Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

SummaryObjective/MethodAggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA).ResultsStructural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover.ConclusionThis data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic

Agronomic biosolids application rates for dryland wheat across a range of northwest climate zones

Predicting agronomic rates is important to derive optimum economic and environmental benefits from biosolids fertilizer applications. We conducted this research to 1) evaluate dryland wheat response to biosolids applications over a range of climate zones in the Pacific Northwest and 2) compare agronomic application rates predicted from yield curves with those predicted from published extension guidance. We applied a range of biosolids rates during the fallow year in ten on-farm dryland wheat experiments located in five counties in central and eastern Washington and in one county in north-central Oregon. Grain yield, protein, and post-harvest soil nitrate were determined. Recommended nitrogen rates for each site were calculated from Extension nutrient management guidance, and compared with biosolids agronomic rate estimates based on 95% maximum yield from the regressions generated for each site. Eight of the ten sites had quadratic yield responses. The two non-responsive sites had high pre-application levels of soil nitrate-N. Protein response was linear at most sites, while soil nitrate accumulation was variable, with the greatest increases at the least responsive sites. Field agronomic rates were within 20 lb N/acre (0 to 0.6 dry tons biosolids/acre) of recommended rates at six of the 10 sites. Greater differences at the other sites resulted from leaching, drought, or high pre-application soil N. At the eight sites that responded to N application, a median biosolids application rate of 2.2 dry ton/acre (approx 200 lb biosolids total N per acre) was required for 95% of maximum grain yield. This research demonstrated that the use of a WA fertilizer guide together with a PNW worksheet for estimating available N from biosolids gave reasonable estimates for biosolids application rates. We suspect that one of the benefits of biosolids for dryland wheat production is that wet crop years increase both grain yield potential and N mineralized from biosolids

Effects of a brief mindfulness-based intervention on emotional regulation and levels of mindfulness in senior students

Mindfulness-based interventions have been applied in diverse populations and achieved mental health benefits. This study examined the effects of a brief mindfulness program for emotional regulation and levels of mindfulness on senior students in Brazil. The intervention consisted of six weekly meetings attended by 30 participants. It is a pre-experimental research, with pre- and post-test comparative and correlation measurements. The preliminary results, which relied on parametrical and non-parametrical tests, revealed a reduction in total emotional regulation difficulties (p = 0.0001; r = − 0.55). Also, there was an increase in the levels of mindfulness in the subtests for both dimensions under evaluation: “Awareness” (p = 0.0001; d = 0.77) and “Acceptance” (p = 0.048; d = 0.37). By associating the amount of meditative practices performed by students with the variables, a significant positive correlation was found with the mindfulness dimension “Awareness” (rP = 0.422; p = 0.020), and there was a significant negative correlation with Difficulties in emotion regulation (rS = − 0.478; p = 0.008) and with its respective subscales “Non-acceptance” (rS = − 0.654; p = 0.0001) and “Clarity” (rS = − 0.463; p = 0.010). In conclusion, the application of a brief mindfulness-based intervention is promising in Brazilian university contexts; moreover, it can bring benefits to students, e.g., an increase in emotion regulation as well as in levels of mindfulness. We suggest that further research should use an experimental design and follow-up.info:eu-repo/semantics/publishedVersio

Health-related quality of life after ileoanal pull-through evaluation and assessment of new health status measures

AbstractBACKGROUND & AIMS: Health-related quality of life (HRQL) after proctocolectomy is a critical parameter for management decisions in patients with chronic pancolitis. The aim of this study was to evaluate the HRQL of patients with ileoanal pull-through and to validate new, easy-to-administer HRQL measures. METHODS:The Sickness Impact Profile (SIP), Short Form 36 (SF-36), Rating Form of Inflammatory Bowel Disease (IBD) Patient Concerns (RFIPC), and the time trade-off (TTO) were used to measure HRQL of pull-through patients. The SF-36 and the RFIPC were validated. RESULTS: HRQL of patients with ileoanal pull-through was better than that of a national sample of patients with IBD (SIP and RFIPC) and similar to that of a normal population (SF-36). Physical and psychosocial subscales of the SF-36 correlated with the SIP, affirming the construct validity of the SF-36. The RFIPC results correlated with the SIP and SF-36 results, suggesting that it is also a valid health status measure for these patients. TTO results correlated with the physical subscales of the SIP and SF-36, reflecting the impact of physical health on this group. CONCLUSIONS: HRQL of patients with ileoanal pull-through is excellent. The SF-36 and RFIPC are valid health status measures that can be used by clinicians and researchers in these patients. (Gastroenterology 1997 Jul;113(1):7-14

