Are structural abnormalities on knee MRI associated with osteophyte development? Data from the Osteoarthritis Initiative.

OBJECTIVE: To assess which structural abnormalities on knee MRI are associated with development of osteophytes in middle-aged subjects without radiographic knee osteoarthritis. DESIGN: We included subjects from the Osteoarthritis Initiative, aged 40-55 years, Kellgren & Lawrence grade 0 in both knees, and knee MRIs from both knees available at baseline, 24, 48 and 72 months. Structural exposures on MRI assessed using MOAKS included cartilage damage, bone marrow lesions, meniscal tear, meniscal extrusion, and Hoffa/effusion synovitis. We assessed whether each structural exposure was associated with the development of osteophytes on MRI in the medial and lateral tibiofemoral, and patellofemoral compartment. We estimated hazard ratios (HR) including 95% confidence intervals (CI) for osteophyte development using a mixed complementary log-log regression model adjusted for age, sex, and body mass index. RESULTS: We included 680 knees from 340 subjects with a mean (SD) age of 50 years (3.0), and 51% men. In the medial tibiofemoral compartment, the absolute risk of osteophyte development in the first 24-month period was 4% in knees without, and 15% in knees with medial meniscal tear. Corresponding adjusted HR was 6.6 (95%CI = 3.4-12.9). In the lateral tibiofemoral compartment, the adjusted HR for developing osteophytes having a lateral meniscal tear was 3.3 (95%CI = 1.3-8.4). In the patellofemoral compartment, patellofemoral cartilage damage was most clearly associated with developing osteophytes (HR = 2.6, 95%CI = 1.8-3.7). CONCLUSIONS: Meniscal tear seem to be the strongest structural risk factor for the development of tibiofemoral osteophytes, and patellofemoral cartilage damage for the development of patellofemoral osteophytes, respectively. Local biomechanical factors are important in early osteophyte development.

A naturally aging knee, or development of early knee osteoarthritis?

AIM: To study the development of early knee osteoarthritis (OA) in subjects with and without risk factors for knee OA. METHODS: We studied 340 subjects from the Osteoarthritis Initiative (OAI), aged 45-55 years (51% women), free of radiographic knee OA at baseline (n = 294 with and n = 46 without knee pain and other OA risk factors). At baseline, 24, 48, 72 and 96 months we compared the two groups for prevalence and overlap of knee OA as defined by magnetic resonance imaging (MRI-based OA), x-rays (Kellgren-Lawrence grade [KLG] ≥ 1), and pain, using a logistic mixed model. We studied the group differences (%) over time by subtracting the OA prevalence of those without risk factors from the group with risk factors. RESULTS: The group with OA risk factors had higher proportions of MRI-based OA than the group without OA risk factors at all visits, but the difference diminished at 72 months (72 months difference = 11.9%, 95% confidence intervals [CI] = -2.3-26.1). Further, at 72 months, the presence of KLG ≥ 1 were similar in the two groups (-3.5%, 95% CI = -15.2-8.2). The proportion fulfilling all three OA definitions was 1.7% at 24 months and 4.8% at 72 months of those with OA risk factors and 0% and 2.2%, respectively, in those without. CONCLUSION: Structural changes of the knee are common irrespective of the presence of pain or other OA risk factors. Such structural changes in absence of knee symptoms should probably be considered as risk factors for early OA rather than disease.

Risk factors for meniscal body extrusion on MRI in subjects free of radiographic knee osteoarthritis: longitudinal data from the Osteoarthritis Initiative.

