Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's) : an ARChiVe Cohort Study

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n\u2009=\u200948) or GPA (n\u2009=\u2009183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding

Variation in protein abundance profiles in the M. semitendinosus of lambs bred from sires selected on the basis of growth and muscling potential

Relative abundance of proteins localised in the nuclear-enriched, total cell membrane and cytosolic fractions of the semitendinosus muscle was compared between lambs bred from control (C), high muscling (M), and high growth rate (G) sires. In total, 31 proteins were identified whose abundance was differentially regulated between sire type. Differences in hind-limb muscle development between M lambs and C and G lambs were reflected in levels of proteins that regulate or function in cellular mechanisms of protein and energy metabolism. Despite no apparent difference in hind-limb muscle growth in G lambs compared to C, G lambs exhibited marked differences in proteins involved in regulation and function of energy metabolism. These results detail pathways that can be specifically targeted to enhance muscle accretion and growth in lambs. The development of means to manipulate these cellular mechanisms may yield greater gains in muscle accretion and growth rate than breeding on the basis for genetic capacity alone

Influence of finishing systems and sampling site on fatty acid composition and retail shelf-life of lamb

Thirty 7-month-old crossbred lambs (Poll Dorset Border Leicester Merino) finished over 5 weeks on either low quality pasture or grain-with-hay on a farm in southern Victoria were assessed for carcass parameters, muscle fat composition and retail colour stability. Lambs on the grain diet had a mix of barley grain (80%) and lentils (20%) at 800 g/head.day (air-dry basis ∼ad libitum) with cape weed (Arctotheca calendula) hay available at all times. Lambs under grazing had predominantly rye grass (Lolium perenne) and barley grass (Hordeum leporinum) available ad libitum. Carcass weight tended to be higher (P ≤ 0.14) in grain-fed lambs than in grass-fed lambs, but fatness indicated by GR (total muscle + fat tissue thickness at 11 cm from midline) did not differ between feeding systems. Fatty acid composition was determined in the loin from the forequarter (M. longissimus thoracis) and lumbar (M. longissimus lumborum) regions and from the leg region (M. semimembranosus). This showed that grain-finished lamb had higher muscle fat (P 0.001) and omega-6 fatty acid (P 0.001) content. Alpha-linolenic acid, eicosapentaenoic acid (EPA) or total omega-3 fat did not differ (P 0.05) between feeding groups. Saturated fatty acids were greater (P 0.01) in both loin sampling sites than the leg. The levels of EPA, docosahexaenoic acid and docosapentaenoic acid were lower (P 0.01) in the forequarter (9%) or lumbar (11%) sites than the leg sampling site. The distribution pattern of fatty acids across the three sampling sites did not differ between feed types. Retail colour stability determined over 4 days of display (only performed in muscle from the lumbar site), evaluated by the redness (HunterLab a*-value) and metmyoglobin formation (reflectance ratio at 630:580-nm wavelengths) was superior for grass-fed lamb compared with short-term grain-finished lamb. The results demonstrate that the health claimable omega-3 fat mainly EPA or total omega-3 fat content in lamb was not altered by short-term grain finishing compared with lamb finished under pasture grazing conditions

An independent validation association study of carcass quality, shear force, intramuscular fat percentage and omega-3 polyunsaturated fatty acid content with gene markers in Australian lamb

