Quadriceps weakness in knee osteoarthritis: the effect on pain and disability

OBJECTIVES—(1) To determine the importance of quadriceps strength, structural change, and psychological status in terms of knee pain in the community. (2) To determine the relative importance of quadriceps function, structural change, and psychological status with respect to disability in subjects with knee pain.
METHODS—300 men and women with pain and 300 controls without pain (aged 40-79) were seen. Isometric quadriceps strength (MVC) was measured and muscle activation was assessed by twitch superimposition. Disability (Western Ontario McMaster Osteoarthritis Index (WOMAC)) and anxiety and depression were assessed (Hospital Anxiety and Depression Index (HAD)). Radiographs were obtained of the tibiofemoral and patellofemoral joints and total score for osteophyte, narrowing, and sclerosis calculated for each knee.
RESULTS—Subjects with knee pain had lower voluntary quadriceps strength than those without pain (p<0.005). Quadriceps activation was also lower (p<0.005), but did not fully explain the reduction in strength. When analysed by multiple logistic regression: quadriceps strength (odds ratio 18.8, CI 4.8, 74.1 for MVC 10 kgF); depression (odds ratio 2.4, CI 1.0, 5.5 for HAD score8); and radiographic change (odds ratio 4.1, CI 1.9, 8.6 for radiographic score 4) were independently associated with pain. In those with knee pain, disability was independently associated with quadriceps strength (odds ratio 8.2, CI 1.5, 44.4 for MVC 10 kgF) and depression (odds ratio 6.2, CI 2.1, 18.0 for HAD score8); but not with radiographic score.
CONCLUSIONS—Quadriceps strength is strongly associated with knee pain and disability in the community, even when activation and psychological factors are taken into account. This has important therapeutic implications.

Keywords: quadriceps; osteoarthritis; pain; disability     

Correlation between radiographically diagnosed osteophytes and magnetic resonance detected cartilage defects in the patellofemoral joint

OBJECTIVE—To assess the correlation between radiographically diagnosed osteophytes in the axial and lateral view of the patellofemoral joint (PFJ) and (1) magnetic resonance (MR) detected cartilage defects in the same joint and (2) knee pain.
METHODS—Fifty seven pepole with chronic knee pain, (aged 41-58 years, mean 50 years) were examined with axial and lateral radiograms when standing of the right and the left PFJ. The presence and grade of osteophytes was assessed. On the same day, a MR examination was performed of the signal knee with proton density and T2 weighted turbo spin-echo sequences in the sagittal and axial view on a 1.0 T imager. Cartilage defects in the PFJ were noted. The subjects were questioned for current knee pain for each knee.
RESULTS—Osteophytes at the PFJ had a specificity varying between 59 and 100% and a positive predictive value between 74 and 100% for MR detected cartilage defects. The corresponding values for osteophytes at the lateral aspect of the femoral trochlea were both 100%. In PFJ with narrowing (<5 mm) osteophytes had a sensitivity and a positive predictive value of 90 and 95% respectively for MR detected cartilage defects, while in PFJ with non-narrowing (5 mm) the corresponding values were 75 and 65% and the specificity was 50%. A correlation (p<0.05) between osteophytes at the inferior pole of the patella and knee pain was found.
CONCLUSIONS—Osteophytes at the PFJ are associated with MR detected cartilage defects in the same joint. The relation was strong for osteophytes at the lateral femoral trochlea and in the PFJ with narrowing (<5 mm), but weak in the PFJ with non-narrowing (5 mm).

Keywords: knee; radiograms; osteoarthritis; osteophyte     

Discordance between pain and radiographic severity in knee osteoarthritis: Findings from quantitative sensory testing of central sensitization

Objective

Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures.