OBJECTIVE: To determine risk factors associated with increased meniscal body extrusion on knee magnetic resonance (MR) images in subjects free of radiographic osteoarthritis (OA). METHODS: We selected 340 subjects (aged 45-55 years, mean [SD] body mass index 26.7 [4.4], 51% women) with Kellgren-Lawrence grade 0 in both knees and bilateral knee MR images available at the baseline, 24 months, 48 months, and 72 month exam from the Osteoarthritis Initiative (OAI). We assessed mid-coronal 3-T MR images from baseline through the 72-month exam. One observer measured widths of the tibia plateau and medial or lateral meniscal body extrusion for baseline and 72 months follow-up. Another observer assessed meniscal integrity at all four time points. We calculated an extrusion ratio ([meniscal body extrusion]/[tibia width] × 100) to account for knee size. We evaluated risk factors for increased meniscal body extrusion ratio from baseline to 72 months by a multivariable linear regression mixed model for medial and lateral compartment, respectively. RESULTS: In the medial compartment female sex (ß = 0.35; 95% confidence interval [CI] 0.16-0.53), incident meniscal tear (ß = 0.29; 95% CI 0.22-0.55), and the baseline value of the extrusion ratio (ß = 0.63; 95% CI 0.56-0.70) were associated with increased extrusion ratio by 72 months. Results were similar for the lateral compartment. CONCLUSIONS: Only female sex, incident meniscal tear, and higher baseline value of extrusion are risk factors for increased meniscal body extrusion in subjects free of radiographic OA. The results suggest that meniscal extrusion may contribute to and mediate the well-known increase in knee OA incidence in middle-aged women.

Diagnostic and prognostic value of bone biomarkers in progressive knee osteoarthritis: a 6-year follow-up study in middle-aged subjects.

OBJECTIVE: To determine the value of bone markers in early-stage progressive knee osteoarthritis (OA), a population-based cohort of middle-aged subjects with chronic knee complaints was followed over 6 years (two consecutive two 3-year periods). METHODS: Tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age at baseline 45 ± 6.2 years) in 2002, 2005 and 2008. Bone formation was assessed by the serum concentration of procollagen type I amino-terminal propeptide (sPINP); bone resorption by the level of the C-terminal cross-linked telopeptides of type I collagen (sCTx-I); and bone mineralization by the values of osteocalcin (sOC) by electrochemiluminescence immunoassay. A novel marker of bone resorption, urinary osteocalcin midfragments (uMidOC), was assayed using enzyme linked immunosorbent assay (ELISA). RESULTS: Several diagnostic associations were found between the bone markers (PINP, OC, MidOC) and progressive OA expressed by TF osteophytosis. The increasing output of MidOC demonstrated several-fold higher risk for progressive TF osteophytosis [odds ratio (OR) 5.32; 95% confidence interval (CI) 1.41-20.06, P = 0.014] than other bone markers. The values of PINP had prognostic value for subsequent more severely expressed knee OA progression [r(s) = 0.460, P = 0.005]. CONCLUSIONS: Bone metabolism is activated in early-stage knee OA. OA progression was preceded by the enhanced bone formation (by PINP) and accompanied by the activation of bone formation (by PINP), non-collagenous bone resorption (by MidOC), as well as by changes in mineralization (by OC). All three bone markers had diagnostic value, and one of them, PINP, had also a predictive value for knee OA progression, especially for progressive osteophytosis.

Association of ADAM12-S protein with radiographic features of knee osteoarthritis and bone and cartilage markers.