Previous association studies revealed several single nucleotide polymorphisms (SNPs) that explained the observed phenotypic variation for meat tenderness and long-chain omega-3 polyunsaturated fatty acid (PUFA) content of Australian lamb. To confirm the validity of these associated SNPs at predicting meat tenderness and omega-3 PUFA content, an independent validation study was designed. The OvineSNP50 genotypes of these animals were used to impute the 192 SNP Meat Quality Research (MQR) panel genotypes on nearly 6200 animals from the Cooperative Research Centre for Sheep Industry Innovation Information Nucleus Flock and Sheep Genomics Falkiner Memorial Field Station flock. Association analysis revealed numerous SNP from the 192 SNP MQR panel that were associated with carcass quality - fat depth at the C-site and eye muscle depth; shear force at day 1 and day 5 after slaughter (SF1 and SF5); and omega-3 PUFA content at P < 0.01. However, 1 SNP was independently validated for SF5 (i.e. CAST_101781475). The magnitude of the effect of each significant SNP and the relative allele frequencies across Merino-, Maternal- and Terminal-sired progeny was determined. The independently validated SNP for SF5 and the associated SNP with omega-3 PUFA content will accelerate efforts to improve these phenotypic traits in Australian lamb

Discovery and trait association of single nucleotide polymorphisms from gene regions of influence on meat tenderness and long-chain omega-3 fatty acid content in Australian lamb

Whole genome association studies in humans have shown a strong relationship between omega-3 levels in plasma and single nucleotide polymorphisms (SNP) located close to genes whose protein products are involved in the biosynthesis of long-chain omega-3 fatty acids. In sheep and other livestock species, the calpain/calpastatin system is the principal influence on natural variation in meat tenderness between animals. Using targeted next generation sequencing, we sequenced the fatty acid desaturase locus (FADS1/2/3), ELOVL2 and SLC26A10 and the calpain/calpastatin (CAPN1/2/3 and CAST) gene loci of 35 industry sires from the Australian flock. A total of 753 SNP were identified and 182 of these SNP were selected for incorporation onto a research SNP panel that represented the genetic variation across the nine genes. A total of 1252 animals were genotyped from the Australian Sheep CRC Information Nucleus Flock for these SNP and the genomic association was calculated for omega-3 fatty acid content and objective meat tenderness in lamb. Six SNP within CAST and CAPN2 showed association with shear force at Day 5 post-mortem at a significance level of P ≤ 0.01. When these were fitted simultaneously in a mixed-model analysis with fixed effects and covariates, three SNP remained significant. These SNP each had an unfavourable effect on shear force of between 1.1 and 1.8 N, with a combined effect of 4.1 N. The frequency of the favourable alleles in the progeny measured indicates that these SNP hold good potential for improving the management of meat tenderness across Merino, Border Leicester and Terminal sire types. No SNP within the FADS1/2/3, ELOVL2 and SLC26A10 gene regions were associated with lamb muscle omega-3 levels. This indicates that genetic variation in the long-chain omega-3 biosynthesis pathway genes analysed here may not be important for omega-3 content in lamb within the Information Nucleus Flock population

1H NMR spectroscopy of serum reveals unique metabolic fingerprints associated with subtypes of surgically induced osteoarthritis in sheep

Osteoarthritis (OA) is a highly prevalent joint disease. Its slow progressive nature and the correlation between pathological changes and clinical symptoms mean that OA is often well advanced by the time of diagnosis. In the absence of any specific pharmacological treatments, there is a pressing need to develop robust biomarkers for OA. We have adopted a nuclear magnetic resonance (NMR)-based metabolomic strategy to identify molecular responses to surgically induced OA in an animal model. Sheep underwent one of three types of surgical procedure (sham (control), meniscal destabilization, MD or anterior cruciate ligament transaction, ACLT), and for every animal a serum sample was collected both pre- and postoperatively, thus, affording two types of "control" data for comparison. 1D 1H NMR spectra were acquired from each sample at 800 MHz and the digitized spectral data were analyzed using principal components analysis and partial least-squares regression discriminant analysis. Our approach, combined with the study design, allowed us to separate the metabolic responses to surgical intervention from those associated with OA. We were able to identify dimethyl sulfone (DMSO 2) as being increased in MD after 4 weeks, while ACLT-induced OA exhibited increased 3-methylhistidine and decreased branched chain amino acids (BCAAs). The findings are discussed in the context of interpretation of metabolomic results in studies of human disease, and the selection of appropriate "control" data sets