Forced mobilization accelerates pathogenesis: characterization of a preclinical surgical model of osteoarthritis

Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). In this study we present a comprehensive, longitudinal evaluation of OA pathogenesis in a rat model of OA, including histologic and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis. Male Sprague-Dawley rats underwent joint destabilization surgery by anterior cruciate ligament transection and partial medial meniscectomy. The contralateral joint was evaluated as a secondary treatment, and sham surgery was performed in a separate group of animals (controls). Furthermore, the effects of walking on a rotating cylinder (to force mobilization of the joint) on OA pathogenesis were assessed. Destabilization-induced OA was investigated at several time points up to 20 weeks after surgery using Osteoarthritis Research Society International histopathology scores, in vivo micro-computed tomography (CT) volumetric bone mineral density analysis, and biochemical analysis of type II collagen breakdown using the CTX II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes that enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized joint. This surgical model of OA with forced mobilization is suitable for longitudinal preclinical studies, and it is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization

Polymer particles for the intra-articular delivery of drugs to treat osteoarthritis

Osteoarthritis (OA) is a leading cause of chronic disability. It is a progressive disease, involving pathological changes to the entire joint, resulting in joint pain, stiffness, swelling, and loss of mobility. There is currently no disease-modifying pharmaceutical treatment for OA, and the treatments that do exist suffer from significant side effects. An increasing understanding of the molecular pathways involved in OA is leading to many potential drug targets. However, both current and new therapies can benefit from a targeted approach that delivers drugs selectively to joints at therapeutic concentrations, while limiting systemic exposure to the drugs. Delivery systems including hydrogels, liposomes, and various types of particles have been explored for intra-articular drug delivery. This review will describe progress over the past several years in the development of polymer-based particles for OA treatment, as well as their in vitro, in vivo, and clinical evaluation. Systems based on biopolymers such as polysaccharides and polypeptides, as well as synthetic polyesters, poly(ester amide)s, thermoresponsive polymers, poly(vinyl alcohol), amphiphilic polymers, and dendrimers will be described. We will discuss the role of particle size, biodegradability, and mechanical properties in the behavior of the particles in the joint, and the challenges to be addressed in future research

MotivATE: A Pretreatment Web-Based Program to Improve Attendance at UK Outpatient Services Among Adults With Eating Disorders.

BACKGROUND: In the UK, eating disorders affect upward of 725,000 people per year, and early assessment and treatment are important for patient outcomes. Around a third of adult outpatients in the UK who are referred to specialist eating disorder services do not attend, which could be related to patient factors related to ambivalence, fear, and a lack of confidence about change. This lack of engagement has a negative impact on the quality of life of patients and has implications for service costs. OBJECTIVE: To describe the development of a Web-based program ("MotivATE") designed for delivery at the point of referral to an eating disorder service, with the aim of increasing service attendance. METHODS: We used intervention mapping and a person-based approach to design the MotivATE program and conducted a needs assessment to determine the current impact of service nonattendance on patients (via a review of the qualitative evidence) and services (through a service provision survey to understand current issues in UK services). Following the needs assessment, we followed the five steps of program development outlined by Bartholomew et al (1998): (1) creating a matrix of proximal program objectives; (2) selecting theory-based intervention methods and strategies; (3) designing and organizing the program; (4) specifying adoption and implementation plans; and (5) generating program evaluation plans. RESULTS: The needs assessment identified current nonattendance rates of 10%-32%. We defined the objective of MotivATE as increasing attendance rates at an eating disorder service and considered four key determinants of poor attendance: patient ambivalence about change, low patient self-efficacy, recognition of the need to change, and expectations about assessment. We chose aspects of motivational interviewing, self-determination theory, and the use of patient stories as the most appropriate ways to enable change. Think-aloud piloting with people with lived experience of an eating disorder resulted in positive feedback on the MotivATE program. Participants related well to the stories used. Nonetheless, because of feedback, we further modified the program in line with patients' stage of change and addressed issues with the language used. A consultation with service staff meant that we could make clear implementation plans. Finally, a randomized controlled trial is currently underway to evaluate the MotivATE program. CONCLUSIONS: Using intervention mapping, we have developed a novel pretreatment Web-based program that is acceptable to people with eating disorders. To our knowledge, this is the first such program. The model of development described here could be a useful template for designing further programs for other difficult-to-engage populations