One health: the importance of companion animal vector-borne diseases

The international prominence accorded the 'One Health' concept of co-ordinated activity of those involved in human and animal health is a modern incarnation of a long tradition of comparative medicine, with roots in the ancient civilizations and a golden era during the 19th century explosion of knowledge in the field of infectious disease research. Modern One Health tends to focus on zoonotic pathogens emerging from wildlife and production animal species, but one of the most significant One Health challenges is rabies for which there is a canine reservoir. This review considers the role of small companion animals in One Health and specifically addresses the major vector-borne infectious diseases that are shared by man, dogs and cats. The most significant of these are leishmaniosis, borreliosis, bartonellosis, ehrlichiosis, rickettsiosis and anaplasmosis. The challenges that lie ahead in this field of One Health are discussed, together with the role of the newly formed World Small Animal Veterinary Association One Health Committee

Canine Morphology: Hunting for Genes and Tracking Mutations

In this essay, Abigail Shearin and Elaine Ostrander discuss the proposed genomic mechanisms for the extraordinary level of phenotypic variation observed in the domestic dog and the evidence detailing the variants responsible for the many shapes, sizes, textures, and colors of man's best friend

Ontogeny vs. phylogeny in Primate/Canid comparisons: a meta-analysis of the object choice task

The Object Choice Task (OCT) is a widely used paradigm with which researchers measure the ability of a subject to comprehend deictic (directional) cues, such as pointing gestures and eye gaze. There is a widespread belief that nonhuman primates evince only a weak capacity to use deictic cues; in contrast, domestic dogs (Canis familiaris) tend to demonstrate high success rates. This pattern of canid superiority has been taken to support the Domestication Hypothesis, which posits enhancing effects of artificial selection on the sociocognitive abilities of dogs and humans. Here we review nearly two decades of published findings, using variants of the OCT. We find systematic confounds with species classification in task-relevant preparation of the subjects, in the imposition of a barrier between reward and subject, and in the specific deictic cues used to indicate the location of hidden objects. Thus, the widespread belief that dogs outperform primates on OCTs is undermined by the systematic procedural differences in the assessments of these skills, differences that are confounded with taxonomic classification

Prion Shedding from Olfactory Neurons into Nasal Secretions

This study investigated the role of prion infection of the olfactory mucosa in the shedding of prion infectivity into nasal secretions. Prion infection with the HY strain of the transmissible mink encephalopathy (TME) agent resulted in a prominent infection of the olfactory bulb and the olfactory sensory epithelium including the olfactory receptor neurons (ORNs) and vomeronasal receptor neurons (VRNs), whose axons comprise the two olfactory cranial nerves. A distinct glycoform of the disease-specific isoform of the prion protein, PrPSc, was found in the olfactory mucosa compared to the olfactory bulb, but the total amount of HY TME infectivity in the nasal turbinates was within 100-fold of the titer in the olfactory bulb. PrPSc co-localized with olfactory marker protein in the soma and dendrites of ORNs and VRNs and also with adenylyl cyclase III, which is present in the sensory cilia of ORNs that project into the lumen of the nasal airway. Nasal lavages from HY TME-infected hamsters contained prion titers as high as 103.9 median lethal doses per ml, which would be up to 500-fold more infectious in undiluted nasal fluids. These findings were confirmed using the rapid PrPSc amplification QuIC assay, indicating that nasal swabs have the potential to be used for prion diagnostics. These studies demonstrate that prion infection in the olfactory epithelium is likely due to retrograde spread from the olfactory bulb along the olfactory and vomeronasal axons to the soma, dendrites, and cilia of these peripheral neurons. Since prions can replicate to high levels in neurons, we propose that ORNs can release prion infectivity into nasal fluids. The continual turnover and replacement of mature ORNs throughout the adult lifespan may also contribute to prion shedding from the nasal passage and could play a role in transmission of natural prion diseases in domestic and free-ranging ruminants