ADAM12 (A disintegrin and metalloprotease) is one of the candidate genes demonstrating susceptibility to osteoarthritis. The purpose of this study was to investigate the relationship between ADAM12-S protein and radiographic knee osteoarthritis (KOA) and its correlation to several bone and cartilage biomarkers. The ADAM12-S protein was measured in 276 subjects (60% women, aged 32-60 years), including 181 individuals with and 95 without radiographic KOA features. The radiographs were obtained from both tibiofemoral (TF) and patellofemoral (PF) joints. The serum levels of ADAM12-S protein were measured by DELFIA1/AutoDELFIA research kit. The ADAM12-S protein was found in detectable ranges in 43 subjects (16 men), without statistical difference between the two genders. In the whole group, the ADAM12-S was related to radiographic KOA grades in TF (P = 0.004) as well in PF joint (P = 0.003). We also found a correlation between ADAM12-S protein and osteophytes in TF and/or PF joints (P = 0.003). No correlations were found between serum levels of S-CTx-I (C-terminal cross-linked telopeptides of type I collagen) or S-PINP (type I procollagen N-terminal propeptide) and ADAM12-S. Similarly, in the whole group, the ADAM12-S protein was not correlated with U-CTx-II (urinary C-telopeptide fragments of type II collagen); however, in the female group, trend to positive correlation between the investigated biomarkers (P = 0.019) was observed. The ADAM12-S protein could be elevated in some KOA cases, and this elevation correlates with the grades of the disease, mostly owning to development of osteophytes. This finding suggests the possible involvement of the ADAM12-S protein in the pathogenesis of KOA.

Combined PCDD/F destruction and particulate control in a baghouse: experience with a catalytic filter system at a medical waste incineration plant.

Phoenix Services, Inc., owns and operates the Baltimore Regional Medical Waste Incinerator in Baltimore, MD. New regulations for dioxins and furans imposed a limit that was considerably below historical emission levels. To determine a method to comply with the new dioxin/furan regulations, Phoenix Services performed trials with powdered activated carbon (PAC). Although the results with carbon were acceptable, Phoenix Services decided to replace their woven fiberglass filter bags with catalytic filters that simultaneously destroy dioxins and furans and collect particulate matter (PM). The catalytic filter system offered several advantages to Phoenix Services, including destruction of dioxins and furans instead of adsorption on carbon. The catalytic filters also offered a passive solution that did not require new carbon injection equipment. In January 2000, a campaign to measure dioxins/furans and PM was undertaken. The measurements allowed the catalytic filter system to be evaluated. Some of the key findings of this investigation are The dioxin/furan emission was less than 0.1 ng toxicity equivalents (TEQ)/Nm3 at 11% O2. This concentration is approximately 2 orders of magnitude less than historical averages and it is well below the new regulatory limits, for both existing and new sources of this type; the amount of dioxin/furans destroyed by the catalytic filters was approximately 1.73 ng TEQ/Nm3 at 11% O2; and the particulate emission was 12-17 times less than the regulatory limit.

Monte Carlo Markov chain methods for genome screening.

We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait, MAO level, and a discrete trait, Collaborative Study on the Genetics of Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were analyzed and effects of marker map features were examined. For MAO, modest signals were found on chromosomes 1 and 17 for raw data, and 15 for covariate-adjusted data. For alcoholism, a strong signal was found on chromosome 1 with modest signals on chromosomes 4 and 10.

Gene-culture coevolution and sex ratios: II. Sex-chromosomal distorters and cultural preferences for offspring sex.

Cultural preferences for the sex of offspring may produce behavior, such as female infanticide, sex-selective abortion and sex-selective parental investment, which alter the sex ratio in a population. Empirical evidence suggests that some genetic sex-ratio distorters are located on the sex chromosomes. Interactions between cultural preferences and sex-linked sex-ratio distorters are examined. Criteria for the spread of cultural preferences and sex-chromosomal distorter alleles are derived analytically, and the coevolution of preferences and distorters is examined through numerical iteration. Evolutionary equilibria and trajectories of gene-culture interactions involving sex-chromosomal distorter alleles may produce severely male- or female-biased primary sex ratios and adult sex ratios in populations. Adult sex ratios, primary sex ratios, allele frequencies and the prevalence of cultural preferences in the population are sensitive to initial conditions and cultural transmission parameters. During the coevolutionary process phenoallelic association is observed in many cases and is associated with unusual dynamics.