Methods

A total of 113 participants (66.7% women; mean ± SD age 61.05 ± 8.93 years) with knee OA participated in the study. Radiographic evidence of joint pathology was graded according to the Kellgren/Lawrence scale. Central sensitization was indexed through quantitative sensory testing, including heat and pressure–pain thresholds, tonic suprathreshold pain (cold pressor test), and repeated phasic suprathreshold mechanical and thermal pain. Subgroups were constructed by dichotomizing clinical knee pain scores (median split) and knee OA grade scores (grades 1–2 versus 3–4), resulting in 4 groups: low pain/low knee OA grade (n = 24), high pain/high knee OA grade (n = 32), low pain/high knee OA grade (n = 27), and high pain/low knee OA grade (n = 30).

Results

Multivariate analyses revealed significantly heightened pain sensitivity in the high pain/low knee OA grade group, while the low pain/high knee OA grade group was less pain‐sensitive. Group differences remained significant after adjusting for differences on psychosocial measures, as well as age, sex, and race.

Conclusion

The results suggest that central sensitization in knee OA is especially apparent among patients with reports of high levels of clinical pain in the absence of moderate‐to‐severe radiographic evidence of pathologic changes of knee OA.

     

Cytokine Gene Polymorphisms Associating With Severe Acute Graft-Versus-Host Disease in HLA-Identical Sibling Transplants

It is now well known that the initial phase of graft-versus-hostdisease (GVHD) involves cytokine release during preconditioning of therecipient of an allogeneic bone marrow transplant (BMT). Tumor necrosisfactor (TNF), in particular, has been implicated in pathologicaldamage and is released pretransplant due to irradiation and cytotoxicpreconditioning regimens. Interleukin-10 (IL-10), a naturalimmunosuppressant of TNF , may be involved in downregulation ofthese responses, which may be an individual patient-specific effect. Inthis study, we determined the genotype for polymorphisms associatedwith TNF and IL-10 in 80 potential allo-BMT recipients andcorrelated the genotype with the severity of GVHD in 49 patients forwhom clinical data relating to GVHD was available. The widely studiedTNF 308 polymorphism does not show any significantassociations, but the d3 homozygous allele of the TNFd microsatelliteis preferentially associated with grade III/IV GVHD (7 of 11 patients)compared with its occurrence in 8 of 38 patients with grade 0/II GVHD(P = .006). Alleles of the IL-10 1064 promoterregion microsatellite polymorphism that possess greater numbers ofdinucleotide (CA) repeats also significantly associate with more severeGVHD. This region has been demonstrated to be important in theregulation of the IL-10 promoter. Eighteen of 38 patients with grade0-II GVHD possessed alleles with greater numbers (12 or more) ofdinucleotide repeats, compared with 9 of 11 cases with grade III-IVGVHD (P < .02). Of the 38 patients with grade 0-II GVHD, 3 of38 had a both TNFd3/d3 and IL-10 (12-15) genotype,compared with 6 of 11 patients with grade III-IV GVHD (P < .001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P = .43 and .51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokineactivation during the pretransplant conditioning regimens, and theseresults are the first to suggest a genetic predisposition to thisimportant transplant-related complication.     

Reconstitution of adhesive properties of human platelets in liposomes carrying both recombinant glycoproteins Ia/IIa and Ib alpha under flow conditions: specific synergy of receptor-ligand interactions

