The wound healing effect of local leukocyte platelet-rich plasma after total hip arthroplasty: A randomized controlled trial.

Rapid wound closure is important after arthroplasty procedures to prevent postoperative complications. Platelets are rich in growth factors and leukocytes contribute to innate immunity. We hypothesized that topical leukocyte platelet-rich plasma (L-PRP) derived from the blood of patients would be beneficial to wound healing. In this randomized controlled trial, patients subjected to elective total hip arthroplasty (THA) were assigned by concealed allocation either L-PRP application onto the sutured fascia or no application (control) after the THA intervention. In addition, all patients received 1.5 g protein/kg, 5 g L-arginine, 500 mg vitamin C and 44 mg zinc daily over the 4-week postoperative period to obtain optimal nutrition. The primary endpoint was complete healing of the skin incision. The secondary endpoints were blood transfusions, length of hospital stay, pain and wound infections. Sixteen patients in the L-PRP group and 17 patients in the control group completed the trial. L-PRP treatment accelerated complete wound healing after 3 weeks (seven in the L-PRP group vs. zero in the control group, p = 0.003) and after 4 weeks (12 in the L-PRP group vs. six in the control group, p = 0.037). No postoperative superficial wound infections occurred within 4 weeks, and there were no significant differences in the other secondary outcomes. L-PRP generated in 10 sex-matched healthy volunteers revealed increased concentrations of platelets (5.8-fold) and leukocytes (2.3-fold) compared with those in whole blood. Furthermore, the concentration of keratinocyte mitogen epidermal growth factor in L-PRP (380 ± 130 pg/ml, mean ± SD) was higher (p < 0.001) than that in serum (130 ± 26 pg/ml). In conclusion, a single intraoperative local application of L-PRP promoted wound healing after THA, possibly mediated by EGF receptor agonists.

False profile view is independently associated with serum metal levels in patients with metal-on-metal hip arthroplasty.

PURPOSE: Elevated levels of serum metal ions can be found in some patients with metal-on-metal (MoM) hip replacements. This study seeks to identify whether there is a significant association between the contact patch to rim distance (CPRD) and the anterior center edge angle (ACEA), respectively, and serum cobalt (Co) and chromium (Cr) levels in patients treated with unilateral MoM hip replacements by using standing anteroposterior and false profile view radiographs. METHODS: This is a retrospective analysis on 53 patients with either unilateral ReCap or M2a-Magnum MoM hip replacements operated in 2006 or 2007. Univariate linear regression and multivariable linear regression (MLR) analyses were performed using the CPRD and ACEA along with risk factors for elevated serum levels of Co and Cr previously suggested in the literature as explanatory variables. Serum Co and Cr were measured using inductively coupled plasma mass spectrometry. RESULTS: The MLR model showed that the same three variables (gender, CPRD and ACEA) were significantly associated with serum levels of both Co and Cr explaining approximately half of the variation. A univariate analysis showed a polynomial association between both anteversion angle and the ACEA with serum levels of Co and Cr. The vertex of the polynomial function was located at approximately 20° and 40°, respectively. CONCLUSION: Gender, CPRD and ACEA are independently associated with serum levels of Co and Cr. Both ACEA and anteversion angles have optimae associated with low serum metal levels which may be useful for post-surgery evaluation of cup positioning.

A Randomized Seven-Year Study on Performance of the Stemmed Metal M2a-Magnum and Ceramic C2a-Taper, and the Resurfacing ReCap Hip Implants.

BACKGROUND: The large-diameter metal-on-metal hip prostheses were expected to have low wear and reduced dislocation rate compared to the traditional metal-on-polyethylene implants. We compare 2 such prostheses, the ReCap resurfacing implant and the M2a-Magnum stemmed implant, with the C2a ceramic-on-ceramic stemmed implant as to clinical performance, serum concentrations of prosthesis metals, and the durability of the implants in a randomized, controlled clinical trial at 7 years of follow-up. METHODS: All included patients had osteoarthritis. Preoperatively, the size of the implants was estimated from a magnetic resonance imaging (MRI) scan. Follow-up data included serum cobalt and chromium concentrations, Oxford and Harris Hip Scores, leg press and abduction force, 6-minute walk distance, WOMAC and SF-36 self-assessment scores, and from the 7th postoperative year also ultrasonography (US) examination of the soft tissue adjacent to the implant as well as MRI with metal artifact reduction sequence (MARS-MRI) when indicated. RESULTS: One hundred fifty-two hips in 146 patients were included. The serum cobalt and chromium concentrations were significantly higher for the 2 metal-on-metal prostheses than for the ceramic-on-ceramic, with the M2a-Magnum as the highest. No significant difference was found between the groups concerning physical performance measurements and scores as well as dislocations and prosthesis survival. Five revisions were done and concerned all groups, for reasons of pain, high serum cobalt and chromium concentrations, cystic fluid collection around the joint, and infection. Metal concentrations, US, and MARS-MRI contributed to the decision making regarding prosthesis revision. CONCLUSION: Metal concentrations were significantly higher for the metal-on-metal prostheses than for the ceramic-on-ceramic. The clinical performance was good in all 3 prosthesis groups. Metal concentrations, US, and MARS-MRI findings were of use to identify hips needing revision. ID Number in ClinicalTrials.gov PRS: NCT00284674.

