Pain and functional trajectories in symptomatic knee osteoarthritis over up to 12 weeks of exercise exposure.

OBJECTIVE: Exercise is the recommended treatment for knee osteoarthritis (OA). However, heterogeneous patterns in treatment response are poorly understood. Our purpose was to identify pain and functional trajectories from exercise interventions in knee OA, and to determine their association with baseline factors. METHODS: Prospective cohort of 171 participants (mean age 61 years; BMI 32 kg/m2, 71% female; 57% white) with symptomatic knee OA from a randomized trial comparing 12-week Tai Chi and Physical Therapy. We analyzed weekly Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain (0-500) and function (0-1700) scores using group-based trajectory models. Associations between baseline factors and trajectories were examined using multinomial logistic regression. RESULTS: We identified four pain trajectories: Lower-Early Improvement (43%), Moderate-Early Improvement (32%), Higher-Delayed Improvement (15%), and Higher-No Improvement (10%). We found similar trajectories for function, except that the lower function trajectories diverged into gradual (12%) or delayed-improvement (15%). Compared with the Lower-Early Improvement pain trajectory, moderate and higher trajectories were associated with poorer physical and psychosocial health. A similar pattern of associations were found among the function trajectories. CONCLUSIONS: We found four distinct trajectories for pain and function over up to 12-weeks of exercise interventions. While most participants experienced improvements over a short-term exposure, subgroups with greater baseline pain/physical disability had either gradual, delayed, or no improvements. These findings help disentangle the heterogeneity of treatment response and may advance patient-centered care in knee OA.

Mindfulness is associated with psychological health and moderates pain in knee osteoarthritis.

OBJECTIVE: Previous studies suggest that higher mindfulness is associated with less pain and depression. However, the role of mindfulness has never been studied in knee osteoarthritis (OA). We evaluate the relationships between mindfulness and pain, psychological symptoms, and quality of life in knee OA. METHOD: We performed a secondary analysis of baseline data from our randomized comparative trial in participants with knee OA. Mindfulness was assessed using the Five Facet Mindfulness Questionnaire (FFMQ). We measured pain, physical function, quality of life, depression, stress, and self-efficacy with commonly-used patient-reported measures. Simple and multivariable regression models were utilized to assess associations between mindfulness and health outcomes. We further tested whether mindfulness moderated the pain-psychological outcome associations. RESULTS: Eighty patients were enrolled (60.3 ± 10.3 years; 76.3% female, body mass index: 33.0 ± 7.1 kg/m2). Total mindfulness score was associated with mental (beta = 1.31, 95% CI: 0.68, 1.95) and physical (beta = 0.69, 95% CI:0.06, 1.31) component quality of life, self-efficacy (beta = 0.22, 95% CI:0.07, 0.37), depression (beta = -1.15, 95% CI:-1.77, -0.54), and stress (beta = -1.07, 95% CI:-1.53, -0.60). Of the five facets, the Describing, Acting-with-Awareness, and Non-judging mindfulness facets had the most associations with psychological health. No significant association was found between mindfulness and pain or function (P = 0.08-0.24). However, we found that mindfulness moderated the effect of pain on stress (P = 0.02). CONCLUSION: Mindfulness is associated with depression, stress, self-efficacy, and quality of life among knee OA patients. Mindfulness also moderates the influence of pain on stress, which suggests that mindfulness may alter the way one copes with pain. Future studies examining the benefits of mind-body therapy, designed to increase mindfulness, for patients with OA are warranted.

The relationship of tibial bone perfusion to pain in knee osteoarthritis.

