Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative.

OBJECTIVE: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). DESIGN: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by ≥80% of participants were retained, and participants could suggest additional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if ≥80% rated it ≥6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if ≥80% of participants rated it ≥9 and as "optional" if ≥80% rated it ≥7. RESULTS: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. CONCLUSION: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context.

Physical therapy vs internet-based exercise training for patients with knee osteoarthritis: results of a randomized controlled trial.

OBJECTIVE: To compare the effectiveness of physical therapy (PT, evidence-based approach) and internet-based exercise training (IBET), each vs a wait list (WL) control, among individuals with knee osteoarthritis (OA). DESIGN: Randomized controlled trial of 350 participants with symptomatic knee OA, allocated to standard PT, IBET and WL control in a 2:2:1 ratio, respectively. The PT group received up to eight individual visits within 4 months. The IBET program provided tailored exercises, video demonstrations, and guidance on progression. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, range 0 [no problems]-96 [extreme problems]), assessed at baseline, 4 months (primary time point) and 12 months. General linear mixed effects modeling compared changes in WOMAC among study groups, with superiority hypotheses testing differences between each intervention group and WL and non-inferiority hypotheses comparing IBET with PT. RESULTS: At 4-months, improvements in WOMAC score did not differ significantly for either the IBET or PT group compared with WL (IBET: -2.70, 95% Confidence Interval (CI) = -6.24, 0.85, P = 0.14; PT: -3.36, 95% (CI) = -6.84, 0.12, P = 0.06). Similarly, at 12-months mean differences compared to WL were not statistically significant for either group (IBET: -2.63, 95% CI = -6.37, 1.11, P = 0.17; PT: -1.59, 95% CI = -5.26, 2.08, P = 0.39). IBET was non-inferior to PT at both time points. CONCLUSIONS: Improvements in WOMAC score following IBET and PT did not differ significantly from the WL group. Additional research is needed to examine strategies for maximizing benefits of exercise-based interventions for patients with knee OA. TRIAL REGISTRATION: NCT02312713.

Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial.

AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2)  = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Self-efficacy for exercise, more than disease-related factors, is associated with objectively assessed exercise time and sedentary behaviour in rheumatoid arthritis.

OBJECTIVES: Until recently, reports of physical activity in rheumatoid arthritis (RA) were limited to self-report methods and/or leisure-time physical activity. Our objectives were to assess, determine correlates of, and compare to well-matched controls both exercise and sedentary time in a typical clinical cohort of RA. METHOD: Persons with established RA (seropositive or radiographic erosions; n = 41) without diabetes or cardiovascular disease underwent assessments of traditional and disease-specific correlates of physical activity and 7 days of triaxial accelerometry. Twenty-seven age, gender, and body mass index (BMI)-matched controls were assessed. RESULTS: For persons with RA, objectively measured median (25th-75th percentile) exercise time was 3 (1-11) min/day; only 10% (n = 4) of participants exercised for ≥ 30 min/day. Time spent in sedentary activities was 92% (89-95%). Exercise time was not related to pain but was inversely related to disease activity (r = -0.3, p < 0.05) and disability (r = -0.3, p < 0.05) and positively related to self-efficacy for endurance activity (r = 0.4, p < 0.05). Sedentary activity was related only to self-efficacy for endurance activity (r = -0.4, p < 0.05). When compared to matched controls, persons with RA exhibited poorer self-efficacy for physical activity but similar amounts of exercise and sedentary time. CONCLUSIONS: For persons with RA and without diabetes or cardiovascular disease, time spent in exercise was well below established guidelines and activity patterns were predominantly sedentary. For optimal care in RA, in addition to promoting exercise, clinicians should consider assessing sedentary behaviour and self-efficacy for exercise. Future interventions might determine whether increased self-efficacy can increase physical activity in RA.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

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 lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. 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. 10). 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 health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. 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 mortality18-20.

Exercise dose response in muscle.