Clinical Performance of the ASR and ReCap Resurfacing Implants­7 Years Follow-Up.

We perform a non-randomized, consecutive pilot study on the ASR and ReCap resurfacing hip implants and have completed 7 years follow-up. Forty-six non-osteoporotic patients with hip osteoarthritis and anatomical conditions suitable for resurfacing were divided into 2 equal groups and operated sequentially, starting with the ASR implants. Sixteen patients operated with ASR and 19 patients with ReCap have been followed-up. There were no significant differences between the two groups preoperatively as to physical function, pain, or femoral BMD. The serum concentrations of cobalt and chromium were higher in the ASR group from 1/2 to 7 years postoperatively. Five of 16 ASR implants have been revised, and none of the ReCap implants. BMD below the femoral component increased in both groups.

Cytokine measurements and possible interference from heterophilic antibodies--problems and solutions experienced with rheumatoid factor.

Cytokines are important in the understanding of the immune process in health and disease and are valuable indicators in diagnostics. Measurements of cytokines are based on immunometric methods, and it is important to understand possible pitfalls in these methods to produce reliable cytokine data. This paper focuses on obtaining optimal measurements when applying enzyme-linked immunosorbent assay (ELISA) or multiplex immunoassays (MIA). Cytokines are measured in serum or plasma, as well as in various other body fluids, all containing a series of antibodies and the possibility of interference from these. Some antibodies, such as heterophilic and human anti-animal antibodies, are able to interfere with all immunoassays, but the immunometric techniques are most prone to serious interference from this source. Another type, rheumatoid factor (RF) is a composite of different autoimmune antibodies which can be present in both blood and synovial fluid. RF is present in some arthritic diseases as well as in some other medical conditions. When present, especially RF IgM is known to interfere with the immunometric measurements. A possible and affordable solution to diminish this interference is PEG precipitation, but other efficient, but more expensive, methods, such as precipitation using Protein L or commercially available blocking agents, are also available. Interference of RF is at present not tested in all cytokine assays, but degree of interference from RF, human anti-animal and heterophilic antibodies, as well as from other possible disease-specific antibodies, must always be considered when developing and applying new assays for cytokine measurements.

Effect of day length on eye growth, myopia progression, and change of corneal power in myopic children.

OBJECTIVE: Because of the northern location of Denmark, the length of the day over the year varies from 7 to 17.5 hours. Experimental and clinical results suggest that the development of myopia may be related to ambient light exposure. The purpose of current study was to investigate whether axial eye growth, myopia progression, or corneal power change in Danish myopic children varies with the length of the day. DESIGN: Cross-sectional study. PARTICIPANTS: Two hundred thirty-five children 8 to 14 years of age found to have myopia during screening for a clinical trial (ClinicalTrial.gov identifier, NCT00263471; accessed December 6, 2005). All children found to have any value of spherical equivalent that was myopic (<0 diopters [D]) at the first of 2 visits were included. METHODS: Cycloplegic refraction was measured using an autorefractor, axial eye length, and corneal power using an automatic combined noncontact partial coherence interferometer and keratometer. The accumulated number of daylight hours during the measurement period was calculated for each participant using an astronomical table. MAIN OUTCOME MEASURES: Change over 6 months in axial length, refraction, and corneal power. RESULTS: Accumulated hours of daylight ranged from 1660 to 2804 hours. Significant correlations were found between hours of daylight and eye elongation (P = 0.00), myopia progression (P = 0.01), and corneal power change (P = 0.00). In children with an average of 2782 ± 19 hours of daylight, axial eye growth was 0.12 ± 0.09 mm, myopia progression was 0.26 ± 0.27 D, and corneal power change was 0.05 ± 0.10 D per 6 months, whereas in children with an average of 1681 ± 24 hours of daylight, axial eye growth was 0.19 ± 0.10 mm, myopia progression was 0.32 ± 0.27 D, and corneal power change was -0.04 ± 0.08 D per 6 months. CONCLUSIONS: Eye elongation and myopia progression seem to decrease in periods with longer days and to increase in periods with shorter days. Children should be encouraged to spend more time outside during daytime to prevent myopia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Oral administration of caffeine metabolite 7-methylxanthine is associated with slowed myopia progression in Danish children.