Liposomes carrying both recombinant glycoprotein Ia/IIa (rGPIa/IIa)and Ib (rGPIb) (rGPIa/IIa-Ib-liposomes) instantaneously and irreversibly adhered to the collagen surface in the presence ofsoluble von Willebrand factor (VWF) at high shear rates, in markedcontrast with translocation of liposomes carrying rGPIb alone onthe VWF surface. In the absence of soluble VWF, the adhesion ofrGPIa/IIa-Ib-liposomes to the collagen surface decreased with increasing shear rates, similar to liposomes carrying rGPIa/IIa alone.While adhesion of liposomes with exofacial rGPIa/IIa and rGPIbdensities of 2.17 × 10³ and 1.00 × 10⁴molecules per particle, respectively, was efficient at high shear rates, reduction in rGPIb density to 5.27 × 10³molecules per particle resulted in decreased adhesion even in thepresence of soluble VWF. A 50% reduction in the exofacial rGPIa/IIadensity resulted in a marked decrease in the adhesive ability of theliposomes at all shear rates tested. The inhibitory effect of antibodyagainst GPIb (GUR83-35) on liposome adhesion was greater at highershear rates. Further, the anti-GPIa antibody (Gi9) inhibited liposomeadhesion more than GUR83-35 at all shear rates tested. These resultssuggest that the rGPIa/IIa-collagen interaction dominates the adhesionof rGPIa/IIa-Ib-liposomes to the collagen surface at low shearrates, while the rGPIa/IIa-collagen and rGPIb-VWF interactioncomplements each other, and they synergistically provide the neededfunctional integration required for liposome adhesion at high shearrates. This study thus has confirmed for the first time the proposedmechanisms of platelet adhesion to the collagen surface under flowconditions using the liposome system.     

Prospective Randomized Multicenter Clinical Trial on the Use of Interferon alpha -2a Plus Acitretin Versus Interferon alpha -2a Plus PUVA in Patients With Cutaneous T-Cell Lymphoma Stages I and II

Cutaneous T-cell lymphoma (CTCL) constitutes a malignantproliferative disease involving mostly CD4⁺ T cellsarising in the skin. Because of the lack of curative treatment options,interferons (IFN) have been introduced into the therapy of CTCL.Although effective even in advanced disease, response rates were about50% and the duration of response was short. To improve the results ofinterferon monotherapy, combinations of IFN with oral photochemotherapy(PUVA) or retinoids were investigated in nonrandomized trials showinghigher response rates. We have therefore conducted this prospectiverandomized multicenter trial to compare these two combinationtherapies, ie, IFN plus PUVA and IFN plus acitretin. IFN -2awas administered at 9 MU three times weekly subcutaneously in bothgroups, with lower increasing doses during the first week.Photochemotherapy was applied after oral intake of 8-methoxypsoralen(0.6 mg/kg body weight) 5× weekly during the first 4 weeks, 3×weekly from weeks 5 through 23, and 2× weekly from weeks 24 through48, with escalating doses beginning with 0.25 J/cm².Twenty-five milligrams of acitretin was administered daily during thefirst week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients wereevaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretingroup. With 70% complete remissions in the IFN+PUVA group, thistreatment was significantly superior to the IFN+acitretin group withonly 38.1% complete remissions. Time to response was significantlyshorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild tomoderate and did not differ significantly in both treatment groups.However, there were more adverse events leading to studydiscontinuation in the IFN+acitretin group. Based on these findings,we conclude that IFN plus oral photochemotherapy is superior toIFN plus acitretin, inducing more complete remissions in patientswith CTCL stages I and II.     

Ligand binding to integrin alpha(v)beta(3) requires tyrosine 178 in the alpha(v) subunit

Integrin _v3 has been implicatedin angiogenesis and other biological processes. However, theligand-binding sites in _v, a non-I-domain  subunit,remain to be identified. Recently in _IIb, the otherpartner of the ₃ subunit, several discontinuous residuesimportant for ligand binding were identified in the predicted loopsbetween repeats 2 and 3 (W3 4-1 loop) and within repeat 3 (W3 2-3 loop). Based on these findings, alanine-scanning mutagenesis in293 cells was used to investigate the role of these loops (cysteine [C]142-C155 and glycine [G]172-G181) of _v in ligandbinding. Wild-type _v3 was able to bindsoluble fibrinogen following integrin activation either by 0.5 mMmanganese dichloride (MnCl₂) or a mutation of₃ threonine (T)562 to asparagine. However, mutation oftyrosine (Y)178 to alanine in the predicted G172-G181 loop of_v abolished fibrinogen binding, and alanine (A)substitutions at adjacent residues phenylalanine (F)177 and tryptophan(W)179 had a similar effect. Cells expressing Y178A_valso failed to bind to immobilized fibrinogen. Moreover, the Y178Amutation abolished the binding of WOW-1 Fab, a monovalentligand-mimetic anti-_v3 antibody, and theexpression of ₃ ligand-induced binding sites (LIBS)induced by arginine-glycine-aspartic acid-tryptophan (RGDW). In sharpcontrast to the data obtained with _IIb, none of the mutations in the predicted W3 4-1 loop in _v impairedligand binding. These results implicate _v Y178 in ligandbinding to _v3, and they suggest thatthere are key structural differences in the adhesive ligand-bindingsites of _v3 and_IIb3.     

