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Aim: Complete arthrocentesis of the effusive knee ameliorates patient pain, reduces intra‐articular and intraosseous pressure, removes inflammatory cytokines, and has been shown to substantially improve the therapeutic outcomes of intra‐articular injections. However, conventional arthrocentesis incompletely decompresses the knee, leaving considerable residual synovial fluid in the intra‐articular space. The present study determined whether external pneumatic circumferential compression of the effusive knee permitted more successful arthrocentesis and complete joint decompression. Methods: Using a paired sample design, 50 consecutive effusive knees underwent conventional arthrocentesis and then arthrocentesis with pneumatic compression. Pneumatic compression was applied to the superior knee using a conventional thigh blood pressure cuff inflated to 100 mm Hg which compressed the suprapatellar bursa and patellofemoral joint, forcing fluid from the superior knee to the anterolateral portal where the fluid could be accessed. Arthrocentesis success and fluid yield in mL before and after pneumatic compression were determined. Results: Successful diagnostic arthrocentesis (≥3 mL) of the effusive knee was 82% (41/50) with conventional arthrocentesis and increased to 100% (50/50) with pneumatic compression (P =.001). Synovial fluid yields increased by 144% (19.8 ± 17.1 mL) with pneumatic compression (conventional arthrocentesis; 13.7 ± 16.4 mL, pneumatic compression: 33.4 ± 26.5 mL; 95% CI: 10.9 < 19.7 < 28.9 mL, P <.0001). Conclusions: Conventional arthrocentesis routinely does not fully decompress the effusive knee. External circumferential pneumatic compression markedly improves arthrocentesis success and fluid yield, and permits complete decompression of the effusive knee. Pneumatic compression of the effusive knee with a thigh blood pressure cuff is an inexpensive and widely available technique to improve arthrocentesis outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background The extended knee lateral midpatellar portal for intraarticular injection of the knee is accurate but is not practical for all patients. We hypothesized that a modified anteriolateral portal where the synovial membrane of the medial femoral condyle is the target would be highly accurate and effective for intraarticular injection of the knee. Methods 83 subjects with non-effusive osteoarthritis of the knee were randomized to intraarticular injection using the modified anteriolateral bent knee versus the standard lateral midpatellar portal. After hydrodissection of the synovial membrane with lidocaine using a mechanical syringe (reciprocating procedure device), 80 mg of triamcinolone acetonide were injected into the knee with a 2.0-in (5.1-cm) 21-gauge needle. Baseline pain, procedural pain, and pain at outcome (2 weeks and 6 months) were determined with the 10 cm Visual Analogue Pain Score (VAS). The accuracy of needle placement was determined by sonographic imaging. Results The lateral midpatellar and anteriolateral portals resulted in equivalent clinical outcomes including procedural pain (VAS midpatellar: 4.6 ± 3.1 cm; anteriolateral: 4.8 ± 3.2 cm; p = 0.77), pain at outcome (VAS midpatellar: 2.6 ± 2.8 cm; anteriolateral: 1.7 ± 2.3 cm; p = 0.11), responders (midpatellar: 45%; anteriolateral: 56%; p = 0.33), duration of therapeutic effect (midpatellar: 3.9 ± 2.4 months; anteriolateral: 4.1 ± 2.2 months; p = 0.69), and time to next procedure (midpatellar: 7.3 ± 3.3 months; anteriolateral: 7.7 ± 3.7 months; p = 0.71). The anteriolateral portal was 97% accurate by real-time ultrasound imaging. Conclusion The modified anteriolateral bent knee portal is an effective, accurate, and equivalent alternative to the standard lateral midpatellar portal for intraarticular injection of the knee. Trial Registration ClinicalTrials.gov: NCT00651625

Nontoxic botulinum for drug delivery: Botulism is a severe and potentially fatal disease characterized by muscle paralysis. The causing agent, botulinum neurotoxins (BoNTs), has the ability to enter motor neurons and to block neurotransmission. In two independent studies, Miyashita et al. and McNutt et al. used nontoxic derivative of BoNT to deliver therapeutic antibodies against BoNTs in neurons. Miyashita et al. targeted BoNT/A and BoNT/B and reported therapeutic effects in mice. Using a similar approach targeting BoNT/A, McNutt et al. increased survival after lethal challenge in mice, guinea pigs, and monkeys. This approach provided a safe and effective treatment against BoNT intoxication and could be exploited for targeting other intracellular proteins in neurons. Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets. [ABSTRACT FROM AUTHOR]

Byline: Philip A. Band, PhD and David S. Hungerford, MD ABSTRACT: Five meta-analyses that evaluated the safety and efficacy of chondroitin sulfate (CS) in osteoarthritis management were published in recent [...]

