Dental caries prevalence as evidence for agriculture and subsistence variation during the Yayoi period in prehistoric Japan: biocultural interpretations of an economy in transition

The Yayoi period represents the earliest point of agricultural dependence in Japan, dating from approximately 2500 BP to AD 300. Yayoi period people consumed wet-rice as a primary subsistence base. This article uses dental caries prevalence to interpret the biocultural implications of agriculture among these people by testing the following hypotheses: 1) Yayoi period agriculturalists had greater frequencies of carious teeth than Jomon period foragers, 2) regional variation in carious tooth frequencies will be observed among Yayoi period agriculturalists, while 3) variation in carious tooth frequencies will be observed between male and female agriculturalists. Statistically significant differences in carious teeth were observed between the agriculturalists from Southern Honshu and all other samples. These differences suggest greater reliance on cariogenic plants among farmers from Southern Honshu and are consistent with an agricultural economy. The people of the Yayoi period from Tanegashima Island and Northern Kyushu did not have significantly different carious tooth frequencies compared to Jomon period foragers. This suggests that rice alone was not a more cariogenic dietary substance than those consumed by Jomon period foragers but a cariogenic food nonetheless. Dietary heterogeneity between the prehistoric people of the Yayoi period from Southern Honshu and those from Northern Kyushu and Tanegashima Island is also inferred from these differences. Significantly greater frequencies of carious teeth among older aged Yayoi period females compared with males suggest dietary differences between the sexes.     

The metabolism of synthetic leukotriene B4 in synovial fluid and whole human blood

The metabolism in vitro of synthetic leukotriene B4 (LTB4) in synovial fluid from rheumatoid arthritis and osteoarthritis patients and in whole blood from these same patient groups and from normal volunteers has been studied. A linear relationship existed between a plot of the time of incubation of samples with LTB4 and the percentage of the initial concentration of LTB4 at each time point. The slope of this line, the rate constant for metabolism, has been used to compare different samples. LTB4 was metabolised more rapidly in the synovial fluid of rheumatoid arthritis patients than osteoarthritis patients. Furthermore, LTB4 was metabolised more rapidly in the blood of rheumatoid arthritis patients than either osteoarthritis patients or normal volunteers. These differences in metabolism correlate with the polymorphonuclear leukocyte (PMN) and albumin content of samples. It is suggested that binding of LTB4 to albumin in vivo will in part determine the available concentration of LTB4 in inflammatory lesions.     

Gene selection in arthritis classification with large-scale microarray expression profiles

The use of large-scale microarray expression profiling to identify predictors of disease class has become of major interest. Beyond their impact in the clinical setting (i.e. improving diagnosis and treatment), these markers are also likely to provide clues on the molecular mechanisms underlining the diseases. In this paper we describe a new method for the identification of multiple gene predictors of disease class. The method is applied to the classification of two forms of arthritis that have a similar clinical endpoint but different underlying molecular mechanisms: rheumatoid arthritis (RA) and osteoarthritis (OA). We aim at both the classification of samples and the location of genes characterizing the different classes. We achieve both goals simultaneously by combining a binary probit model for classification with Bayesian variable selection methods to identify important genes.We find very small sets of genes that lead to good classification results. Some of the selected genes are clearly correlated with known aspects of the biology of arthritis and, in some cases, reflect already known differences between RA and OA.     

Why is obesity associated with osteoarthritis? Insights from mouse models of obesity

Obesity is one of the most significant, and potentially most preventable, risk factors for the development of osteoarthritis, and numerous studies have shown a strong association between body mass index and osteoarthritis of the hip, knee, foot and hand. However, the mechanism(s) by which obesity contributes to the onset and progression of osteoarthritis are not fully understood. The strong association between body mass index, altered limb alignment, and osteoarthritis of the knee--and the protective effects of weight loss--support the classic hypothesis that the effects of obesity on the joint are due to increased biomechanical loading and associated alterations in gait. However, obesity is now considered to be a low-grade systemic inflammatory disease, and recent studies suggest that metabolic factors associated with obesity alter systemic levels of pro-inflammatory cytokines that are also associated with osteoarthritis. Thus, the ultimate influence of obesity on osteoarthritis may involve a complex interaction of genetic, metabolic, and biomechanical factors. In this respect, mouse models of obesity can provide excellent systems in which to examine causal relationships among these factors. In recent years, there have been surprisingly few reports examining the effects of obesity on osteoarthritis using mouse models. In this paper, we review studies on mice and other animal models that provide both direct and indirect evidence on the role of obesity and altered diet in the development of osteoarthritis. We also examine the use of different body mass indices for characterizing "obesity" in mice by comparing these indices to typical adiposity levels observed in obese humans. Taken together, evidence from studies using mice suggest that a complex interaction of environmental and genetic factors associated with obesity contribute to the incidence and severity of osteoarthritis. The ability to control these factors, together with the development of methods to conduct more intricate measures of local biomechanical factors, make mouse models an excellent system to study obesity and osteoarthritis.     