Aging-Associated Endothelial Dysfunction in Humans Is Reversed by

BackgroundConsidering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain.DesignWe cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age.ResultsIn 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: β=0.49; p = 0.0001, OAKHQOL pain: β=-0.46; p = 0.0002, WOMAC pain: β=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: β= 0.27; p = 0.02, OAKHQOL pain: β =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found.ConclusionSerum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.     

Pain in women with knee and/or hip osteoarthritis is related to systemic inflammation and to adipose tissue dysfunction: Cross-sectional results of the KHOALA cohort

BackgroundConsidering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain.DesignWe cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age.ResultsIn 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: β=0.49; p = 0.0001, OAKHQOL pain: β=-0.46; p = 0.0002, WOMAC pain: β=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: β= 0.27; p = 0.02, OAKHQOL pain: β =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found.ConclusionSerum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.     

History of knee surgery is associated with higher prevalence of neuropathic pain-like symptoms in patients with severe osteoarthritis of the knee

Objective

Neuropathic pain (NP) mechanisms contribute to the pain experience in osteoarthritis (OA). We aimed to characterise the factors that contribute to NP-like symptoms in knee OA patients.

Patients and methods

A total of 139 patients with knee OA were recruited from secondary care, and completed a nurse- administered PainDetect questionnaire (PD-Q ), a visual analogue scale (VAS) for pain intensity, and the Western Ontario MacMaster questionnaire (WOMAC). Cases with any previous history of total joint replacement were excluded.

Results

Almost 75% of patients had non-zero PD-Q scores, and 34% had PD-Q scores corresponding to possible NP. No association was seen between PD-Q scores and duration of symptoms, gender, and radiographic severity. Possible NP was strongly associated (p < 1 × 10⁻³) with worse quality of life scores, worse sleep scores, higher pain intensity, worse WOMAC pain, stiffness and function scores. A history of previous knee surgery (arthroscopy, ligament repair or meniscectomy) was strongly associated with possible NP (odds ratio [OR] = 6.86; 95% CI = 1.78–26.43; p < 0.005). This association remained statistically significant after adjustment for pain intensity (OR = 6.37; 95% CI = 1.55–26.11; p < 0.010) whereas an association between history of knee surgery and the other measures of pain was found to be mediated by PD-Q scores.

Conclusions

NP-like symptoms are highly prevalent in patients with clinically severe painful OA and are a significant contributor to decreased quality of life and higher pain intensity. The cross-sectional association with previous history of knee surgery suggests that some of the NP-like symptoms may result from nerve damage.     

Presentation of ovalbumin internalized via the immunoglobulin-A Fc receptor is enhanced through Fc receptor gamma-chain signaling

The mechanism of enhanced presentation of ovalbumin (OVA)internalized as immunoglobulin A (IgA)-OVA via the IgA Fc receptor (FcR) was analyzed by focusing on the role of the FcR-associated  chain. Comparison of B-cell transfectants expressing FcR plus wild-type (WT)  chain or  chain in which theimmunoreceptor tyrosine-based activation motif (ITAM) was altered bytyrosine mutation or substitution with the ITAM of FcRIIA showedthat signaling-competent ITAM was not required for endocytosis ofIgA-OVA. However, antigen presentation was impaired by ITAM changes.Signaling-competent -chain ITAM appeared necessary for transport ofligated FcR to a lamp-1⁺ late endocytic compartment forremodeling and/or activation of that compartment and also for efficientdegradation of IgA complexes. Moreover, FcR ligation also activatedefficient processing of nonreceptor-targeted antigen. Theresults suggest that -chain signaling activates the antigenprocessing compartment.     

