hz vibration. Surface EMG from the triceps surae and tibialis anterior muscles, and 3D lower limb kinematics and ground reaction forces were simultaneously collected. In response to vibration, the SLR was depressed in the triceps surae muscles at all speeds. This coincided with short-lasting yielding at the ankle joint at speeds between 7 and 12 km/h, suggesting that the SLR contributes to muscle stiffness regulation by minimising ankle yielding during the early contact phase of running. Furthermore, at the fastest speed of 15 km/h, the SLR was still depressed by vibration in all muscles but yielding was no longer evident. This finding suggests that the SLR has greater functional importance at slow to intermediate running speeds than at faster speeds

Knee loading stimulates cortical bone formation in murine femurs

BACKGROUND: Bone alters its architecture and mass in response to the mechanical environment, and thus varying loading modalities have been examined for studying load-driven bone formation. The current study aimed to evaluate the anabolic effects of knee loading on diaphyseal cortical bone in the femur. METHODS: Using a custom-made piezoelectric loader, 0.5-N loads were laterally applied to the left knee of C57/BL/6 mice at 5, 10, 15, and 20 Hz for 3 minutes per day for 3 consecutive days. Animals were sacrificed for examination 13 days after the last loading. The contralateral femur was used as a non-loading control, and the statistical significance of loading effects was evaluated with p < 0.05. RESULTS: Although diaphyseal strains were measured as small as 12 μstrains, bone histomorphometry clearly demonstrated frequency-dependent enhancement of bone formation. Compared to a non-loading control, bone formation on the periosteal surface was significantly enhanced. The loading at 15 Hz was most effective in elevating the mineralizing surface (1.7 x; p < 0.05), mineral apposition rate (1.4 x; p < 0.001), and bone formation rate (2.4 x; p < 0.01). The loading at 10 Hz elevated the mineralizing surface (1.4 x; p < 0.05), mineral apposition rate (1.3 x; p < 0.01), and bone formation rate (1.8 x; p < 0.05). The cross-sectional cortical area and the cortical thickness in the femoral diaphysis were significantly increased by loading at 10 Hz (both 9%) and 15 Hz (12% and 13%, respectively). CONCLUSION: The results support the anabolic effects of knee loading on diaphyseal cortical bone in the femur with small in situ strain, and they extend our knowledge on the interplay between bone and joints. Strengthening the femur contributes to preventing femoral fractures, and the discovery about the described knee loading might provide a novel strategy to strengthen osteoporotic bones. Further analyses are required to understand the biophysical and molecular mechanism behind knee loading

Characterization of Two Malaria Parasite Organelle Translation Elongation Factor G Proteins: The Likely Targets of the Anti-Malarial Fusidic Acid

Malaria parasites harbour two organelles with bacteria-like metabolic processes that are the targets of many anti-bacterial drugs. One such drug is fusidic acid, which inhibits the translation component elongation factor G. The response of P. falciparum to fusidic acid was characterised using extended SYBR-Green based drug trials. This revealed that fusidic acid kills in vitro cultured P. falciparum parasites by immediately blocking parasite development. Two bacterial-type protein translation elongation factor G genes are identified as likely targets of fusidic acid. Sequence analysis suggests that these proteins function in the mitochondria and apicoplast and both should be sensitive to fusidic acid. Microscopic examination of protein-reporter fusions confirm the prediction that one elongation factor G is a component of parasite mitochondria whereas the second is a component of the relict plastid or apicoplast. The presence of two putative targets for a single inhibitory compound emphasizes the potential of elongation factor G as a drug target in malaria

Knee stability assessment on anterior cruciate ligament injury: Clinical and biomechanical approaches

Anterior cruciate ligament (ACL) injury is common in knee joint accounting for 40% of sports injury. ACL injury leads to knee instability, therefore, understanding knee stability assessments would be useful for diagnosis of ACL injury, comparison between operation treatments and establishing return-to-sport standard. This article firstly introduces a management model for ACL injury and the contribution of knee stability assessment to the corresponding stages of the model. Secondly, standard clinical examination, intra-operative stability measurement and motion analysis for functional assessment are reviewed. Orthopaedic surgeons and scientists with related background are encouraged to understand knee biomechanics and stability assessment for ACL injury patients

Population genetics of benzimidazole-resistant Haemonchus contortus and Haemonchus placei from buffalo and cattle: implications for the emergence and spread of resistance mutations

The population genetics of nematode parasites are poorly understood with practical reference to the selection and spread of anthelmintic resistance mutations. Haemonchus species are important to study the nematode population genetics due to their clinical importance in ruminant livestock, and the availability of genomic resources. In the present study, it has been examined that Haemonchus contortus and Haemonchus placei populations from three buffalo and nine cattle hosts. Seventy-three individual adult worms of H. contortus and 148 of H. placei were analysed using a panel of seven microsatellite markers. The number of alleles per locus in H. contortus and H. placei indicated that all populations were polymorphic for the microsatellites used in the present study. Genetic diversity parameters included high levels of allelic richness and heterozygosity, indicating effective population sizes, high mutation rates and high transmission frequencies in the area. Genetic structure parameters revealed low genetic differentiation between and high levels of genetic variation within H. contortus and H. placei populations. Population dynamic analyses showed an absence of heterozygosity excess in both species, suggesting that there was no deviation from genetic drift equilibrium. Our results provide a proof of concept for better understanding of the consequences of specific control strategies, climatic change or management strategies on the population genetics of anthelmintic resistance alleles in Haemonchus spp. infecting co-managed buffalo and cattle