OBJECTIVE: To confirm altered perfusion within tibial bone marrow lesions (BMLs) and improve our understanding on the relationship between BMLs and pain in knee osteoarthritis (OA). METHODS: Participants with moderate to severe knee OA were recruited and pain was assessed using the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Subchondral tibial BMLs were identified and graded on magnetic resonance imaging (MRI) proton density-weighted (PDW) fat suppressed images. A pharmacokinetic model was used to analyze perfusion parameters on dynamic contrast enhanced (DCE) MRI which represent transfer rates in and out of the BMLs. The relation between perfusion and pain was evaluated using multivariable linear regression after adjustment for BML grade, age, gender and body mass index (BMI). RESULTS: There were 37 participants (mean age 64.9 years, range 46-86) with radiographic Kellgren and Lawrence grades of 3 and 4 in the study knee; 75.6% had BMLs that were classified grades 1 and 2. The mean WOMAC pain score was 10.3 (0-20 scale). There was a significant correlation between BML K(el) (rate of contrast elimination) and BML grade (P = 0.001 univariate, P = 0.002 multivariate analyses), although we did not demonstrate any significant multivariate association between BML perfusion and pain. We also found an inverse relationship between pain at sleep and BML grade (P < 0.05). CONCLUSIONS: The absence of any significant association between bone perfusion and pain implies that the relationship of tibial BMLs to pain in OA is still incompletely understood. BMLs are just one component of the whole knee joint and are formed from various causes, all of which interact and collectively contribute to the genesis of pain in OA.

The effect of a patellar brace on three-dimensional patellar kinematics in patients with lateral patellofemoral osteoarthritis.

OBJECTIVE: Patellar bracing is a mechanical treatment strategy for patellofemoral osteoarthritis (OA) that aims to unload the lateral compartment of the joint by translating the patella medially. Our objective was to determine whether a patellar brace can correct patellar kinematics in patients with patellofemoral OA. DESIGN: We assessed the effect of a patellar brace on three-dimensional patellar kinematics (flexion, spin and tilt; proximal, lateral and anterior translation) at sequential, static knee postures, using a validated magnetic resonance imaging (MRI)-based method, in 19 patients with radiographic lateral patellofemoral OA. Differences in kinematics between unbraced and braced conditions were assessed in the unloaded and loaded knee (15% bodyweight load) using hierarchical linear random-effects models. Random slope and quadratic terms were included in the model when significant (P<0.05). RESULTS: Bracing with load caused the patellae to translate 0.46 mm medially (P<0.001), tilt 1.17° medially (P<0.001), spin 0.62° externally (P=0.012) and translate 1.09 mm distally (P<0.001) and 0.47 mm anteriorly (P<0.001) over the range of knee flexion angles studied. Bracing also caused the patellae to extend in early angles of knee flexion (P<0.001). The brace caused similar trends for the unloaded condition, though magnitudes of the changes varied. CONCLUSION: Bracing changed patellar kinematics, but these changes did not appear large enough to be clinically meaningful because no reduction in pain was observed in the parent study.

Knee alignment differences between Chinese and Caucasian subjects without osteoarthritis.

OBJECTIVE: Despite the lower prevalence of obesity (a known risk factor for osteoarthritis (OA)), the prevalence of lateral tibiofemoral OA is higher in Chinese communities compared with Caucasian communities. One potential explanation is the difference in knee alignment between the two populations. We measured various knee alignment indices among Chinese and Caucasians and assessed whether these indices were different between the two racial groups. METHODS: We selected participants from the Framingham Osteoarthritis Study (FOA) and the Beijing Osteoarthritis Study (BOA), all without knee OA (Kellgren & Lawrence grade <2). Bilateral, fully extended anteroposterior knee radiographs were measured for the following angles in both knees: the anatomic axis (AA), the condylar angle (CA), the tibial plateau angle and the condylar-plateau angle (CP). We compared the mean of each measurement between the two racial groups adjusting for age and body mass index using linear regression and stratified by sex. RESULTS: The mean AA, CA and CP were significantly different in the BOA compared with the FOA. For women, the mean AA and CA were significantly more valgus in BOA subjects, while in men, the mean AA and CP were more valgus in BOA subjects. CONCLUSIONS: There are significant differences in knee morphology between Chinese and Caucasian cohorts, which result in a more valgus alignment of the distal femur in Chinese. This would serve to shift the mechanical loading towards the lateral compartment, and provide a possible explanation why Chinese have a higher prevalence of lateral tibiofemoral OA.

Mutant yields and mutational spectra of the heterocyclic amines MeIQ and PhIP at the S1 locus of human-hamster AL cells with activation by chick embryo liver (CELC) co-cultures.