Greater rates of cartilage loss in painful knees than in pain‐free knees after adjustment for radiographic disease stage: Data from the Osteoarthritis Initiative

Objective

To investigate whether rates of cartilage loss differ in knees with frequent baseline pain versus those without pain, after adjustment for radiographic osteoarthritis (OA) stage.

Methods

One knee in each of 718 Osteoarthritis Initiative participants was examined: 310 with calculated Kellgren/Lawrence (K/L) grade 2, 299 with calculated K/L grade 3, and 109 with calculated K/L grade 4. Twelve‐month change in (subregional) cartilage thickness was assessed by magnetic resonance imaging. Change in cartilage thickness in the central subregion of the weight‐bearing medial femoral condyle and ordered value 1 (OV1) were selected as primary end points. Frequent knee symptoms were defined as pain, aching, or stiffness on most days of at least 1 month during the previous year.

Results

The mean 12‐month rate of change in cartilage thickness in the central subregion of the medial femoral condyle was −12 μm (standardized response mean [SRM] −0.15) in knees without pain (n = 146), −27 μm (SRM −0.25) in those with infrequent pain (n = 255), and −54 μm (SRM −0.32) in those with frequent pain (n = 317). Rates differed significantly between frequently painful knees and pain‐free knees after adjustment for age, sex, body mass index, and calculated K/L grade (P = 0.011, R² = 2.6%, partial R² for frequent pain = 1.4%). Similar results were found in stratified samples of calculated K/L grade 2/calculated K/L grade 3 knees, and in analyses restricted to knees with consistent pain frequency between baseline and followup. OV1 results showed similar trends but were not significant.

Conclusion

Knees with frequent pain display greater rates of medial cartilage loss longitudinally than knees without pain, with or without adjustment or stratification for radiographic disease stage. Enrollment of participants with frequent knee pain in clinical trials can increase the observed rate of structural progression (i.e., cartilage loss) and sensitivity to change.

     

Association of pain with frequency and magnitude of knee loading in knee osteoarthritis

Objective

Although the relationship between pain and the magnitude of medial knee loading has been previously studied, the contribution of frequency of loading has not. The objective of this study was to determine whether the addition of loading frequency (steps/day) to loading magnitude (knee adduction moment [KAM] impulse) helps explain variance in knee pain in people with knee osteoarthritis (OA).

Methods

Participants were adults with symptomatic knee OA with radiographic signs in the medial knee compartment (n = 38, 10 women). Pain was measured using the pain subscale of the Knee Injury and Osteoarthritis Outcome Score. Participants wore an accelerometer for 1 week to determine the average number of steps/day. The external KAM impulse was calculated from 3‐dimensional gait analysis as participants ambulated at self‐selected speeds. Knee extensor strength was measured with an isokinetic dynamometer. Linear regression was used to examine the relationship between pain and steps/day after controlling for the KAM impulse, knee extensor strength, and body mass index (BMI).

Results

After controlling for BMI (R² = 0.02), knee extensor strength (R = 0.26, P < 0.05), and KAM impulse (R = 0.11, P < 0.05), steps/day contributed an additional 9% of variance in pain (P < 0.05). This model accounted for a total of 49% of the variance in pain (F[4,33] = 7.77, P < 0.05).

Conclusion

Increased knee loading frequency and magnitude were associated with increased pain. Objective measures of loading frequency should be considered when investigating the incidence and progression of knee OA.     