Exercise increases peak VO2 partially through muscle adaptations. However, understanding muscle adaptations related to exercise dose is incomplete. This study investigated exercise training dose on capillaries per fiber and capillaries per area; and citrate synthase from vastus lateralis and related both to changes in peak VO2. This randomized trial compared 3 exercise doses: low amount-moderate intensity (n=40), low amount-high intensity (n=47), high amount-high intensity (n=41), and a control group (n=35). Both measures of capillary supply increased in all exercise groups (p<0.05). Low amount-high intensity and high amount-high intensity improved citrate synthase (p<0.05) and the low amount-moderate intensity citrate synthase approached significance (p=0.059). Muscle improvements were only related to improvements in peak VO2 in high amount-high intensity (citrate synthase, r=0.304; capillaries:fiber, r= - 0.318; p<0.05 and capillaries/mm2 r= - 0.310, p<0.05). These data suggest muscle adaptations occur following both low and high exercise doses, but are only related to improved peak VO2 following high amount-high intensity training.

Feed restriction delays developmental fast skeletal muscle myosin heavy chain isoforms in turkey poults selected for differential growth.

Genetic selection has been very successful at significantly increasing BW and breast muscle proportion in commercial broiler and turkey strains. The mechanisms of breast muscle growth in poultry and the interactive effects of nutritional status and selection are not fully understood. The hypothesis underlying the current study is that feed restriction, simply as a vehicle for controlling early growth, would delay the temporal expression pattern of neonatal (nMyHC) and adult (aMyHC) fast skeletal muscle myosin heavy chain (MyHC) isoforms in the pectoralis major muscle of turkey poults. The poultry growth model used to evaluate this hypothesis consisted of a randombred control turkey line (RBC2) that represents commercial turkeys of the 1960s and a line developed from the RBC2 by selection for BW at 16 wk of age (F line). The F line has significantly heavier breast muscles than the RBC2 concomitant with increased BW, but the proportion of breast muscle relative to BW is similar. A quantitative indirect ELISA using fast skeletal MyHC isoform specific monoclonal antibodies revealed no significant line differences in the temporal expression of posthatch fast skeletal muscle MyHC in ad libitum fed poults. Feed restriction, however, altered the temporal expression patterns of nMyHC and aMyHC in both F line and RBC2 poults compared with the poults fed ad libitum.

Is diabetes associated with poorer self-efficacy and motivation for physical activity in older adults with arthritis?

OBJECTIVES: The primary aim was to explore whether arthritis is associated with poorer self-efficacy and motivation for, and participation in, two specific types of physical activity (PA): endurance training (ET) and strength training (ST). A further objective was to determine whether the added burden of diabetes contributes to a further reduction in these PA determinants and types. METHODS: Self-efficacy and motivation for exercise and minutes per week of ET and ST were measured in 347 older veterans enrolled in a home-based PA counselling intervention. Regression analyses were used to compare high versus low self-efficacy and motivation and PA minutes in persons without arthritis, with arthritis alone, and with arthritis plus diabetes. RESULTS: Persons with arthritis alone reported lower self-efficacy for ET and ST than those without arthritis [odds ratio (OR)ET 0.71, 95% confidence interval (CI) 0.39­1.20; ORST 0.69, 95% CI 0.39­1.20]. A further reduction in self-efficacy for these two types of PA was observed for those with both arthritis and diabetes (ORET 0.65, 95% CI 0.44­0.92; ORST 0.64, 95% CI 0.44­0.93; trend p < 0.001). There was no trend towards a reduction in motivation for PA in those with arthritis alone or with arthritis and diabetes. Persons with arthritis exhibited higher motivation for ET than those without arthritis (ORET 1.85, 95% CI 1.12­3.33). There were no significant differences between the three groups in minutes of ET (p = 0.93), but persons with arthritis plus diabetes reported significantly less ST compared to individuals with arthritis only (p = 0.03). CONCLUSIONS: Despite reduced self-efficacy for ET and ST and less ST in older persons with arthritis, motivation for both PA types remains high, even in the presence of diabetes.

The impact of self-reported arthritis and diabetes on response to a home-based physical activity counselling intervention.