Cooking meat and fish at high temperature creates heterocyclic amines (HA) including 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Several HA are mutagens in the Ames' S9/Salmonella assay. While PhIP is a substantial Ames' test mutagen, it is 1000-fold less active than the extraordinarily potent MeIQ. In contrast, MeIQ is significantly less mutagenic than PhIP in several mammalian cell assays, especially in repair-deficient Chinese hamster ovary (CHO) cells. HA are suspect human carcinogens on the basis of (i) epidemiological evidence, (ii) induction of tumors in rodents and monkeys, (iii) DNA adduct formation and (iv) mutagenic capacity. In this study, MeIQ and PhIP were significant mutagens at the S1 locus of co-cultivated human/hamster hybrid AL cells following metabolic activation by beta-napthoflavone (betaNF)-induced chick embryonic liver cultures (CELC). MeIQ was more mutagenic than PhIP in the CELC+AL cell assay. The mutant response curves increase with dose and then plateau (PhIP), or decrease (MeIQ). The inflections in these response curves coincide with dose-dependent decreases in cytochrome CYP1A1 activity. Molecular analysis of S1- mutants indicates that a substantial fraction, >65%, of the mutations induced by PhIP are deletions of 4.2 to 133 (Mbp); half are larger than 21 Mbp. Mutations induced by MeIQ were smaller, most (56%) being less than 5.7 Mbp. When appropriate metabolic activation is combined with a target locus, which can detect both small and large chromosomal mutations, both MeIQ and PhIP are significant mutagens and clastogens in repair proficient mammalian cells.

Gamma-ray mutagenesis measurement in mammalian cells.

Application of conventional in vitro mutagenesis testing has so far failed to result in marked reduction of the total incidence of cancer. At least part of the reason may lie in the frequent use of a cell target too small to yield adequate sensitivity, and in failure to take into account the effects of cell killing in the assessment of mutagenic action. A single theoretical analysis fits the results of experimental data on gamma-irradiation applied to single marker gene testing in bacteria and to cytogenetic analysis of irradiated mammalian cells, and permits determination of the mean mutagenic dose, DoM, without complication due to cell killing. Cytogenetic monitoring of human lymphocytes which can detect mutagenic effects of gamma-radiation down to doses of < 0.1 Gy (10 rad) will also furnish an estimate of repair effectiveness at these low levels and may well be a useful tool in a program for prevention of cancer and other genetic disease.

Heat protection by deuterium oxide of heat sensitive and wild-type Chinese hamster ovary cells.

The ability of deuterium oxide (D2O) to protect a heat-sensitive and thermotolerance-impaired Chinese hamster ovary (CHO) mutant cell line, HS-36 (Harvey and Bedford 1988), from heat killing was examined and compared to the parent CHO 10B cell line (WT). Both non-thermotolerant (NT) and thermotolerant (TT) G1 populations were examined. D2O differentially protected the NT cell lines from heat killing, with thermal protection ratios (D0) of 2 x 5 and 4 x 3 for HS-36 and WT cells, respectively. D2O provided additional protection to TT cells, but now protected the TT HS-36 cells more than the TT WT cells when the thermal protection ratios of TT cells are compared with those of NT cells (1.15 versus 0.82). The differential protection from heat of the mutant and wild-type lines by D2O may be useful in studies of induced lesions in proteinaceous cellular systems (e.g. the nuclear matrix, cytoskeleton and plasma membrane) using these two paired cell lines.

Thermal response of synchronous CHO cells with different shapes.

This study examines the differential heat sensitivity of rounded suspension cells versus flattened monolayer cells. G1 populations of two different Chinese hamster ovary lines were used to eliminate possible cell cycle artifacts. The cell populations were heated at 43 and 45 degrees C. In all cases, cells treated in suspension were less sensitive to heat killing than cells treated as monolayers.

Radiobiology of alpha particles. IV. Cell inactivation by alpha particles of energies 0.4-3.5 MeV.

In this report the effectiveness of low-energy alpha particles in the range 0.4 to 3.5 MeV for cell killing is investigated. Four cell lines of different nuclear dimensions (AG1522, C3H 10T1/2, CHO-10B, and HS-23) are studied. Monte Carlo simulations are carried out to interpret the experimental results. They are presented as a function of dose to the nucleus, the total track length of alpha particles in the nucleus, and other parameters. It is found that the effectiveness of alpha particles for cell killing decreases with decreasing alpha-particle energy. The maximum RBE value is found to extend to LET values as high as 180 keV/microns. Although the LET might be the same, the effectiveness of alpha particles for cell killing is higher in the ascending part of the Bragg curve compared to descending part of the Bragg curve. The terminal tracks of alpha particles are observed to be less effective for cell killing.