Combined glucosamine and chondroitin sulfate provides functional and structural benefit in the anterior cruciate ligament transection model

Evidence that combined glucosamine sulfate and chondroitin sulfate (Gluchon) or isolated glucosamine (Glu) modifies joint damage in osteoarthritis (OA) is still lacking. We studied joint pain and cartilage damage using the anterior cruciate ligament transection (ACLT) model. Wistar rats were subjected to ACLT of the right knee (OA) or sham operation. Groups received either Glu (500 mg/kg), Gluchon (500 mg/kg glucosamine +400 mg/kg chondroitin) or vehicle (non-treated—NT) per os starting 7 days prior to ACLT until sacrifice at 70 days. Joint pain was evaluated daily using the rat-knee joint articular incapacitation test. Structural joint damage was assessed using histology and biochemistry as the chondroitin sulfate (CS) content of cartilage by densitometry (microgram per milligram dried cartilage), comparing to standard CS. The molar weight (Mw) of the CS samples, used as a qualitative biochemical parameter, was obtained by comparing their relative mobility on a polyacrylamide gel electrophoresis to standard CS. Gluchon, but not Glu, significantly reduced joint pain (P < 0.05) compared to NT. There was an increase in CS content in the OA group (77.7 ± 8.3 μg/mg) compared to sham (53.5 ± 11.2 μg/mg) (P < 0.05). The CS from OA samples had higher Mw compared to sham (P < 0.05). Gluchon administration significantly reversed both the increases in CS content (54.4 ± 12.1 μg/mg) and Mw as compared to NT. Isolated Glu decreased CS content though not reaching statistical significance. Cartilage histology alterations were also significantly prevented by Gluchon administration. Gluchon provides clinical (analgesia) and structural benefits in the ACLT model. This is the first demonstration that biochemical alterations occurring in parallel to histological damage in OA are prevented by Gluchon administration.     

When it hurts,a positive attitude may help: association of positive affect with daily walking in knee osteoarthritis. Results from a multicenter longitudinal cohort study

Objective

While depressive symptoms and knee pain are independently known to impede daily walking in older adults, it is unknown whether positive affect promotes daily walking. This study investigated this association among adults with knee osteoarthritis (OA) and examined whether knee pain modified this association.

Methods

This study is a cross‐sectional analysis of the Multicenter Osteoarthritis Study. We included 1,018 participants (mean ± SD age 63.1 ± 7.8 years, 60% women) who had radiographic knee OA and had worn a StepWatch monitor to record their number of steps per day. High and low positive affect and depressive symptoms were based on the Center for Epidemiologic Studies Depression Scale. Knee pain was categorized as present in respondents who reported pain on most days at both a clinic visit and a telephone screening.

Results

Compared to respondents with low positive affect (27% of all respondents), those with high positive affect (63%) walked a similar number of steps per day, while those with depressive symptoms (10%) walked less (adjusted β ?32.6 [95% confidence interval (95% CI) ?458.9, 393.8] and ?579.1 [95% CI ?1,274.9, 116.7], respectively). There was a statistically significant interaction of positive affect by knee pain (P = 0.0045). Among the respondents with knee pain (39%), those with high positive affect walked significantly more steps per day (adjusted β 711.0 [95% CI 55.1, 1,366.9]) than those with low positive affect.

Conclusion

High positive affect was associated with more daily walking among adults with painful knee OA. Positive affect may be an important psychological factor to consider for promoting physical activity among people with painful knee OA.

     

Relationship Between Knee Pain and Infrapatellar Fat Pad Morphology: A Within‐ and Between‐Person Analysis From the Osteoarthritis Initiative

Objective

Inflammation is known to be strongly associated with knee pain in osteoarthritis. The infrapatellar fat pad represents a potential source of proinflammatory cytokines. Yet the relationship between infrapatellar fat pad morphology and osteoarthritis symptoms is unclear.