PURPOSE: Myopia is associated with an increased risk of permanent vision loss. The caffeine metabolite 7-methylxanthine (7-MX), licensed in Denmark since 2009 as a treatment to reduce the rate of childhood myopia progression, is the only orally administered therapy available. The purpose of the current study was to assess the rate of myopia progression in children taking 7-MX. METHODS: Longitudinal cycloplegic refraction and axial length data for 711 myopic children from Denmark treated with varying doses of oral 7-MX (0-1200 mg per day) were analysed using linear mixed models. RESULTS: The median age at baseline was 11.1 years (range 7.0 -15.0 years). Children were followed for an average of 3.6 years (range 0.9-9.1 years) and the average myopia progression was 1.34 dioptres (D) (range -6.50 to +0.75 D). Treatment with 7-MX was associated with a reduced rate of myopia progression (p<0.001) and axial elongation (p<0.002). Modelling suggested that, on average, an 11-year-old child taking 1000 mg 7-MX daily would develop -1.43 D of myopia over the next 6 years, compared with -2.27 D if untreated. Axial length in this child would increase by 0.84 mm over 6 years when taking a daily dose of 1000 mg of 7-MX, compared with 1.01 mm if untreated. No adverse effects of 7-MX therapy were reported. CONCLUSIONS: Oral intake of 7-MX was associated with reduced myopia progression and reduced axial elongation in this sample of myopic children from Denmark. Randomised controlled trials are needed to determine whether the association is causal.

A randomised, controlled clinical study on total hip arthroplasty using 4 different bearings: results after 10 years.

PURPOSE: To compare 4 different bearings in total hip arthroplasty (THA) in a randomised controlled clinical study on clinical performance. METHODS: 393 patients with osteoarthritis of the hip or avascular necrosis were included and allocated to 1 of the head-and-cup couples zirconia-on-polyethylene (group A), metal-on-metal (group B), zirconia-on-polyethylene with the liner moulded into the shell (group C), or alumina-on-alumina (group D). In the individual case the surgeon could choose other implants if indicated. RESULTS: 299 patients were operated with the allocated prosthesis. The estimated cumulated prosthesis survival percentages and 95% confidence interval after 10 years were: group A 84.6 (75.8-93.4); group B 95.0 (89.5-100); group C 93.2 (86.7-99.7); group D 66.1 (54.5-77.7). The patients' physical function was significantly improved and remained equally good in all 4 groups, however slightly declining with ageing. The luxation rate was initially high, and equal between the groups, but was reduced by improving the surgical procedure introducing capsule repair by reinsertion of the short external hip rotators. CONCLUSIONS: The metal-on-metal or zirconia-on-polyethylene prostheses had high 10-year survival percentages. The longevity of these bearing couples by themselves was not related to the combination of materials. The zirconia-on-polyethylene prosthesis with the liner mounted peroperatively possibly exhibited cases of backside wear which the corresponding bearing couple with moulded polyethylene (Asian) did not. The alumina-on-alumina bearing performed poorly - it was redesigned after our study initiation and later withdrawn from the market.

Latanoprost eye drops increase concentration of glycosaminoglycans in posterior rabbit sclera.

PURPOSE: Glycosaminoglycans are important components of ocular tissues such as the sclera. The pressure reducing effect of a new antiglaucoma drug, latanoprost, is based on an increase in the uveo-scleral outflow by way of modulation of the intracellular matrix of the ciliary body. The purpose of the study was to test the effect of latanoprost on the content of glycosaminoglycans in rabbit cornea and sclera. METHODS: Twelve rabbits were studied. Six rabbits were treated for 12 weeks with latanoprost eye drops and 6 with hydroxypropylmethylcellulose, dextran 70 eye drops for control. Samples were taken from cornea and anterior, lateral, and posterior sclera. Glycosaminoglycans were determined quantitatively by spectrophotometry (uronic acids). RESULTS: A significant increase in the concentration of uronic acids was found in all three localisations of sclera from latanoprost-treated animals. The increase was 26%, 24%, and 20% in anterior, lateral, and posterior sclera, respectively. CONCLUSIONS: Long-term treatment with latanoprost induces biochemical changes in sclera. The results indicate that topically applied latanoprost reaches the posterior parts of the rabbit eye.

Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor blockage on FoxP3 expression in responsive arthritis patients.

Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were investigated in a 12-week prospective cohort study. FoxP3 isoforms, CD25 and CTLA-4 mRNA in blood CD4+ T cells were measured with quantitative real-time PCR. Patients benefitting from the treatment, based on changes in DAS28 scores, revealed a significant decrease in expression of full-length FoxP3 following 12 weeks treatment with TNF receptor 2 fusion protein (Etanercept), but not following treatment with anti-TNF antibodies (Adalimumab or Infliximab). A partial normalization of the CTLA-4/FoxP3fl ratio and a correlation between clinical improvement and change in FoxP3 mRNA expression were also seen in Etanercept responders. These changes were not observed in responsive patients treated with the antibody therapies. Our data suggest that TNF decoy receptor and anti-TNF antibodies differ in their effect on FoxP3 expression in responsive patients. As Etanercept binds both TNF-α and Lymphotoxin-α (LT-α), whereas the antibodies only target TNF-α, LT-α may regulate FoxP3 expression in a subset of RA patients. Our findings support the view that anti-TNF treatment is mainly symptomatic.

A synoviocyte model for osteoarthritis and rheumatoid arthritis: response to Ibuprofen, betamethasone, and ginger extract-a cross-sectional in vitro study.

This study aimed at determining if synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and healthy controls (HC) differ and are suitable disease models in pharmacological studies, and tested their response to some anti-inflammatory drugs. Synovial cells were isolated from synovial membrane or joint fluid. Cells were cultivated and exposed to no or TNF-α stimulation without, or in the presence of, betamethasone, ibuprofen, or a standardized ginger extract. Concentrations of a panel of cytokines, growth factors, and chemokines were mapped for each culture and condition. Our cells secreted an increased amount of the cytokines IL-1ß, IL-6, and IL-8 in response to TNF-α stimulation in all conditions. OA cells showed a higher IL-6 and IL-8 and a lower IL-1ß production, when not stimulated, than RA and HC cells, which were similar. TNF-α stimulation caused similar IL-1ß, IL-6, and IL-8 release in all groups. Ibuprofen showed no effect on cytokine production, while ginger extract was similar to betamethasone. Ginger extract was as effective an anti-inflammatory agent as betamethasone in this in vitro model. Cultured fibroblast-like synoviocytes from OA and RA subjects promise to be a useful pharmacological disease model, but further studies, to support results from such a model are needed.

FoxP3 mRNA splice forms in synovial CD4+ T cells in rheumatoid arthritis and psoriatic arthritis.

Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP3Δ2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Δ2 mRNA in SF CD4+ T cells was increased compared to controls in sero-negative RA and PsA, but not in sero-positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP3Δ2Δ7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from RA patients. A skewed, high expression profile of FoxP3, but not CTLA-4, in sero-negative RA and PsA, indicates that synovial CD4+ T cells may represent unique subsets of T cells which have been induced locally or selectively recruited to the joint.

A prospective randomised study of periprosthetic femoral bone remodeling using four different bearings in hybrid total hip arthroplasty.

We performed a study to assess whether different bearing materials have an impact on femoral bone remodeling within the first four years after a hybrid total hip arthroplasty. 205 of 300 patients were available for 4 years follow-up after being randomly allocated to four prosthetic combinations: A: Zirconia ceramic head, polyethylene cup; B: Cobalt-Chrome-Molybdenum head and cup; C: Zirconia ceramic head, polyethylene moulded on the Titanium shell of the Asian cup; D: Alumina head and cup. Bone mineral density (BMD) was measured with Dual-Energy X-ray Absorptiometry in seven Gruen zones adjacent to the femoral implant. Scans were performed within one week after surgery and four years postoperatively. Clinical outcomes were monitored using the Oxford Hip Score (OHS). A high proportion of patients from group D were excluded due to re-operations (19 patients). BMD decreased significantly in all Gruen zones with the largest declines in group D. BMD changes in Gruen zones 1, 2, 3, 6, and 7 correlated with height, and body weight. Advanced age was associated with an increase in bone loss in Gruen zones 1, 2, 3, 6, and 7. A large stem size was associated with a decline in BMD in Gruen zones 1, 6, and 7.Bone remodeling after total hip arthroplasty may depend on the composition of bearing materials, but age, height, weight, and stem size are also related to changes in BMD.

Rheumatoid factor and its interference with cytokine measurements: problems and solutions.