Assessment of Surrogate Markers for Cardiovascular Disease in Familial Mediterranean Fever-Related Amyloidosis Patients Homozygous for M694V Mutation in MEFV Gene

Cardiovascular disease (CVD) remains underestimated in familial Mediterranean fever-associated AA amyloidosis (FMF-AA). We aimed to compare early markers of endothelial dysfunction and atherosclerosis in FMF-AA with a homozygous M694V mutation (Group 1 = 76 patients) in the Mediterranean fever (MEFV) gene and in patients with other genotypes (Group 2 = 93 patients). Measures of increased risk for future CVD events and endothelial dysfunction, including flow-mediated dilatation (FMD), pentraxin-3 (PTX3), and carotid intima-media thickness (cIMT), and fibroblast growth factor 23 (FGF23) as a marker of atherosclerotic vascular disease were compared between groups. The frequency of clinical FMF manifestations did not differ between the two groups apart from arthritis (76.3% in Group 1 and 59.1% in Group 2, p \u3c 0.05). FMD was significantly lower in Group 1 when compared with Group 2 (MD [95% CI]: −0.6 [(−0.89)–(−0.31)]). cIMT, FGF23, and PTX3 levels were higher in Group 1 (cIMT MD [95% CI]: 0.12 [0.08–0.16]; FGF23 MD [95% CI]: 12.8 [5.9–19.6]; PTX3 MD [95% CI]: 13.3 [8.9–17.5]). In patients with FMF-AA, M694V homozygosity is associated with lower FMD values and higher cIMT, FGF23, and PTX3 levels, suggesting increased CVD risk profiles. These data suggest that a genotype–phenotype association exists in terms of endothelial dysfunction and atherosclerosis in patients with FMF-AA

Assessment of Surrogate Markers for Cardiovascular Disease in Familial Mediterranean Fever-Related Amyloidosis Patients Homozygous for M694V Mutation in MEFV Gene

Cardiovascular disease (CVD) remains underestimated in familial Mediterranean fever-associated AA amyloidosis (FMF-AA). We aimed to compare early markers of endothelial dysfunction and atherosclerosis in FMF-AA with a homozygous M694V mutation (Group 1 = 76 patients) in the Mediterranean fever (MEFV) gene and in patients with other genotypes (Group 2 = 93 patients). Measures of increased risk for future CVD events and endothelial dysfunction, including flow-mediated dilatation (FMD), pentraxin-3 (PTX3), and carotid intima-media thickness (cIMT), and fibroblast growth factor 23 (FGF23) as a marker of atherosclerotic vascular disease were compared between groups. The frequency of clinical FMF manifestations did not differ between the two groups apart from arthritis (76.3% in Group 1 and 59.1% in Group 2, p \u3c 0.05). FMD was significantly lower in Group 1 when compared with Group 2 (MD [95% CI]: −0.6 [(−0.89)–(−0.31)]). cIMT, FGF23, and PTX3 levels were higher in Group 1 (cIMT MD [95% CI]: 0.12 [0.08–0.16]; FGF23 MD [95% CI]: 12.8 [5.9–19.6]; PTX3 MD [95% CI]: 13.3 [8.9–17.5]). In patients with FMF-AA, M694V homozygosity is associated with lower FMD values and higher cIMT, FGF23, and PTX3 levels, suggesting increased CVD risk profiles. These data suggest that a genotype–phenotype association exists in terms of endothelial dysfunction and atherosclerosis in patients with FMF-AA

Forced mobilization accelerates pathogenesis: characterization of a preclinical surgical model of osteoarthritis

Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). In this study we present a comprehensive, longitudinal evaluation of OA pathogenesis in a rat model of OA, including histologic and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis. Male Sprague-Dawley rats underwent joint destabilization surgery by anterior cruciate ligament transection and partial medial meniscectomy. The contralateral joint was evaluated as a secondary treatment, and sham surgery was performed in a separate group of animals (controls). Furthermore, the effects of walking on a rotating cylinder (to force mobilization of the joint) on OA pathogenesis were assessed. Destabilization-induced OA was investigated at several time points up to 20 weeks after surgery using Osteoarthritis Research Society International histopathology scores, in vivo micro-computed tomography (CT) volumetric bone mineral density analysis, and biochemical analysis of type II collagen breakdown using the CTX II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes that enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized joint. This surgical model of OA with forced mobilization is suitable for longitudinal preclinical studies, and it is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization

Adding Flavours: Use of and Attitudes towards Sauces and Seasonings in a Sample of Community-Dwelling UK Older Adults.