Introduction/objectives: We hypothesized that mechanical compression of the knee in rheumatoid arthritis (RA) would mobilize occult extractable fluid and improve arthrocentesis success. Methods: Sixty-seven consecutive knees with RA and 186 knees with OA and were included. Conventional arthrocentesis was performed and success and volume (milliliters) determined; the needle was left intraarticularly, and mechanical compression was applied with an elastomeric knee brace. Arthrocentesis was then resumed until fluid return ceased. Fluid was characterized as to volume and cell counts. Results: In the RA, knee mechanical compression decreased failed diagnostic arthrocentesis from 56.7% (38/67) to 26.9% (18/67) (− 47.4%, p = 0.003) and increased absolute arthrocentesis yield from 4.7 ± 10.3 ml to 9.8 ± 9.8 ml (108% increase, 95% CI − 8.5 < − 5.1 < − 1.7 p = 0.0038). Total extractable fluid yield was 96% greater in RA (9.8 ± 9.8 ml) than OA (5.0 ± 9.4 ml, p = 0.0008), and occult extractable fluid was 77% greater in RA than OA (RA 5.3 ± 8.7 ml, OA 3.0 ± 5.5 ml, p = 0.046). Large effusions versus small effusions in RA demonstrated increased neutrophils in synovial fluid (p = 0.04) but no difference in radiologic arthritis grade (p = 0.87). In contrast, large effusions versus small effusions in OA demonstrated no difference in neutrophils in synovial fluid (p = 0.87) but significant different radiologic arthritis grade (p = 0.04). Conclusion: Mechanical compression improves the success of diagnostic and therapeutic knee arthrocentesis in both RA and OA. Large effusions in RA are associated with increased neutrophil counts but not arthritis grade; in contrast, large effusions in OA are associated with more severe arthritis grades but not increased neutrophil counts. Key points • Mechanical compression of the painful knee improves arthrocentesis success and fluid yield in both rheumatoid arthritis and osteoarthritis. • The painful rheumatoid knee contains approximately 100% more fluid than the osteoarthritic knee. • Large effusions in the osteoarthritic knee are characterized by higher grades of mechanical destruction but not increased neutrophil counts. • In contrast, large effusions in the rheumatoid knee are characterized by higher synovial fluid neutrophil counts but not the grade of mechanical destruction, indicating different mechanisms of effusion formation in rheumatoid arthritis versus osteoarthritis. [ABSTRACT FROM AUTHOR]

We have previously described genetic constructs and expression systems that enable facile production of recombinant derivatives of botulinum neurotoxins (BoNTs) that retain the structural and trafficking properties of wt BoNTs. In this report we describe the properties of one such derivative, BoNT/A ad, which was rendered atoxic by introducing two amino acid mutations to the light chain (LC) of wt BoNT/A, and which is being developed as a molecular vehicle for delivering drugs to the neuronal cytoplasm. The neuronal binding, internalization, and intracellular trafficking of BoNT/A ad in primary hippocampal cultures was evaluated using three complimentary techniques: flow cytometry, immunohistochemistry, and Western blotting. Neuronal binding of BoNT ad was significantly increased when neurons were incubated in depolarizing medium. Flow cytometry demonstrated that BoNT/A ad internalized into neurons but not glia. After 24 hours, the majority of the neuron-bound BoNT/A ad became internalized, as determined by its resistance to pronase E-induced proteolytic degradation of proteins associated with the plasma membrane of intact cells. Significant amounts of the atoxic LC accumulated in a Triton X-100-extractable fraction of the neurons, and persisted as such for at least 11 days with no evidence of degradation. Immunocytochemical analysis demonstrated that the LC of BoNT/A ad was translocated to the neuronal cytoplasm after uptake and was specifically targeted to SNARE proteins. The atoxic LC consistently co-localized with synaptic markers SNAP-25 and VAMP-2, but was rarely co-localized with markers for early or late endosomes. These data demonstrate that BoNT/A ad mimics the trafficking properties of wt BoNT/A, confirming that our platform for designing and expressing BoNT derivatives provides an accessible system for elucidating the molecular details of BoNT trafficking, and can potentially be used to address multiple medical and biodefense needs. [ABSTRACT FROM AUTHOR]