Radiobiology of alpha particles. II. Dosimetry of low-energy alpha particles using parallel-plate ionization chambers and a surface barrier detector.

Three small parallel-plate ionization chambers were developed for measuring dose rates, of primarily low-energy alpha particles in the energy range 0.4-3.5 MeV, at a defined cell-Mylar interface. Spectral energy distributions of these alpha particles were also measured at the same position using a specially designed small-area silicon surface barrier detector. Dose rates were derived from the spectral distributions and compared with those derived from the ionization chambers. Different alpha-particle energies were obtained using a 144-MBq 238Pu collimated source and a variety of Mylar moderator foils of different thicknesses. These measurements, extended to mean alpha-particle energies as low as 0.4 MeV, will enable us to correlate radiobiological data with effects of alpha particles terminating in different regions of cell nuclei.

Wood duck hatch date: relationship to pairing chronology, plasma luteinizing hormone, and steroid hormones during autumn and winter.

We examined variation in courtship activity and hormone levels of male and female wood ducks (Aix sponsa) in relation to hatch date. Young wood ducks were assigned in groups of 8 (4 males and 4 females) to 4 experimental pens; 2 pens contained early-hatched ducks (3-12 April) and 2 pens contained late-hatched ducks (7-16 June). Courtship behaviors occurred less frequently in October and November than in December and January-February for both early- and late-hatched groups. Early-hatched wood ducks participated in courtship more frequently and formed pair bonds sooner than late-hatched individuals. Testosterone (T) and androstenedione (AD) levels of males did not differ between treatment groups; however, average levels of luteinizing hormone (LH) were greater for early-hatched males. Differences in LH occurred in 2 of 12 samples (6 October and 3 November); otherwise, LH did not vary by treatment. Levels of T and LH in males varied temporally, but there was no significant temporal variation in AE levels. Temporal variation in hormone levels was similar for early- and late-hatched males. Estradiol (E), progesterone (P), and LH levels of females did not differ between treatment groups. There was temporal variation in levels of E and LH, but not of P; this variation was similar for early- and late-hatched females. These data indicate that behavioral differences occurring temporally and between early- and late-hatched wood ducks were not related to corresponding differences in hormone levels.

Alterations in specific and general protein synthesis after heat shock in heat-sensitive mutants of CHO cells and their wild-type counterparts.

The rates of general and specific protein synthesis were studied in two heat-sensitive strains of CHO cells (Harvey and Bedford, Radiat. Res. 113, 526-542, 1988), both of which show a reduced ability to develop thermotolerance following an initial 45 degrees C heat shock. After various labeling periods with [35S]methionine, wild-type and mutant labeled proteins were separated by one- and two-dimensional polyacrylamide gel electrophoresis. Autoradiograms showed differences in levels of synthesis of several proteins after a 45 degrees C heat shock. In particular, these were in the hsp-70 group referred to as hsp-70a, b, and c, having molecular weights of 76, 73, and 72 kDa and isoelectric focusing pH values of 5.7, 5.5, and 5.7, respectively. Of particular note were changes in the hsp-70c region of the autoradiograms. We found that there was perhaps a low level of synthesis of hsp-70c in unheated wild-type cells but none was detectable in the mutant lines. After an isosurvival (approximately 10%) pulse of 45 degrees C heat there was a gradual increase in the synthesis of hsp-70c for wild-type but a smaller increase for the heat-sensitive strain 36 (HS-36) cells. In contrast, for HS-23 cells there was a very large initial increase by 5 to 7 h after the heat pulse and then a rapid decrease to undetectable levels by 11 to 13 h. The inhibition and recovery of general protein synthesis for both mutant and wild-type cells was also measured following various heat treatments at 45 degrees C. We observed that inhibition and resumption to a "normal" rate of protein synthesis for HS-23 cells paralleled the same response observed for the wild-type 10B2 cells. In sharp contrast, the time for recovery from the inhibition of protein synthesis for HS-36 cells was severely reduced for all heating times tested. Our results show that the period of delay before resumption of protein synthesis after heating does not always correlate with heat sensitivity or the degree of thermotolerance development. Several explanations for these observations are possible. One is that while synthesis of certain heat-shock proteins may indeed be responsible for the development of thermotolerance, the timing of the synthesis of these proteins in relation to the period of inhibition of general protein synthesis is crucial to such development.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiobiology of alpha particles. I. Exposure system and dosimetry.

