Optimal lameness induction model development using amphotericin B in meat goats.

Lameness continues to be a critical health and welfare concern associated with goat production. Amphotericin B (amp B) is an antimicrobial successful in inducing transient lameness for research purposes previously in livestock animals. The objectives of this study were to (1) identify which of three varying doses of amp B would be most effective in inducing lameness in meat type goats and (2) develop a facial grimace scale for goats. Lameness was produced by an intra-articular injection of amphotericin B into the left hind lateral claw distal interphalangeal joint with either a 5 mg/0.25 mL (high-low, 5 mg of amphotericin B in a volume of 0.25 mL), 5 mg/0.5 mL (high-high, 5 mg of amphotericin B in a volume of 0.5 mL), or a 2.5 mg/0.25 mL (low-low, 2.5 mg of amphotericin B in a volume of 0.25 mL). A saline treatment of 0.5 mL was used as control (0.9% sterile saline solution). Lameness response was analyzed by infrared thermography (IRT) at the induced joint, mechanical-nociception threshold (MNT), visual lameness scoring (VLS), a visual analogue scale (VAS), kinetic gait analysis (KGA), plasma cortisol (CORT), substance P (Sub P), and behavior scoring. The IRT and MNT values differed by timepoint (P ≤ 0.0001). Results from VLS showed the HL treatment was the most effective at inducing lameness (6/6 goats became lame compared to HH 4/6 and LL 2/6). At 24, 48, and 72 h, VAS scores were significantly higher when comparing HL to all other treatment groups (P = 0.0003). Both behavior observers (1 and 2) reported a significant time effect (P = 0.05), with goats exhibiting more facial grimacing at 24 h post-lameness induction. From these data, an optimal dose for a repeatable lameness induction model in goats was aquired. An effective Goat Grimace Scale (GGS) was also developed to evaluate pain responses in goats.

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.

Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.

BACKGROUND: Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. METHODS: We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. RESULTS: Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from ß-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired ß-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. CONCLUSIONS: The ALDH1L2 function is important for CoA-dependent pathways including ß-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

Scientific evidence supporting recommendations on the use of the 9-valent HPV vaccine in a 2-dose vaccine schedule in Australia.

The Australian Technical Advisory Group on Immunisation (ATAGI) updated recommendations on the use of human papillomavirus (HPV) vaccines in the Australian Immunisation Handbook in 2018, regarding the use of the recently available 9-valent (9vHPV) vaccine, Gardasil 9, and a 2-dose schedule for young adolescents for HPV vaccines. This report provides an overview of the relevant scientific evidence that underpinned these updated recommendations. The 9vHPV vaccine includes 5 HPV types (HPV 31, 33, 45, 52 and 58) additional to the 4 that are also covered by the 4vHPV (Gardasil) vaccine (HPV 6,11,16,18). Accordingly, the 9vHPV vaccine is expected to prevent an additional 15% of cervical cancers and up to 20% of other HPV-related cancers. Non-inferior antibody responses after two 9vHPV vaccine doses given 6-12 months apart in girls and boys aged 9-14 years compared to women aged 16-26 years after three doses support the 2-dose schedule for adolescents of this age group. In clinical trials 9vHPV vaccine was well-tolerated with a similar safety profile to 4vHPV vaccine. The switch to 9vHPV vaccine and a 2-dose schedule is anticipated to improve public acceptability of the program and reduce HPV-related disease in the long-term.

Moving forward on strengthening and sustaining National Immunization Technical Advisory Groups (NITAGs) globally: Recommendations from the 2nd global NITAG network meeting.

National Immunization Technical Advisory Groups (NITAGs) provide independent, evidence-informed advice to assist their governments in immunization policy formation. This is complex work and many NITAGs face challenges in fulfilling their roles. Inter-country NITAG collaboration opportunities have the potential to enhance NITAG function and grow the quality of recommendations. Hence the many requests for formation of a network linking NITAGs together so they can learn from each other. The first Global NITAG Network (GNN) meeting, held in 2016, led to a push to launch the GNN and grow the network. At the second GNN meeting, held June 28-29, 2017 in Berlin, the GNN was formally inaugurated. Participants discussed GNN governance, reflected on the April 2017 Strategic Advisory Group of Experts (SAGE) on Immunization conclusions concerning strengthening of NITAGs and also shared NITAG experiences in evaluation and inter-country collaborations and independence. They also discussed the role of Regional Technical Advisory Groups on Immunization (RTAGs) and regional networks. A number of issues were raised including NITAGs and communications, dissemination of recommendations and vaccine implementation as well as implications of off-label recommendations. Participants were alerted to immunization evidence assessment sites and value of sharing of resources. They also discussed potential GNN funding opportunities, developed an action plan for 2017-18 and selected a Steering Committee to help move the GNN forward. All participants agreed on the importance of the GNN and the value in attracting more countries to join the GNN.

Human papillomavirus vaccine coverage among female Australian adolescents: success of the school-based approach.

OBJECTIVE: To describe quadrivalent human papillomavirus (HPV) vaccination coverage achieved in the HPV vaccination catch-up program for girls aged 12-17 years. DESIGN: Analysis of data from the Australian National HPV Vaccination Program Register. PARTICIPANTS: Girls aged 12-17 years as at 30 June 2007. MAIN OUTCOME MEASURES: HPV vaccine coverage by dose (1, 2 and 3), age and state of residence, using Australian Bureau of Statistics estimates of resident populations as the denominator. RESULTS: Notified vaccination coverage for girls aged 12-17 years nationally was 83% for dose 1, 78% for dose 2 and 70% for dose 3. The Australian Capital Territory and Victoria recorded the highest three-dose coverage for the 12-17-year-old cohort overall at 75%. The highest national three-dose coverage rate by age was achieved in 12-year-olds (74%). In Queensland, coverage among Indigenous girls compared with non-Indigenous girls was lower with each dose (lower by 4% for dose 1, 10% for dose 2 and 15% for dose 3). This pattern was not seen in the NT, where initial coverage was 17% lower among Indigenous girls, but the course completion rate among those who started vaccination was identical (84%). CONCLUSIONS: The catch-up HPV vaccination program delivered over 1.9 million doses of HPV vaccine to girls aged 12-17 years, resulting in 70% of girls in this age group being fully vaccinated. The range in coverage achieved and the lower uptake documented among Indigenous girls suggest that HPV vaccination programs can be further improved.