Gene-Culture Coevolution and Sex Ratios: II. Sex-Chromosomal Distorters and Cultural Preferences for Offspring Sex

Cultural preferences for the sex of offspring may produce behavior, such as female infanticide, sex-selective abortion and sex-selective parental investment, which alter the sex ratio in a population. Empirical evidence suggests that some genetic sex-ratio distorters are located on the sex chromosomes. Interactions between cultural preferences and sex-linked sex-ratio distorters are examined. Criteria for the spread of cultural preferences and sex-chromosomal distorter alleles are derived analytically, and the coevolution of preferences and distorters is examined through numerical iteration. Evolutionary equilibria and trajectories of gene-culture interactions involving sex-chromosomal distorter alleles may produce severely male- or female-biased primary sex ratios and adult sex ratios in populations. Adult sex ratios, primary sex ratios, allele frequencies and the prevalence of cultural preferences in the population are sensitive to initial conditions and cultural transmission parameters. During the coevolutionary process phenoallelic association is observed in many cases and is associated with unusual dynamics. Copyright 1997 Academic Press

A gene-culture model of human handedness.

A model of handedness incorporating both genetic and cultural processes is proposed, based on an evolutionary analysis, and maximum-likelihood estimates of its parameters are generated. This model has the characteristics that (i) no genetic variation underlies variation in handedness, and (ii) variation in handedness among humans is the result of a combination of cultural and developmental factors, but (iii) a genetic influence remains since handedness is a facultative trait. The model fits the data from 17 studies of handedness in families and 14 studies of handedness in monozygotic and dizygotic twins. This model has the additional advantages that it can explain why monozygotic and dizygotic twins and siblings have similar concordance rates, and no hypothetical selection regimes are required to explain the persistence of left handedness.

Gene-culture coevolution and sex ratios: the effects of infanticide, sex-selective abortion, sex selection, and sex-biased parental investment on the evolution of sex ratios.

The evolutionary consequences of culturally transmitted practices that cause differential mortality between the sexes, thereby distorting the sex ratio (e.g., female infanticide and sex-selective abortion), are explored using dynamic models of gene-culture coevolution. We investigate how a preference for the sex of offspring may affect the selection of genes distorting the primary sex ratio. Sex-dependent differences in mortality have been predicted to select for a male- or female-biased primary sex ratio, to have no effect, or to favor either under different circumstances. We find that when a mating pair's behavior modifies mortality rates in favor of one sex, but does not change the number of offspring produced in the mating, the primary sex ratio will evolve a bias against the favored sex. However, when the total number of offspring of a mating pair is significantly reduced as a consequence of their prejudice, the primary sex ratio will evolve to favor the preferred sex. These results hold irrespective of whether the sex ratio is distorted by the mother's, the father's or the individual's own autosomal genes. The use of dynamic models of gene-culture coevolution allows us to explore the evolution of alleles which distort the sex ratio, as well as the final equilibrium states of the system. Gene-culture interactions can provide equilibria different from those in purely genetic systems, slow the approach to these equilibria by orders of magnitude, and move the primary (PSR) and the adult sex ratio (ASR) away from any stable equilibrium for hundreds of generations.

Microcalorimetric study on myocardial metabolism in a hibernator and two nonhibernators at 20 degrees C and 37 degrees C.

