The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan
. Caloric ...restriction (CR), defined as lessening caloric intake without depriving essential nutrients
, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)
, and is established to increase healthy lifespan in multiple species
. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref.
). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health
. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies
and contrasting with reports that biological aging may not be modifiable
. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality
.
Abstract Objective Through binding to folate receptor-ß (FR-ß), the new99m Tc–EC20 (Etarfolatide) imaging technique detects activated but not resting macrophages in vivo . The goal of this study was ...to investigate macrophage-related inflammation in osteoarthritis (OA). Methods Twenty-five individuals (50 knees) with symptomatic OA of at least one knee underwent SPECT-CT imaging of both knees and planar imaging of the whole body after injection of Etarfolatide. Scans and knee radiographs were scored blinded to clinical information including knee and other joint site pain severity. Measures of association controlled for age, gender, BMI and employed repeated measures to adjust for correlation between knees. Design Activated macrophages were present in the majority (76%) of knees. The quantity of knee-related macrophages was significantly associated with knee pain severity (R=0.60, p<0.0001) and radiographic knee OA severity including joint space narrowing (R=0.68, p=0.007), and osteophyte (R=0.66, p=0.001). Macrophages were also localized to joints commonly affected by OA including hand finger joints (12%), thumb bases (28%), shoulders (26%), great toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists, ankles and great toes was significantly positively associated with presence of activated macrophages at these sites (p<0.0001-0.04). Conclusions This study provides the first direct in vivo evidence for macrophage involvement in OA in a substantial proportion of human knees. The association of quantity of activated macrophages with radiographic knee OA severity and joint symptoms suggests that drugs targeting macrophages and macrophage-associated inflammatory pathways may have the potential to be both symptom and structure modifying.
Summary Osteoarthritis (OA) is a heterogeneous disorder. The goals of this review are (1) To stimulate use of standardized nomenclature for OA that could serve as building blocks for describing OA ...and defining OA phenotypes, in short to provide unifying disease concepts for a heterogeneous disorder; and (2) To stimulate establishment of ROAD (Risk of OA Development) and ROAP (Risk of OA Progression) tools analogous to the FRAX™ instrument for predicting risk of fracture in osteoporosis; and (3) To stimulate formulation of tools for identifying disease in its early preradiographic and/or molecular stages – REDI (Reliable Early Disease Identification). Consensus around more sensitive and specific diagnostic criteria for OA could spur development of disease modifying therapies for this entity that has proved so recalcitrant to date. We fully acknowledge that as we move forward, we expect to develop more sophisticated definitions, terminology and tools.
Summary Osteoarthritis (OA) is highly prevalent and a leading cause of disability worldwide. Despite the global burden of OA, diagnostic tests and treatments for the molecular or early subclinical ...stages are still not available for clinical use. In recent years, there has been a large shift in the understanding of OA as a “wear and tear” disease to an inflammatory disease. This has been demonstrated through various studies using MRI, ultrasound, histochemistry, and biomarkers. It would of great value to be able to readily identify subclinical and/or sub-acute inflammation, particularly in such a way as to be appropriate for a clinical setting. Here we review several types of biomarkers associated with OA in human studies that point to a role of inflammation in OA.
Summary Objective The microbiome is recognized as a new frontier in medicine with connections to a variety of diseases. We aimed to evaluate the association of lipopolysaccharide (LPS), a key ...pro-inflammatory product of the microbiome, with severity of inflammation, symptoms and radiographic abnormalities of knee osteoarthritis (OA). Design LPS was measured using a recombinant Factor C (rFC) assay, carefully optimized for systemic and synovial fluid (SF) analyses. LPS binding protein (LBP) was tested in both serum and SF of 25 patients (31 knees) from the Etarfolatide cohort for association with OA phenotypic outcomes. Models were adjusted for age, gender and body mass index. Results Based on LPS spike-and-recovery, both serum and SF dilutions of 0.1% were required to achieve recovery rates of at least 75% in all test specimens. Low coefficients of variation (CVs) (<10%) were achieved with both serum and SF dilutions <0.2%. Serum LPS and LBP were associated with the abundance of activated macrophages in the knee joint capsule and synovium. SF LPS and LBP were associated with the abundance of activated macrophages in the synovium. Serum LPS, LBP and SF LPS were associated with knee osteophyte severity. SF LPS was positively associated with knee joint space narrowing (JSN) severity and total WOMAC score. SF LBP was positively associated with self-reported knee pain score. Conclusion These data strongly support a role for LPS in the pathogenesis and severity of structural abnormalities and symptoms of knee OA.
To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and ...Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data.
We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation.
Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node.
These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.
Summary Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality ...of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.
SUMMARY Histological and histochemical methods are important tools in the evaluation of joint tissue samples for degenerative joint diseases, both in humans and in animal models. In this respect, ...standardized, simple, and reliable techniques are mandatory. This chapter describes five basic staining procedures appropriate for macroscopic (Indian ink) and histologic (HE/hematoxylin - eosin) visualization and scoring of cartilage proteoglycan and collagen content (toluidine blue/safranin O and picrosirius red/Goldner's trichrome).
An increasing number of applications of scintillators at low temperatures, particularly in cryogenic experiments searching for rare events, has motivated the investigation of scintillation properties ...of materials over a wide temperature range. This paper provides an overview of the latest results on the study of luminescence, absorption and scintillation properties of materials selected for rare event searches so far. These include CaWO4, ZnWO4, CdWO4, MgWO4, CaMoO4, CdMoO4, Bi4Ge3O12, CaF2, MgF2, ZnSe and Al2O3–Ti. We discuss the progress achieved in research and development of these scintillators, both in material preparation and in the understanding of scintillation mechanisms, as well as the underlying physics. To understand the origin of the performance limitation of self‐activated scintillators we employed a semi‐empirical model of conversion of high energy radiation into light and made appropriate provision for effects of temperature and energy transfer. We conclude that the low‐temperature value of the light yield of some modern scintillators, namely CaWO4, CdWO4 and Bi4Ge3O12, is close to the theoretical limit. Finally, we discuss the advantages and limitations of different materials with emphasis on their application as cryogenic phonon‐scintillation detectors (CPSD) in rare event search experiments.
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