OBJECTIVES: Physical activity (PA) has the potential to improve outcomes in both arthritis and diabetes, but these conditions are rarely examined together. Our objective was to explore whether persons with arthritis alone or those with both arthritis and diabetes could improve amounts of PA with a home-based counselling intervention. METHODS: As part of the Veterans LIFE (Learning to Improve Fitness and Function in Elders) Study, veterans aged 70-92 were randomized to usual care or a 12-month PA counselling programme. Arthritis and diabetes were assessed by self-report. Mixed models were used to compare trajectories for minutes of endurance and strength training PA for persons with no arthritis (n = 85), arthritis (n = 178), and arthritis plus diabetes (n = 84). RESULTS: Recipients of PA counselling increased minutes of PA per week independent of disease status (treatment arm by time interaction p < 0.05 for both; endurance training time p = 0.0006 and strength training time p < 0.0001). Although PA was lower at each wave among persons with arthritis, and even more so among persons with arthritis plus diabetes, the presence of these conditions did not significantly influence response to the intervention (arthritis/diabetes group x time interactions p > 0.05 for both outcomes) as each group experienced a nearly twofold or greater increase in PA. CONCLUSIONS: A home-based PA intervention was effective in increasing minutes of weekly moderate intensity endurance and strength training PA in older veterans, even among those with arthritis or arthritis plus diabetes. This programme may serve as a useful model to improve outcomes in older persons with these pervasive diseases.

Formation of cortical fields on a reduced cortical sheet.

Theories of both cortical field development and cortical evolution propose that thalamocortical projections play a critical role in the differentiation of cortical fields (; ). In the present study, we examined how changing the size of the immature neocortex before the establishment of thalamocortical connections affects the subsequent development and organization of the adult neocortex. This alteration in cortex is consistent with one of the most profound changes made to the mammalian neocortex throughout evolution: cortical size. Removing the caudal one-third to three-fourths of the cortical neuroepithelial sheet unilaterally at an early stage of development in marsupials resulted in normal spatial relationships between visual, somatosensory, and auditory cortical fields on the remaining cortical sheet. Injections of neuroanatomical tracers into the reduced cortex revealed in an altered distribution of thalamocortical axons; this alteration allowed the maintenance of their original anteroposterior distribution. These results demonstrate the capacity of the cortical neuroepithelium to accommodate different cortical fields at early stages of development, although the anteroposterior and mediolateral relationships between cortical fields appear to be invariant. The shifting of afferents and efferents with cortical reduction or expansion at very early stages of development may have occurred naturally in different lineages over time and may be sufficient to explain much of the phenotypic variation in cortical field number and organization in different mammals.

Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics.

Superoxide is produced as a result of normal energy metabolism within the mitochondria and is scavenged by the mitochondrial form of superoxide dismutase (sod2). Mice with inactivated SOD2 (sod2 nullizygous mice) die prematurely, exhibiting several metabolic and mitochondrial defects and severe tissue pathologies, including a lethal spongiform neurodegenerative disorder (Li et al., 1995; Melov et al., 1998, 1999). We show that treatment of sod2 nullizygous mice with synthetic superoxide dismutase (SOD)-catalase mimetics extends their lifespan by threefold, rescues the spongiform encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich ataxia, spongiform encephalopathies, and Alzheimer's and Parkinson's diseases, in which chronic oxidative damage to the brain has been implicated.

DNA-sequence asymmetry directs the alignment of recombination sites in the FLP synaptic complex.

The FLP recombinase promotes site-specific recombination in the 2 micrometer circle of Saccharomyces cerevisiae. FLP recognizes a 48 bp target site (FLP recombination target, or FRT) consisting of three 13 bp protein binding sites, or symmetry elements, flanking an 8 bp spacer region. Efficient recombination also occurs with DNA substrates that have minimal FRT sites, consisting only of the spacer and two surrounding 13 bp symmetry elements arranged in inverse orientation; thus, the wild-type spacer sequence is the main asymmetric feature of the minimal recombination site. FLP carries out recombination with many minimal target sites bearing symmetric or asymmetric mutant spacer sequences; however, the overall directionality of recombination defined in terms of inversion or excision of a DNA domain is determined by spacer-sequence asymmetry. In order to evaluate the potential influence of spacer-sequence asymmetry on structures formed during early steps in recombination, we used electron microscopy to investigate the structure of the FLP synaptic complex, which is the intermediate protein-DNA complex involved in site pairing and strand exchange. Using linear substrate DNAs that have minimal FRTs with wild-type spacer sequences, we find that 85 to 90% of the FLP synaptic complexes examined contain the two FRTs aligned in parallel. This strong preference for parallel site alignment stands in contrast with prevailing models for lambda integrase-class recombination systems, which postulate antiparallel site alignment, and results from biophysical studies on synthetic, immobile four-way DNA junctions. Our results show that the strong preference for parallel alignment can be attributed to conformational preferences of Holliday junctions present in the synaptosome.