The article discusses the characteristics and effectiveness of chondroitin sulfate (CS) for osteoarthritis. The article defines osteoarthritis (OA) as a chronic degenerative disease associated with significant pain and disability. Several meta-analyses that had evaluated the safety and efficacy of CS in osteoarthritis treatment revealed the statistical superiority to placebo in symptomatic improvements in clinical trials.

Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm. [ABSTRACT FROM AUTHOR]

Background/objective: The objective of this study was to determine whether the extended or flexed knee positioning was superior for arthrocentesis and whether the flexed knee positioning could be improved by mechanical compression., Methods: Fifty-five clinically effusive knees underwent arthrocentesis in a quality improvement intervention: 20 consecutive knees in the extended knee position using the superolateral approach, followed by 35 consecutive knees in the flexed knee position with and without an external compression brace placed on the suprapatellar bursa. Arthrocentesis success and fluid yield in milliliters were measured., Results: Fluid yield for the extended knee was greater (191% greater) than the flexed knee (extended knee, 16.9 ± 15.7 mL; flexed knee, 5.8 ± 6.3 mL; P < 0.007). Successful diagnostic arthrocentesis (≥2 mL) was 95% (19/20) in the extended knee and 77% (27/35) in the flexed knee (P = 0.08). After mechanical compression was applied to the suprapatellar bursa and patellofemoral joint of the flexed knee, fluid yields were essentially identical (extended knee, 16.9 ± 15.7 mL; flexed knee, 16.7 ± 11.3 mL; P = 0.73), as were successful diagnostic arthrocentesis (≥2 mL) (extended knee 95% vs. flexed knee 100%, P = 0.12)., Conclusions: The extended knee superolateral approach is superior to the flexed knee for conventional arthrocentesis; however, the extended knee positioning and flexed knee positioning have identical arthrocentesis success when mechanical compression is applied to the superior knee. This new flexed knee technique for arthrocentesis is a useful alternative for patients who are in wheelchairs, have flexion contractures, cannot be supine, or cannot otherwise extend their knee.

Objectives: Osteoarthritis of the knee is a chronic disease associated with pain and reduced quality of life. The ability to reliably measure patient-reported symptoms is important for clinical decision making and evaluation of outcomes. Electronic and web-based tools can eliminate much of the labor-intensive aspects of questionnaire administration and enables both real-time evaluation of responses by physicians and integration of data from multiple sites. This article describes the results of implementing a single integrated electronic questionnaire system into routine orthopedic practice at 2 diverse institutions., Study Design: Case study., Methods: A web-based version of a general quality-of-life questionnaire (EuroQol 5-dimension [EQ-5D]) and the pain domain of a disease-specific questionnaire (Knee Osteoarthritis Outcome Score [KOOS]) were administered in the office waiting room to (n = 666) patients at 2 centers over a 9-month period using touchscreen devices. Data were analyzed and descriptive statistics were calculated to assess feasibility of integration into the distinct work flows and to assess the agreement of the results., Results: The electronic questionnaire had a completion rate of 93% to 95%. Average questionnaire completion times were 3 to 5 minutes at each institution. Mean EQ-5D and KOOS scores for patients pre- and postsurgery were also consistent with prior literature studies., Conclusions: Lessons learned for future adoption of questionnaire systems elsewhere include the need for baseline assessment of clinic work flows to identify the optimal point of administration and the need for IT support. This study demonstrates the feasibility of routinely collecting patient-reported data as part of standard care, which will become increasingly important as the nationwide emphasis on tracking quality and cost-effectiveness of treatments in orthopedics grows.