A 238Pu alpha-particle exposure apparatus was designed and constructed for use in radiobiological studies with cultured cell systems. The system provides a wide dynamic range of absorbed doses and a uniform radiation field. Average dose rate in air was measured with a small-volume ionization chamber. Estimates of dose rate at the cell surface were obtained from measurements taken with a silicon surface barrier detector. Particle fluence uniformity and fluence rate were measured using track etch procedures. The design and dosimetric characterization of the apparatus are discussed.

Protein glycosylation in heat-sensitive and thermotolerance-deficient mutants of Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells are capable of developing a high degree of thermotolerance in response to appropriate heat conditioning. In this study we examined the relationship between thermotolerance development and protein glycosylation using four sublines of CHO cells. Two of these CHO sublines are characterized by an increased heat sensitivity and impaired cellular capacity for thermotolerance development. The data show that thermotolerance development after heat conditioning in the heat-sensitive, thermotolerance-deficient mutants was accompanied by reduced labeling of a Mr 50,000 glycoprotein (GP50), in both soluble and insoluble cell fractions. Similarly, activation of UDP-N-acetylgalactosaminyltransferase (Gal-NAcT) after hyperthermia was almost completely abolished in these cell lines. Both of these endpoints have been correlated previously with thermotolerance expression. The data are consistent with the glycosylation hypothesis that attributes increased heat resistance of thermotolerant cells, at least in part, to enhanced glycosylation and accumulation of endogenous glycoproteins, such as GP50.

Radiobiology of ultrasoft X rays. IV. Flat and round-shaped hamster cells (CHO-10B, HS-23).

The results reported earlier in this series indicated that the relative biological effectiveness (RBE) of ultrasoft X rays decreases with decreasing cell thickness, approaching unity for the thinnest cells used, plateau-phase human skin fibroblasts (HSF). The possible dependence of RBE on the configuration of the cell nucleus is investigated further in this paper using two CHO cell lines that attach well and have similar intrinsic radiosensitivities to 60Co gamma rays. One of the lines forms monolayers similar to V79 cells, while the other remains more spherical during growth. We find an increasing RBE with decreasing X-ray energy for both of these cell lines, consistent with our results using V79 cells. Also consistent with our results obtained with 10T1/2 and HSF cells, we find an increasing RBE with increasing cell thickness. The possible dependence of RBE on radiosensitivity and the use of the concept of mean dose for ultrasoft X rays is discussed.

Isolation and characterization of heat-sensitive, thermotolerant defective mutants of CHO cells.

A replica plating technique was utilized to isolate stable CHO cell mutants that are heat-sensitive and have altered capacities to develop thermotolerance. From a mutagen (EMS) treated population of CHO cells, two strains were isolated. One (HS-36) shows a greatly reduced ability to develop thermotolerance following an initial 45.0 degrees C heat shock. The other (HS-23) also shows a greatly reduced thermotolerance development following a short 45.0 degrees C induction dose, but a greater thermotolerance development following longer 45.0 degrees C induction doses. The dose-survival response following single-dose 45.0 degrees C heating of HS-23 cells suggests the presence of a resistant subpopulation which is not due to contamination from, or reversion to, wild-type cells. Both strains have unique morphological characteristics. Spheroids develop in the central portion of HS-36 colonies, though cells in monolayers are indistinguishable from wild-type parental cells. HS-23 cells grow in firmly attached monolayers, but more than 95% maintain a "rounded" morphology. The remainder show a "flattened" morphology typical of CHO cells. Both strains have parental CHO characteristics as determined by chromosome number, population doubling times, and survival responses to UV light and to gamma rays. Each has maintained its heat-sensitive and altered thermotolerance phenotype for a period of over 6 months in continuous log-phase culture.