Metabolic activity in cardiac tissue slices from the guinea pig (GP), the rat (RT), the nonhibernating summer and winter hedgehog (SH and WH), respectively, was determined at 20 degrees and at 37 degrees C from their rates of heat production, P, (units, W/g tissue) by direct and indirect calorimetry. Energy-linked transport of Na+ and K+ in the tissues was determined from changes in metabolic rate induced by specific inhibition of the Na/K pump, the functional expression of Na/K-ATPase, the pacemaker enzyme in energy production assigned the role of transporting Na+ and K+ out of and into the cell. The results indicate a higher rate of energy production and utilization in the cardiac tissue of the hedgehog than in that of the nonhibernators, the rat and the guinea pig, at both temperatures. At 37 degrees C the rate at which the cardiac tissue from the hedgehog consumed oxygen was as much as six times that registered for the guinea pig. The temperature coefficients of P and of the Na/K pump in the tissues from the two groups of hedgehogs were significantly higher than in the tissues from the rat and the guinea-pig (P < 0.001). The determined metabolic indices, the basal rate of heat production P, the rate of oxygen consumption, P(O2) in thermal units (W/g tissue), and the Na/K-pump capacity (PC) indicate species-specific differences between the animals. Both PC and its variation with temperature, delta PC/delta T(o)C, were in the order WH > SH > RT > GP. These results indicate that the hedgehog's cardiac tissue, in comparison with that of the nonhibernators, has a greater capacity to generate energy in general and for active transport of Na+ and K+ at 37 degrees C after exposure to a lower temperature. A role is suggested for the Na/K-ATPase and some other unique rate-limiting enzymes in the metabolic pathway for the observed differences in temperature tolerance and cardiac performance between hibernators and nonhibernators.

Increased lymphocyte thermogenesis in hyperthyroid patients. Role of Na/K pump function. Evaluation of aerobic/anaerobic metabolism.

The role of the Na/K pump for the increased cell energy expenditure in hyperthyroidism was studied by measuring total lymphocyte heat production rate in samples with and without ouabain inhibition of Na/K ATP-ase. In addition, the relative contribution of aerobic processes to lymphocyte thermogenesis was calculated from oxygen consumption measurements. In 12 patients with clinical and laboratory hyperthyroidism total lymphocyte heat production rate was 3.19 +/- 0.21 pW/cell, significantly higher than in 7 patients with subclinical hyperthyroidism (2.14 +/- 0.11 pW/cell) and in 15 euthyroid subjects (2.26 +/- 0.11 pW/cell) (p less than 0.001). The relative decrease in lymphocyte heat production rate after ouabain, giving a quantitative measure of the activity of the Na/K ATP-ase and reflecting the importance of Na/K pump function for the overall rate of lymphocyte metabolism, was not significantly different between the groups: 19.5 +/- 3.6% in hyperthyroid patients, 14.2 +/- 2.3% in subclinical hyperthyroid patients and 17.8 +/- 3.1% in euthyroid subjects. According to the rate of lymphocyte oxygen consumption, aerobic processes represented 58.4 +/- 6.7% of total lymphocyte energy expenditure in hyperthyroid patients, not significantly different from subclinical hyperthyroidism (62.6 +/- 8.4%) or from euthyroidism (66.6 +/- 2.7%). These data do not support the hypothesis of a specific role of the Na/K pump function for the increased cell thermogenesis in hyperthyroidism and indicate a parallel stimulation of aerobic and anaerobic processes by thyroid hormone excess.

Microcalorimetric evaluation of blood compatibility of hemodialysis membranes.

The study was made in vitro of reactions elicited by contact of granulocytes suspended in autologous plasma with three polymers: polyacrylonitrile (AN); polyetherpoly-carbonate (PC), and regenerated cellulose (Cu). Alterations in basal metabolism and biological function of the human blood granulocytes induced by interfacial reactions were determined by direct microcalorimetry. The polymers, which are commonly used as membranes in artificial kidneys, were found to activate granulocytes to degrees which were inversely correlated with their response to zymosan. The compatibility of the granulocytes and each of the membranes was of the order: AN greater than PC greater than Cu.

Heat production rate in blood lymphocytes as a prognostic factor in non-Hodgkin's lymphoma.

The heat production rate in peripheral blood lymphocytes was evaluated by direct calorimetry in 76 untreated adults with non-Hodgkin's lymphoma (NHL). Elevated values were recorded for 20 out of 54 patients with lymphomas of high or intermediate malignancy grade (37%) and for 1 out of 22 patients (5%) with low grade lymphomas (p = 0.01). Median survival was 39 months for patients with normal values and 8.5 months for those with elevated values (p = 0.005). In a subgroup of 38 patients with high or intermediate grade NHL stage III-IV, 17 patients with abnormally high lymphocyte heat production rates had a significantly shorter survival than 21 patients with normal values (p = 0.01). In a multivariate analysis the prognostic impact of lymphocyte heat production was superior to histologic malignancy grade, clinical stage and age.