Methods

Here we investigate quantitative imaging parameters of infrapatellar fat pad morphology between painful versus contralateral pain‐free legs of subjects with unilateral knee pain and patients with chronic knee pain versus those of matched pain‐free control subjects. A total of 46 subjects with strictly unilateral frequent knee pain and bilateral radiographic osteoarthritis (Kellgren/Lawrence grade 2/3) were drawn from the Osteoarthritis Initiative. Further, 43 subjects with chronic knee pain over 4 years and 43 matched pain‐free controls without pain over this period were studied. Infrapatellar fat pad morphology (volume, surface area, and depth) was determined by manual segmentation of sagittal magnetic resonance images.

Results

No significant differences in infrapatellar fat pad morphology were observed between painful versus painless knees of persons with strictly unilateral knee pain (mean difference ?0.7% (95% confidence interval [95% CI] ?0.6, 0.9; P = 0.64) or between chronically painful knees versus matched painless controls (?2.1% [95% CI ?2.2, 1.1]; P = 0.51).

Conclusion

Independent of the ambiguous role of the infrapatellar fat pad in knee osteoarthritis (a potential source of proinflammatory cytokines or a mechanical shock absorber), the size of the infrapatellar fat pad does not appear to be related to knee pain.

     

Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population

OBJECTIVE—To report the mortality of left ventricular systolic dysfunction (LVD), assessed objectively by echocardiography, and its association with natriuretic peptide hormones in a random sample of 1640 men and women aged 25-74 years from a geographical, urban population.
METHODS—Left ventricular function was measured by echocardiography in 1640 attendees studied in 1992-3. LVD was defined as a left ventricular ejection fraction (LVEF)  30%. Plasma concentrations of N-terminal atrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP) were measured by standard radioimmunoassays. Mortality was documented at four years.
RESULTS—The four year all cause mortality rate in the whole cohort was 4.9% (80 deaths). It was 21% (nine deaths) in those with an LVEF  30% and 4% in those whose LVEF was > 30% (p < 0.001). The median (interquartile range) BNP concentration in those who died was 16.9 pg/ml (8.8-27) and 7.8 pg/ml (3.4-13) in survivors (p < 0.0001). Similarly, N-ANP had a median concentration of 2.35 ng/ml (1.32-3.36) in those with a fatal outcome and 1.27 ng/ml (0.9-2.0) in those alive at four years (p < 0.0001). Subjects with an LVEF  40% also had a significant mortality rate of 17% if they also had a BNP concentration  17.9 pg/ml compared with 6.8% if their BNP was below this concentration (p = 0.013). Multivariate analysis revealed the independent predictors of four year all cause mortality to be increasing age (p < 0.001), a BNP concentration  17.9 pg/ml (p = 0.006), the presence of ischaemic heart disease (p = 0.03), and male sex (p = 0.04).
CONCLUSIONS—LVD is associated with a considerable mortality rate in this population. BNP also independently predicts outcome. In addition to its role as a diagnostic aid in chronic heart failure and LVD, it provides prognostic information and clarifies the meaning of a given degree of LVD.


Keywords: epidemiology; left ventricular dysfunction; natriuretic peptides     

Dynamic Effects of Depressive Symptoms on Osteoarthritis Knee Pain

Objective

To estimate the dynamic causal effects of depressive symptoms on osteoarthritis (OA) knee pain.

Methods

Marginal structural models were used to examine dynamic associations between depressive symptoms and pain over 48 months among older adults (n = 2,287) with radiographic knee OA (Kellgren/Lawrence grade 2 or 3) in the Osteoarthritis Initiative. Depressive symptoms at each annual visit were assessed (threshold ≥16) using the Center for Epidemiologic Studies Depression Scale. OA knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, rescaled to range from 0 to 100.