The metabolism leukotriene B4 in synovial fluid and whole human blood

The metabolism of synthetic leukotriene B₄ (LTB₄) in synovial fluid from rheumatoid arthritis and osteoarthritis patients and in whole blood from these same patient groups and from normal volunteers has been studied. A linear relationship existed between a plot of the time of incubation of samples with LTB₄ and the percentage of the initial concentration of LTB₄ at each time point. The slope of this line, the rate constant for metabolism, has been used to compare different samples. LTB₄ was metabolised more rapidly in the synovial fluid of rheumatoid arthritis patients than osteoarthritis patients. Furthermore, LTB₄ was metabolised more rapidly in the blood of rheumatoid arthritis patients that either osteoarthritis patients or normal volunteers. These differences in metabolism correlate with the polymorphonuclear leukocyte (PMN) and albumin content of samples. It is suggested that binding of LTB₄ to albumin will in part determine the available concentration of LTB₄ in inflammatory lesions.     

Comparing the prevalence of rheumatic diseases in China with the rest of the world

Geographic or ethnic differences in the occurrence of disease often provide insights into causes of disease and possible opportunities for disease prevention. Persons in China appear to have a consistently lower prevalence of rheumatoid arthritis and fibromyalgia than persons in the United States and Europe; reasons for these prevalence differences might include genetic differences, differences in environmental exposures or a combination of both. With increasing obesity, gout is becoming endemic in China. Finally, symptomatic knee osteoarthritis is extremely common in China and constitutes a major public health problem there.     

Human manipulative behavior in the Central European Late Eneolithic and Early Bronze Age: humeral bilateral asymmetry

It is assumed that the transition from the Late Eneolithic to the Early Bronze Age in Central Europe was associated with substantial changes in subsistence and the perception of gender differences. However, the archeological record itself does not entirely support this model. Alternatively, this transition may be interpreted as a continuous process. We used asymmetry in external dimensions, and asymmetry in size and distribution of cortical tissue of humeri to elucidate the nature of this transition with respect to differences in manipulative behavior. The total sample of 67 individuals representing five archaeological cultures was used. The results indicate that the pattern of asymmetry of the humeral external measurements and the cross-sectional parameters taken at 35% of humeral biomechanical length remain stable during the Late Eneolithic and Early Bronze Age. However, females of both periods show fluctuating asymmetry for all of the cross-sectional parameters, but directional asymmetry for biomechanical length. Males are nonsignificantly shifted from the line of equivalence for biomechanical length, but exhibit directional asymmetry for the cortical area and polar moment of area. Only distal articular breadth yields fluctuating asymmetry for both females and males in both periods. Thus, the transition from the Late Eneolithic to the Early Bronze Age can be seen as a continuous process that probably affected only a limited part of human activities. We interpret the differences between females and males of both periods as evidence of gender-specific activities; males might have been associated with extra-domestic agricultural labor that resulted in asymmetrical manipulative loading and females with domestic labor with symmetrical manipulative loading in both periods.     

Degenerative joint disease in African great apes: an evolutionary perspective

Degenerative joint disease is investigated in the spine and major peripheral joints (shoulder, elbow, hip and knee) in samples of chimpanzees (Pan troglodytes schweinfurthii; P. troglodytes troglodytes), lowland gorillas (Gorilla gorilla gorilla), and bonobos (P. paniscus). The P. troglodytes schweinfurthii sample comes from Gombe National Park, Tanzania, while the other samples are derived from museum materials originally collected in west/central Africa. Total data for African ape samples include 5807 surfaces for ascertainment of vertebral osteophytosis, 12,479 surfaces for determination of spinal osteoarthritis, and 1211 joints for evaluation of peripheral joint osteoarthritis. All apes display significantly less spinal disease than in a comparable human sample, and these differences are most likely a consequence of human biomechanical adaptations for bipedal locomotion. Apes are also generally less involved in the major peripheral joints than are humans, but human groups are themselves highly variable in prevalence of peripheral osteoarthritis. These data agree with other findings of low prevalence of degenerative joint prevalence in free-ranging apes, but contrast markedly with evidence derived from colony-reared Old World monkeys.     

