Lameness is one of the most significant endemic disease problems facing the dairy industry. Claw horn lesions (principally sole hemorrhage, sole ulcer, and white line disease) are some of the most prevalent conditions. Despite the fact that thousands of animals are treated for these conditions every year, experimental evidence is limited on the most effective treatment protocols. A randomized, positively controlled clinical trial was conducted to test the recovery of newly lame cows with claw horn lesions. Animals on 5 farms were locomotion scored every 2wk. Cows were eligible for recruitment if they had 2 nonlame scores followed by a lame score and had a claw horn lesion on a single claw of a single foot. Following a therapeutic trim, enrolled cows were randomly allocated to 1 of 4 treatments: treatment 1-no further treatment (positive control; TRM), treatment 2-trim plus a block on the sound claw (TB), treatment 3-trim plus a 3-d course of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (TN), treatment 4-trim plus a block plus ketoprofen (TBN). The primary outcome measure was locomotion score 35d after treatment, by an observer blind to treatment group. Descriptive statistics suggested that treatment groups were balanced at the time of enrollment, that is, randomization was successful. Based on a sound locomotion score (score 0) 35d after treatment, the number of cures was 11 of 45 (24.4%) for TRM, 14 of 39 (35.9%) for TB, 12 of 42 (28.6%) for TN, and 23 of 41 (56.1%) for TBN. The difference between TBN and TRM was significant. To test for confounding imbalances between treatment groups, logistic regression models were built with 2 outcomes, either sound (score 0) or nonlame (score 0 or 1) 35d after treatment. Compared with TRM, animals that received TBN were significantly more likely to cure to a sound outcome. Farm, treatment season, lesion diagnosis, limb affected, treatment operator, and stage of lactation were included in the final models. Our work suggests that lameness cure is maximized with NSAID treatment in addition to the common practices of therapeutic trimming and elevation of the diseased claw using a block when cows are newly and predominantly mildly lame.

A positively controlled, randomised controlled trial (RCT) was undertaken to test recovery of cows with claw horn lesions resulting in lameness of greater than two weeks duration. Cows on seven commercial farms were mobility scored fortnightly and selected by lameness severity and chronicity. Study cows all received a therapeutic trim then random allocation of: no further treatment (trim only (TRM)), plastic shoe (TS) or plastic shoe and NSAID (TSN). Recovery was assessed by mobility score at 42 (±4) days post treatment by an observer blind to treatment group. Multivariable analysis showed no significant effect of treatment with an almost identical, low response rate to treatment across all groups (Percentage non-lame at outcome: TRM – 15 per cent, TS – 15 per cent, TSN – 16 per cent). When compared with results of a similar RCT on acutely lame cows, where response rates to treatment were substantially higher, it can be concluded that any delay in treatment is likely to reduce the rate of recovery, suggesting early identification and treatment is key. Thirty-eight per cent of animals treated in this study were lame on the contralateral limb at outcome suggesting that both hindlimbs should be examined and a preventive or if necessary a therapeutic foot trim performed when lameness is identified particularly if the duration of lameness is unknown.

No abstract

To explore the nature of amino acid substitutions that influence association with TAP, we compared a site‐directed mutant of HLA‐B*0702 (Y116D) to unmutated HLA‐B7 in regard to TAP interaction. We found that the mutant had stronger association with TAP, and, in addition, with tapasin and calreticulin. These data confirm the importance of position 116 for TAP association, and indicate that (1) an aspartic acid at the 116 position can facilitate the interaction, and (2) association with tapasin and calreticulin is affected along with TAP. Furthermore, we tested three natural subtypes of HLA‐B15, and found that a B15 subtype with a tyrosine at position 116 (B*1510) was strongly associated not only with TAP, but also with tapasin and calreticulin. In contrast, two B15 subtypes with a serine at position 116 (B*1518 and B*1501) exhibited very little or no association with any of these proteins. Thus, very closely related HLA‐B subtypes can differ in regard to interaction with the entire assembly complex. Interestingly, when their surface expression was tested by flow cytometry, the HLA‐B15 subtypes with little to no detectable intracellular assembly complex association had a slightly, yet consistently, higher level of the open heavy chain form than did the B15 subtype with intracellular assembly complex association. These data suggest that the relatively low strength or short length of interaction between endoplasmic reticulum proteins and natural HLA class I molecules can decrease their surface stability.

BackgroundDue to the complex molecular structure and proprietary manufacturing processes of monoclonal antibodies (mAbs), differences in structure and function may be expected during development of biosimilar mAbs. Important regulatory requirements for approval of biosimilar products involve comprehensive assessments of any potential differences between proposed biosimilars and reference mAbs, including differences in all known mechanisms of action, using sensitive and relevant methods. Any identified structural differences should not result in differences in biofunctional or clinical activity.ObjectiveA comprehensive assessment comparing the Amgen biosimilar candidate ABP 501 with FDA-licensed adalimumab (adalimumab [US]) and EU-authorized adalimumab (adalimumab [EU]) was conducted to demonstrate similarity in biofunctional activity.MethodsThe functional similarity assessment included testing of binding kinetics to soluble tumor necrosis factor α (TNFα) and relative binding to transmembrane TNFα. The neutralization of TNFα-induced caspase activation, TNFα- and lymphotoxin-α (LTα)-induced chemokine production, and cytotoxicity was also tested. Binding to Fc-gamma receptors FcγRIa, FcγRIIa (131H), FcγRIIIa (158V and 158F), and neonatal Fc receptor (FcRn) was compared with the reference mAbs, as was antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ResultsThe data demonstrate that ABP 501 is similar to both adalimumab (US) and adalimumab (EU) with respect to evaluated biofunctional activities.ConclusionSimilarity in biofunctional activity is a critical component of the totality of evidence required for demonstration of biosimilarity. The functional similarity demonstrated for ABP 501 comprehensively assesses the known mechanisms of action of adalimumab, supporting the conclusion that ABP 501, adalimumab (US), and adalimumab (EU) are likely to be clinically similar.