Infections associated with subclavian Uldall catheters.

During a 12-month period, the use of a subclavian vein Uldall catheter (UC) for hemodialysis or plasmapheresis in 27 patients was studied prospectively. Ten patients had ten UC site infections. Organisms associated with these infections included Staphylococcus epidermidis (five), Staphylococcus aureus (four), Proteus mirabilis (two), and Enterococcus (one). The four S aureus infections occurred 1, 2, 4, and 9 days after UC insertion, whereas the five S epidermidis infections occurred 6, 17, 17, 26, and 97 days after insertion. Five patients had associated bacteremias; in one of these patients, the bacteremia was the major cause of death. The incidence of UC site infection and bacteremia based was higher than the incidence of infection reported with any other type of vascular access for hemodialysis. Further studies are necessary to define whether the UC should be routinely employed for temporary vascular access.

Thalamo-cortical connections of areas 3a and M1 in marmoset monkeys.

The present investigation is part of a broader effort to examine cortical areas that contribute to manual dexterity, reaching, and grasping. In this study we examine the thalamic connections of electrophysiologically defined regions in area 3a and architectonically defined primary motor cortex (M1). Our studies demonstrate that area 3a receives input from nuclei associated with the somatosensory system: the superior, inferior, and lateral divisions of the ventral posterior complex (VPs, VPi, and VPl, respectively). Surprisingly, area 3a receives the majority of its input from thalamic nuclei associated with the motor system, posterior division of the ventral lateral nucleus of the thalamus (VL), the mediodorsal nucleus (MD), and intralaminar nuclei including the central lateral nucleus (CL) and the centre median nucleus (CM). In addition, sparse but consistent projections to area 3a are from the anterior pulvinar (Pla). Projections from the thalamus to the cortex immediately rostral to area 3a, in the architectonically defined M1, are predominantly from VL, VA, CL, and MD. There is a conspicuous absence of inputs from the nuclei associated with processing somatic inputs (VP complex). Our results indicate that area 3a is much like a motor area, in part because of its substantial connections with motor nuclei of the thalamus and motor areas of the neocortex (Huffman et al. [2000] Soc. Neurosci. Abstr. 25:1116). The indirect input from the cerebellum and basal ganglia via the ventral lateral nucleus of the thalamus supports its role in proprioception. Furthermore, the presence of input from somatosensory thalamic nuclei suggests that it plays an important role in somatosensory and motor integration.

Organization and connections of V1 in Monodelphis domestica.

We examined the internal organization and connections of the primary visual area, V1, in the South American marsupial Monodelphis domestica. Multiunit electrophysiological recording techniques were used to record from neurons at multiple sites. Receptive field location, size, progressions, and reversals were systematically examined to determine the visuotopic organization of V1 and its boundaries with adjacent visual areas. As in other mammals, a virtually complete representation of the visual hemifield was observed in V1, which was coextensive with a region of dense myelination. The vertical meridian was represented at the rostrolateral boundary of the field, the upper visual quadrant was represented caudolaterally, whereas the lower visual quadrant was represented rostromedially. Injections of fluorescent tracers into V1 revealed dense connections with cortex immediately adjacent to the rostrolateral boundary, in peristriate cortex (PS or V2). Connections were also consistently observed with a caudotemporal area (CT), entorhinal cortex (EC), and multimodal cortex (auditory/visual, A/V). These results demonstrate that M. domestica possess a highly differentiated neocortex with clear functional and architectonic cortical field boundaries, as well as discrete patterns of cortical connections. Some connections of V1 are similar to those observed in eutherian mammals, such as connections with V2 and extrastriate areas (e.g., CT), which suggests that there are general features of visual system organization that all mammals possess due to retention from a common ancestor. On the other hand, connections of V1 with EC and multimodal cortex may be a primitive feature of visual cortex that was lost in some lineages, may be a derived feature of marsupial neocortex, or may be a feature particular to mammals with small brains.