Results

Depressive symptoms at each visit were generally not associated with greater OA knee pain at subsequent time points. Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients ranged from 1.78 (95% confidence interval [95% CI] ?0.73, 4.30) to 2.58 (95% CI 0.23, 4.93) within the first and fourth years, and the depressive symptoms by time interaction were not statistically significant (P = 0.94). However, there was a statistically significant dose‐response relationship between the persistence of depressive symptoms and OA knee pain severity (P = 0.002). Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients were 0.89 (95% CI ?0.17, 1.96) for 1 visit with depressive symptoms, 2.35 (95% CI 0.64, 4.06) for 2 visits with depressive symptoms, and 3.57 (95% CI 0.43, 6.71) for 3 visits with depressive symptoms.

Conclusion

The causal effect of depressive symptoms on OA knee pain does not change over time, but pain severity significantly increases with the persistence of depressed mood.

     

Variable protection of beta 3-integrin--deficient mice from thrombosis initiated by different mechanisms

Platelet integrin IIb3 (GPIIb/IIIa) plays a central role inthe initiation of arterial thrombosis, but its contribution todisseminated microvascular thrombosis is less well defined. Therefore,wild-type mice (3^+/+), 3-integrin-deficient mice(3^/), and wild-type mice treated with a hamstermonoclonal antibody (1B5) that blocks murine IIb3 function weretested in models of large-vessel and microvascular thrombosis. In thelarge-vessel model, ferric chloride was used to injure the carotidartery, and the time to thrombosis was measured. In 3^+/+mice, the median time to occlusion was 6.7 minutes, whereas occlusion did not occur in any of the 3^/ mice tested(P < .001). Fab and F(ab')₂ fragments of1B5 increased the median time to occlusion. To initiate systemicintravascular thrombosis, prothrombotic agents were administeredintravenously, and platelet thrombus formation was monitored by thedecrease in circulating platelet count. Three minutes after theinjection of adenosine diphosphate (ADP), collagen + epinephrine,or tissue factor, the platelet counts in 3^+/+ micedecreased by 289, 424, and 429 × 10³/µL, respectively.3^/ mice and wild-type mice pretreated with 1B5 Fab(1 mg/kg, IP) were nearly completely protected from the effects of ADP.In contrast, 3^/ mice were only partially protectedfrom the effects of collagen + epinephrine and minimally protectedfrom the effects of tissue factor. In all cases, less fibrin becamedeposited in the lungs of 3^/ mice than in wild-typemice. These results suggest that though IIb3 plays adominant role in large-vessel thrombosis, it plays a variable role insystemic intravascular thrombosis.     

Eosinophil Tethering to Interleukin-4-Activated Endothelial Cells Requires Both P-Selectin and Vascular Cell Adhesion Molecule-1

We examined the mechanisms used by eosinophils to tether andaccumulate on interleukin-4 (IL-4)-stimulated human umbilical veinendothelial cells (HUVECs) under flow conditions. As previously reported, HUVECs treated for 24 hours with 20 ng/mL IL-4 had increased expression of P-selectin and vascular cell adhesion molecule-1 (VCAM-1)but not E-selectin. We found that eosinophils tethered and rolled onIL-4-stimulated HUVECs at physiologic shear stresses. Eosinophilrolling was quickly followed by firm adhesion. Treatment with either ananti-P-selectin monoclonal antibody (MoAb) or an anti-VCAM-1 MoAbdecreased both eosinophil tethering and accumulation at 2 dyn/cm². VCAM-1 interacts with 4-integrins expressed oneosinophils. We found that an anti-4-integrin MoAb also blockedeosinophil tethering and accumulation at 2 dyn/cm². None ofthese MoAbs alone had an impact on eosinophil accumulation at lowershear stresses, but when either an anti-VCAM-1 or an anti-4-integrin MoAb was used in combination with ananti-P-selectin MoAb, all eosinophil tethering and accumulation onIL-4-stimulated HUVECs were blocked. This was true at both high andlow shear stresses. These data show that both P-selectin and VCAM-1 are required to tether eosinophils at high shear stresses, but at low shearstresses these adhesion proteins can act independently to recruiteosinophils to IL-4-stimulated HUVECs.