Adding flavours can encourage food intake in older adults for health benefits. The use and attitudes of 22 community-dwelling UK older adults (15 females, aged 65-83 years) towards foods and products that add flavour, e.g., sauces and seasonings, were investigated. Participants used foods/products to add flavour when cooking and eating from 0 to 17 times/day. Taste and flavour were important, and foods/products could add flavour, make foods more pleasant and did not cause discomfort. There were concerns, however, over the healthiness of some foods/products, while consuming a healthy diet and one's health were important. Reasons for adding flavours largely centred around 'meal enhancement', reasons for not adding flavours focused on 'the product itself' and 'characteristics of the meal', but there was 'variation' and many 'individual differences'. Our findings highlight the benefits of adding flavours for food intakes, particularly the use of naturally flavoursome foods, such as herbs, spices, onion and garlic

Three decades of advancements in osteoarthritis research: insights from transcriptomic, proteomic, and metabolomic studies.

Osteoarthritis (OA) is a complex disease involving contributions from both local joint tissues and systemic sources. Patient characteristics, encompassing sociodemographic and clinical variables, are intricately linked with OA rendering its understanding challenging. Technological advancements have allowed for a comprehensive analysis of transcripts, proteomes and metabolomes in OA tissues/fluids through omic analyses. The objective of this review is to highlight the advancements achieved by omic studies in enhancing our understanding of OA pathogenesis over the last three decades. We conducted an extensive literature search focusing on transcriptomics, proteomics and metabolomics within the context of OA. Specifically, we explore how these technologies have identified individual transcripts, proteins, and metabolites, as well as distinctive endotype signatures from various body tissues or fluids of OA patients, including insights at the single-cell level, to advance our understanding of this highly complex disease. Omic studies reveal the description of numerous individual molecules and molecular patterns within OA-associated tissues and fluids. This includes the identification of specific cell (sub)types and associated pathways that contribute to disease mechanisms. However, there remains a necessity to further advance these technologies to delineate the spatial organization of cellular subtypes and molecular patterns within OA-afflicted tissues. Leveraging a multi-omics approach that integrates datasets from diverse molecular detection technologies, combined with patients' clinical and sociodemographic features, and molecular and regulatory networks, holds promise for identifying unique patient endophenotypes. This holistic approach can illuminate the heterogeneity among OA patients and, in turn, facilitate the development of tailored therapeutic interventions

Strong molecular hydrogen emission and kinematics of the multiphase gas in radio galaxies with fast jet-driven outflows

Observations of ionized and neutral gas outflows in radio-galaxies (RGs) suggest that AGN radio jet feedback has a galaxy-scale impact on the host ISM, but it is still unclear how the molecular gas is affected. We present deep Spitzer IRS spectroscopy of 8 RGs that show fast HI outflows. All of these HI-outflow RGs have bright H2 mid-IR lines that cannot be accounted for by UV or X-ray heating. This suggests that the radio jet, which drives the HI outflow, is also responsible for the shock-excitation of the warm H2 gas. In addition, the warm H2 gas does not share the kinematics of the ionized/neutral gas. The mid-IR ionized gas lines are systematically broader than the H2 lines, which are resolved by the IRS (with FWHM up to 900km/s) in 60% of the detected H2 lines. In 5 sources, the NeII line, and to a lesser extent the NeIII and NeV lines, exhibit blue-shifted wings (up to -900km/s with respect to the systemic velocity) that match the kinematics of the outflowing HI or ionized gas. The H2 lines do not show broad wings, except tentative detections in 3 sources. This shows that, contrary to the HI gas, the H2 gas is inefficiently coupled to the AGN jet-driven outflow of ionized gas. While the dissipation of a small fraction (<10%) of the jet kinetic power can explain the dynamical heating of the molecular gas, our data show that the bulk of the warm molecular gas is not expelled from these galaxies.Comment: 26 pages, 15 figures, Accepted for ublication in Ap