Organization of somatosensory cortex in three species of marsupials, Dasyurus hallucatus, Dactylopsila trivirgata, and Monodelphis domestica: neural correlates of morphological specializations.

The organization of somatosensory neocortex was investigated in three species of marsupials, the northern quoll (Dasyurus hallucatus), the striped possum (Dactylopsila trivirgata), and the short-tailed opossum (Monodelphis domestica). In these species, multiunit microelectrode mapping techniques were used to determine the detailed organization of the primary somatosensory area (SI). In the striped possum and quoll, the topography of somatosensory regions rostral (R), and caudal (C) to SI were described as well. Lateral to SI, two fields were identified in the striped possum, the second somatosensory area (SII) and the parietal ventral area (PV); in the quoll, there appeared to be only one additional lateral field which we term SII/PV. Visual and auditory cortices adjacent to somatosensory cortex were also explored, but the details of organization of these regions were not ascertained. In these animals, electrophysiological recording results were related to cortical myeloarchitecture and/or cytochrome oxidase staining. In one additional species, the fat-tailed dunnart (Sminthopsis crassicaudata), an architectonic analysis alone was carried out, and compared with the cortical architecture and electrophysiological recording results in the other three species. We discuss our results on the internal organization of SI in relation to the morphological specializations that each animal possesses. In addition, we discuss the differences in the organization of SI, and how evolutionary processes and developmental and adult neocortical plasticity may contribute to the observed variations in SI.

Oxidative signalling and inflammatory pathways in Alzheimer's disease.

It is well established that inflammation and oxidative stress are key components of the pathology of Alzheimer's disease (AD), but how early in the pathological cascade these processes are involved or which specific molecular components are key, has not been fully elucidated. This paper describes the pharmacological approach to understand the molecular components of inflammation and oxidative stress on the activation of microglial cells and neuronal cell viability. We have shown that activation of microglia with the 42-amino-acid form of the beta-amyloid peptide (A beta 42) activates the production of cyclooxygenase-2, the inducible form of nitric oxide synthase and tumour necrosis factor-alpha and there appears to be little interactive feedback between these three mediators. Moreover, we explore the effects of a series of salen-manganese complexes, EUK-8, -134 and -189, which are known to possess both superoxide and catalase activity. These compounds are able to protect cells from insults produced by hydrogen peroxide or peroxynitrite. Moreover, EUK-134 was also able to limit the output of prostaglandin E2 from activated microglial cells. The mechanisms underlying these effects are discussed. Together, these data support a pivotal role for oxidative stress and inflammation as key mediators of the pathological cascade in AD and provide some ideas about possible therapeutic targets.

Intrinsic activity of human immunodeficiency virus type 1 protease heterologous fusion proteins in mammalian cells.

We have generated various mammalian expression constructs that produce fusion proteins of human immunodeficiency virus type 1 (HIV-1) protease (PR) with the HIV-1 Nef protein. The expression of these proteins is inducible by the HIV-1 Tat protein. High-level expression of proteolytically active PR was produced from PR imbedded into Nef coding sequences, flanked by PR cleavage sites. The fusion protein was cleaved nearly to completion and did not exhibit the regulated processing that is seen with the virally encoded PR. No cytotoxic effect of PR expression was detected. The self-cleavage of PR could be inhibited by a specific inhibitor of HIV-1 PR (U75875). Elimination of the aminoterminal PR cleavage site did not have a measurable effect on cleavage of the precursor fusion protein. The cleaved fusion proteins appeared to be extremely unstable in the transfected cells. These findings demonstrate the intrinsic activity of HIV-1 PR in mammalian cells, in the context of a heterologous fusion protein.