Gene therapy for osteoarticular disorders

Osteoarticular disorders are the major cause of disability in Europe and North America. It is estimated that rheumatoid arthritis affects 1 % of the population and that more than two third of people over age 55 develop osteoarthritis. Because there are no satisfactory treatments, gene therapy offers a new therapeutic approach. The delivery of cDNA encoding anti-arthritic proteins to articular cells has shown therapeutic efficacy in numerous animal models in vivo. Through the development and the experimental progresses that have been made for both rheumatoid arthritis and osteoarthritis, this review discusses the different gene therapy strategies available today and the safety issues with which they may be associated. Among the different vectors available today, adeno-associated virus seems the best candidate for a direct in vivo gene delivery approach for the treatment of joint disorders.     

Aging-Related Differences in Chondrocyte Viscoelastic Properties

The biomechanical properties of articular cartilage change profoundly with aging. These changes have been linked with increased potential for cartilage degeneration and osteoarthritis. However, less is known about the change in biomechanical properties of chondrocytes with increasing age. Cell stiffness can affect mechanotransduction pathways and may alter cell function. We measured aging-related changes in the biomechanical properties of chondrocytes. Human chondrocytes were isolated from knee articular cartilage within 48 hours after death or from osteochondral specimens obtained from knee arthroplasty. Cells were divided into two age groups: between 18 and 35 years (18 -- 35); and greater than 55 years (55+) of age. The 55+ group was further subdivided based on visual grade of osteoarthritis: normal (N) or osteoarthritic (OA). The viscoelastic properties of the cell were measured using the previously described micropipette cell aspiration technique. The equilibrium modulus, instantaneous modulus, and apparent viscosity were significantly higher in the 55+ year age group than in the 18 -- 35 age group. On the other hand, no differences were found in the equilibrium modulus, instantaneous modulus, or apparent viscosity between the N and OA groups. The increase in cell stiffness can be attributed to altered mechanical properties of the cell membrane, the cytoplasm, or the cytoskeleton. Increased stiffness has been reported in osteoarthritic chondrocytes, which in turn has been attributed to the actin cytoskeleton. A similar mechanism may be responsible for our finding of increased stiffness in aging chondrocytes. With advancing age, changes in the biomechanical properties of the cell could alter molecular and biochemical responses.     

Gait and neuromuscular pattern changes are associated with differences in knee osteoarthritis severity levels

Knee osteoarthritis (OA) is a multifactoral, progressive disease process of the musculoskeletal system. Mechanical factors have been implicated in the progression of knee OA, but the role of altered joint mechanics and neuromuscular control strategies in progressive mechanisms of the disease have not been fully explored. Previous biomechanical studies of knee OA have characterized changes in joint kinematics and kinetics with the disease, but it has been difficult to determine if these biomechanical changes are involved in the development of disease, are in response to degenerative changes in the joint, or are compensatory mechanisms in response to these degenerative changes or other related factors as joint pain. The goal of this study was to explore the association between biomechanical changes and knee OA severity in an effort to understand the changing role of biomechanical factors in the progression of knee OA. A three-group cross-sectional model was used that included asymptomatic subjects, subjects clinically diagnosed with moderate knee OA and severe knee OA subjects just prior to total joint replacement surgery. Principal component analysis and discriminant analysis were used to determine the combinations of electromyography, kinematic and kinetic waveform pattern changes at the knee, hip and ankle joints during gait that optimally separated the three levels of severity. Different biomechanical mechanisms were important in discriminating between severity levels. Changes in knee and hip kinetic patterns and rectus femoris activation were important in separating the asymptomatic and moderate OA gait patterns. In contrast, changes in knee kinematics, hip and ankle kinetics and medial gastrocnemius activity were important in discriminating between the moderate and severe OA gait patterns.     

A novel approach to measure the contribution of matrix metalloproteinase in the overall net proteolytic activity present in synovial fluids of patients with arthritis

Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis.     