Thyroid hormones and thermogenesis: a microcalorimetric study of overall cell metabolism in lymphocytes from patients with different degrees of thyroid dysfunction.

We used microcalorimetry to measure lymphocyte heat production rate in patients with clinical and laboratory hyperthyroidism (serum TSH decreases, serum FT4 increases, serum FT3 increases), subclinical hyperthyroidism (serum TSH decreases, serum FT1 increases, serum FT3 =), and subclinical hypothyroidism (serum TSH increases, serum FT4 decreases, serum FT3 =) compared with healthy controls (N = 13). The lymphocyte heat production rate was significantly correlated to the free thyroxine level (r = 0.53, p less than 0.01) and to the free triiodothyronine level (r = 0.51, p less than 0.01) when calculated from pooled data for the three patients groups. The hyperthyroid patients (N = 8) had a significantly increased lymphocyte heat production rate, 3.43 +/- 0.25 pW/cell, as compared with 2.31 +/- 0.12 pW/cell in the control group (p less than 0.001). The groups with subclinical hyperthyroidism (N = 7) and subclinical hypothyroidism (N = 9) had lymphocyte heat production rates of 2.14 +/- 0.11 and 2.56 +/- 0.15 pW/cell, respectively, not significantly different from that in the controls. Consistently, there was no significant difference between patients with subclinical hyperthyroidism (N = 5) and controls (N = 5) with regard to lymphocyte energy production as calculated from separately measured oxygen consumption rates in vitro, 1.36 +/- 0.20 and 1.56 +/- 0.12 pW/cell, respectively. Thus microcalorimetry seems to be suitable for studying the influence of thyroid hormones on cellular metabolism. Subclinical thyroid dysfunction does not seem to alter the overall rate of lymphocyte metabolism.

Cell metabolic activity in acromegaly: a microcalorimetric study of lymphocyte metabolism.

A discrepancy between the clinical impression of disease activity and basal serum levels of growth hormone is often seen in patients with acromegaly. A slightly better relation has been found to serum levels of IGF-I, but a technique for evaluation of cell metabolic activity in this disease is still missing. For this purpose we used microcalorimetry to determine heat production rate in lymphocytes from 15 patients with acromegaly. The mean heat production rate was 2.90 +/- 0.15 pW/cell, significantly higher than in 13 healthy subjects, 2.31 +/- 0.12 pW/cell (p less than 0.01). Heat production rates did not correlate significantly with basal growth hormone levels, but increased, in a statistically significant manner (p less than 0.001), in parallel with the score index used to evaluate the clinical activity of the disease. Using the technique of microcalorimetry we could thus demonstrate an increased metabolic activity at a cellular level in patients with acromegaly, a finding that is in accordance with the view that an increased cell metabolic activity is a component of the disease process in acromegaly.

Effects of calcium entry blockers on human platelet metabolism measured by microcalorimetry.

1. The direct overall metabolic effects of calcium entry blockers on human platelets were evaluated using a sensitive microcalorimetric method. 2. The effect on platelet metabolism of four calcium entry blockers with different profiles of action was examined and compared with the relaxant response on human cerebral vessels in vitro. 3. Diltiazem (10(-8), 10(-4) M) and nifedipine (10(-10), 10(-6) M) were without effect on overall platelet metabolism. On the other hand flunarizine (10(-4) M) and verapamil (10(-4) M) significantly reduced metabolism, while lower concentrations of these agents did not change heat production. 4. The thermogenic response occurred at concentrations of the calcium entry blockers that were much higher than those observed during therapy and the concentrations which relax human cerebral arteries in vitro.