Use of cytokines as biomarkers for disease is getting more widespread. Cytokines are conveniently determined by immunoassay, but interference from present antibodies is known to cause problems. In rheumatoid arthritis (RA), interference of rheumatoid factor (RF) may be problematic. RF covers a group of autoantibodies from immunoglobulin subclasses and is present in 65-80% of RA patients. Partly removal of RF is possible by precipitation. This study aims at determining the effects of presence of RF in blood and synovial fluid on cytokine measurements in samples from RA patients and finding possible solutions for recognized problems. IL-1ß, IL-4, IL-6, and IL-8 were determined with multiplex immunoassays (MIA) in samples from RA patients prior to and after polyethylene glycol (PEG 6000) precipitation. Presence of RF does interfere with MIA. PEG 6000 precipitation abolishes this RF interference. We recommend PEG precipitation for all immunoassay measurements of plasma samples from RA patients.

A microdialysis study of topically applied diclofenac to healthy humans: Passive versus iontophoretic delivery.

Topical application of NSAIDs is an alternative route to systemic administration when a local anti-inflammatory effect of the underlying tissue is a treatment option. The aim of the present microdialysis study was to assess and compare plasma and tissue levels of diclofenac when topically applied with or without iontophoresis in healthy adults. Fourteen healthy adults (26±9.4 years) were randomized to diclofenac applied by iontophoresis, or by a gel, in a crossover design. Diclofenac concentrations were measured in plasma and in microdialysis perfusates from the underlying tissues. Iontophoretic application resulted in the highest plasma concentration of 3.4±0.5 ng/ml (SEM given) compared to 0.4 ng/ml (at the detection limit) with gel, whereas no differences were observed between tissue concentrations for the two application methods, both being very low, below or around the detection limit. Iontophoresis caused skin reactions in 25% of the participants. Iontophoresis of diclofenac as compared to traditional topical application was not superior in order to increase the NSAID concentration locally and appears to have a higher frequency of skin reactions.

Systemic 7-methylxanthine in retarding axial eye growth and myopia progression: a 36-month pilot study.

The adenosine antagonist 7-methylxanthine (7-mx) works against myopia in animal models. In a clinical trial, 68 myopic children (mean age 11.3 years) received either placebo or 7-mx tablets for 12 months. All participants subsequently received 7-mx for another 12 months, after which treatment was stopped. Axial length was measured with Zeiss IOL-Master and cycloplegic refraction with Nikon Retinomax at -6, 0, 12, 24, and 36 months. Axial growth was reduced among children treated with 7-mx for 24 months compared with those only treated for the last 12 months. Myopia progression and axial eye growth slowed down in periods with 7-mx treatment, but when the treatment was stopped, both myopia progression and axial eye growth continued with invariable speed. The results indicate that 7-mx reduces eye elongation and myopia progression in childhood myopia. The treatment is safe and without side effects and may be continued until 18-20 years of age when myopia progression normally stops.

Melanoma-associated spongiform scleropathy: biochemical changes and possible relation to tumour extension.

PURPOSE: To investigate biochemical changes of the sclera in eyes with melanoma-associated spongiform scleropathy (MASS), and to analyse possible relationships between these changes and tumour extension. METHODS: Sections from 364 eyes, enucleated for choroidal and ciliary body melanoma, were examined for MASS and scleral tumour extension. Biochemical analysis was also performed on eight scleral specimens with MASS and eight specimens (controls) from morphologically normal sclera of the same eyes. The scleral thickness of each specimen was measured. Samples were delipidized, dried and weighed. The weight ratios of collagen-related amino acids were calculated based on quantitation by liquid chromatography. Amounts of glycosaminoglycans (GAGs) were determined by electrophoresis. RESULTS: Melanoma-associated spongiform scleropathy was seen in 140 eyes (38.5%). Tumour scleral extension was observed in 82 eyes. Of these 82 eyes, 75 (91.5%) had MASS (p<0.05). Biochemically, the majority of the main amino acids of the scleral collagen and total proteins were significantly lower in areas with MASS than in the control specimens. Specific GAGs and total GAGs were found in significantly higher concentrations in areas with MASS than in the control specimens. Scleral thickness was also significantly higher in areas with MASS than in the control specimens. CONCLUSIONS: The reduced content of collagen manifested by decreased amino acids and total proteins indicates collagen degradation in the vicinity of the tumour. The concomitant excessive deposition of GAGs accumulates water and may cause loosening of the already degraded collagen bundles, giving a histopathological picture of MASS. These changes could facilitate tumour cell migration and may explain the high incidence of MASS in eyes with scleral tumour extension.