Aggrecanases and cartilage matrix degradation

The loss of extracellular matrix macromolecules from the cartilage results in serious impairment of joint function. Metalloproteinases called 'aggrecanases' that cleave the Glu³⁷³–Ala³⁷⁴ bond of the aggrecan core protein play a key role in the early stages of cartilage destruction in rheumatoid arthritis and in osteoarthritis. Three members of the ADAMTS family of proteinases, ADAMTS-1, ADAMTS-4 and ADAMTS-5, have been identified as aggrecanases. Matrix metalloproteinases, which are also found in arthritic joints, cleave aggrecans, but at a distinct site from the aggrecanases (i.e. Asn³⁴¹–Phe³⁴²). The present review discuss the enzymatic properties of the three known aggrecanases, the regulation of their activities, and their role in cartilage matrix breakdown during the development of arthritis in relation to the action of matrix metalloproteinases.     

Arthritis in Roman Britain.

The pattern of arthritis in Roman Britain was investigated by examining the skeletons of 416 adults from the Roman cemetery at Poundbury Camp near Dorchester, Dorset. The mean height of the people was not much less than that of the current British population, and the prevalence of right handedness was similar to our own. There was a high prevalence of osteoarthritis for such a relatively young community, with particularly severe changes in the vertebral column. The pattern of joints affected by osteoarthritis was different from that seen now, but the prevalence of vertebral ankylosing hyperostosis was much the same. Rheumatoid arthritis was seen as often as the expected rat would indicate, given that the population died young, but it was rare. Other forms of arthritis, including gout and ankylosing spondylitis, were not seen.     

Changes in pain catastrophizing predict later changes in fibromyalgia clinical and experimental pain report: cross-lagged panel analyses of dispositional and situational catastrophizing

Introduction

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be important in the development of inflammatory models of rheumatoid arthritis and there is encouraging data that its blockade may have clinical relevance in patients with rheumatoid arthritis. The aims of the current study were to determine whether GM-CSF may also be important for disease and pain development in a model of osteoarthritis.

Methods

The role of GM-CSF was investigated using the collagenase-induced instability model of osteoarthritis. We studied both GM-CSF-/- mice and wild-type (C57BL/6) mice treated prophylactically or therapeutically with a monoclonal antibody to GM-CSF. Disease development (both early and late) was evaluated by histology and knee pain development was measured by assessment of weight distribution.

Results

In the absence of GM-CSF, there was less synovitis and matrix metalloproteinase-mediated neoepitope expression at week 2 post disease induction, and less cartilage damage at week 6. GM-CSF was absolutely required for pain development. Therapeutic neutralization of GM-CSF not only abolished the pain within 3 days but also led to significantly reduced cartilage damage.

Conclusions

GM-CSF is key to the development of experimental osteoarthritis and its associated pain. Importantly, GM-CSF neutralization by a therapeutic monoclonal antibody-based protocol rapidly and completely abolished existing arthritic pain and suppressed the degree of arthritis development. Our results suggest that it would be worth exploring the importance of GM-CSF for pain and disease in other osteoarthritis models and perhaps clinically for this form of arthritis.     

Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development

Introduction

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be important in the development of inflammatory models of rheumatoid arthritis and there is encouraging data that its blockade may have clinical relevance in patients with rheumatoid arthritis. The aims of the current study were to determine whether GM-CSF may also be important for disease and pain development in a model of osteoarthritis.

Methods

The role of GM-CSF was investigated using the collagenase-induced instability model of osteoarthritis. We studied both GM-CSF-/- mice and wild-type (C57BL/6) mice treated prophylactically or therapeutically with a monoclonal antibody to GM-CSF. Disease development (both early and late) was evaluated by histology and knee pain development was measured by assessment of weight distribution.

Results

In the absence of GM-CSF, there was less synovitis and matrix metalloproteinase-mediated neoepitope expression at week 2 post disease induction, and less cartilage damage at week 6. GM-CSF was absolutely required for pain development. Therapeutic neutralization of GM-CSF not only abolished the pain within 3 days but also led to significantly reduced cartilage damage.

Conclusions

GM-CSF is key to the development of experimental osteoarthritis and its associated pain. Importantly, GM-CSF neutralization by a therapeutic monoclonal antibody-based protocol rapidly and completely abolished existing arthritic pain and suppressed the degree of arthritis development. Our results suggest that it would be worth exploring the importance of GM-CSF for pain and disease in other osteoarthritis models and perhaps clinically for this form of arthritis.     

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.