Objective: The present randomized controlled study investigated whether sonographic needle guidance affected the outcomes of intra-articular injection for osteoarthritis of the knee., Methods: Ninety-four noneffusive knees with osteoarthritis were randomized to injection by conventional palpation-guided anatomic landmark injection or sonographic image-guided injection enhanced with a 1-handed mechanical (the reciprocating procedure device) syringe. After intra-articular placement and synovial space dilation were confirmed by sonography, a syringe exchange was performed, and 80 mg of triamcinolone acetonide was injected with the second syringe through the indwelling intra-articular needle. Baseline pain, procedural pain, pain at outcome (2 weeks and 6 months), responders, therapeutic duration, reinjection rates, total cost, and cost per responder were determined., Results: Relative to conventional palpation-guided anatomic landmark methods, sonographic guidance for injection of the knee resulted in 48% reduction in procedural pain (P < 0.001), a 42% reduction in pain scores at outcome (P < 0.03), 107% increase in the responder rate (P < 0.001), 52% reduction in the nonresponder rate (P < 0.001), a 36% increase in therapeutic duration (P = 0.01), a 13% reduction ($17) in cost per patient per year, and a 58% ($224) reduction in cost per responder per year for a hospital outpatient (P < 0.001)., Conclusions: Sonographic needle guidance reduced procedural pain and improved the clinical outcomes and cost-effectiveness of intra-articular injections of the osteoarthritic knee.

Objective: We studied whether sonographic needle guidance affected the outcomes of intraarticular (IA) injection for inflammatory arthritis., Methods: Joints with inflammatory arthritis (n = 244; 76% rheumatoid arthritis, 3% small joints, 51% intermediate, and 46% large) were randomized to injection by conventional palpation-guided anatomic injection (120 joints) or sonographic image-guided injection enhanced with a 1-handed reciprocating procedure device mechanical syringe (124 joints). A 1-needle, 2-syringe technique was used. After IA placement and synovial space dilation were confirmed by sonography, a syringe exchange was performed, and triamcinolone acetonide was injected with the second syringe through the indwelling IA needle. Baseline pain, procedural pain, pain at outcome (2 weeks and 6 months), responders, therapeutic duration, reinjection rates, total cost, and cost per responder were determined., Results: Relative to conventional palpation-guided methods, sonographic guidance for injection of inflammatory arthritis resulted in an 81% reduction in injection pain (p < 0.001), 35% reduction in pain scores at outcome (p < 0.02), 38% increase in the responder rate (p < 0.003), 34% reduction in the non-responder rate (p < 0.003), 32% increase in therapeutic duration (p = 0.01), 8% reduction ($7) in cost/patient/year, and a 33% ($64) reduction in cost/responder/year for a hospital outpatient (p < 0.001)., Conclusion: Sonographic needle guidance improves the performance, clinical outcomes, and cost-effectiveness of IA injections for inflammatory arthritis. (Clinical Trial Identifier NCT00651625).

Objective: This randomized controlled study addressed whether sonographic needle guidance affected clinical outcomes of intraarticular (IA) joint injections., Methods: In total, 148 painful joints were randomized to IA triamcinolone acetonide injection by conventional palpation-guided anatomic injection or sonographic image-guided injection enhanced with a one-handed control syringe (the reciprocating device). A one-needle, 2-syringe technique was used, where the first syringe was used to introduce the needle, aspirate any effusion, and anesthetize and dilate the IA space with lidocaine. After IA placement and synovial space dilation were confirmed, a syringe exchange was performed, and corticosteroid was injected with the second syringe through the indwelling IA needle. Baseline pain, procedural pain, pain at outcome (2 weeks), and changes in pain scores were measured with a 0-10 cm visual analog pain scale (VAS)., Results: Relative to conventional palpation-guided methods, sonographic guidance resulted in 43.0% reduction in procedural pain (p < 0.001), 58.5% reduction in absolute pain scores at the 2 week outcome (p < 0.001), 75% reduction in significant pain (VAS pain score > or = 5 cm; p < 0.001), 25.6% increase in the responder rate (reduction in VAS score > or = 50% from baseline; p < 0.01), and 62.0% reduction in the nonresponder rate (reduction in VAS score < 50% from baseline; p < 0.01). Sonography also increased detection of effusion by 200% and volume of aspirated fluid by 337%., Conclusion: Sonographic needle guidance significantly improves the performance and outcomes of outpatient IA injections in a clinically significant manner.