Structural Adaptations of the Primate Flexor Carpi Ulnaris After Tendon Transfer.

PURPOSE: Muscle remodeling occurs after tendon transfer. However, it is not known whether these adaptations are permanent and clinically significant. This study examined the early and late structural adaptations following a standard tendon transfer in a primate model. METHODS: A flexor carpi ulnaris (FCU) to extensor digitorum communis (EDC) transfer was performed in 8 adult monkeys. A sham operation was performed in the contralateral forearm. Four animals were sacrificed at 5 months (early cohort) and 4 at 16 months (late cohort). The transferred FCU, contralateral FCU, and EDC muscles were removed for analysis. Fiber length (FL), physiological cross-sectional area (PCSA), and gross morphology of the transferred FCU were compared with the contralateral EDC and FCU. RESULTS: In the early cohort, the FL of the transferred FCU was longer than the control FCU and similar to the contralateral EDC. The PCSA of the transferred FCU was lower than that of the control FCU but greater than the control EDC. In the late cohort, the difference in FL and PCSA between the transferred FCU and the control FCU persisted. The PCSA of the transferred FCU was similar to that of the control EDC. The bipennate transferred FCU had also undergone gross morphological changes to resemble the multipennate EDC. CONCLUSIONS: This study demonstrates, in a primate model, that the FCU undergoes structural adaptations to resemble the EDC following an FCU-to-EDC transfer. However, these adaptations are incomplete and not sustained over time. CLINICAL RELEVANCE: This study demonstrates that there is muscle plasticity in tendon transfers in a primate model. However, it is important to match potential donor muscles to the recipient during tendon transfer.

Control strategies to re-establish glenohumeral stability after shoulder injury.

BACKGROUND: Muscles are important "sensors of the joint instability". The aim of this study was to identify the neuro-motor control strategies adopted by patients with anterior shoulder instability during overhead shoulder elevation in two planes. METHODS: The onset, time of peak activation, and peak magnitude of seven shoulder muscles (posterior deltoid, bilateral upper trapezius, biceps brachii, infraspinatus, supraspinatus and teres major) were identified using electromyography as 19 pre-operative patients with anterior shoulder instability (mean 27.95 years, SD = 7.796) and 25 age-matched asymptomatic control subjects (mean 23.07 years, SD = 2.952) elevated their arm above 90 degrees in the sagittal and coronal planes. RESULTS: Temporal characteristics of time of muscle onsets were significantly different between groups expect for teres major in the coronal plane (t = 1.1220, p = 0.2646) Patients recruited the rotator cuff muscles earlier and delayed the onset of ipsilateral upper trapezius compared with subjects (p<0.001) that control subjects. Furthermore, significant alliances existed between the onsets of infraspinatus and supraspinatus (sagittal: r = 0.720; coronal: r = 0.756 at p<0.001) and ipsilateral upper trapezius and infraspinatus (sagittal: r = -0.760, coronal: r = -0.818 at p<0.001). The peak activation of all seven muscles occurred in the mid-range of elevation among patients with anterior shoulder instability whereas subjects spread peak activation of all 7 muscles throughout range. Peak magnitude of patients' infraspinatus muscle was six times higher (sagittal: t = -8.6428, coronal: t = -54.1578 at p<0.001) but magnitude of their supraspinatus was lower (sagittal: t = 36.2507, coronal: t = 35.9350 at p<0.001) that subjects. CONCLUSIONS: Patients with anterior shoulder instability adopted a "stability before mobility" neuro-motor control strategy to initiate elevation and a "stability at all cost" strategy to ensure concavity compression in the mid-to-150 degrees of elevation in both sagittal and coronal planes.

RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines.

Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1ß, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects.

Suppressive effect of secretory phospholipase A2 inhibitory peptide on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice.

INTRODUCTION: Secretory phospholipase A2 (sPLA2) and matrix metalloproteinase (MMP) inhibitors are potent modulators of inflammation with therapeutic potential, but have limited efficacy in rheumatoid arthritis (RA). The objective of this study was to understand the inhibitory mechanism of phospholipase inhibitor from python (PIP)-18 peptide in cultured synovial fibroblasts (SF), and to evaluate its therapeutic potential in a human tumor necrosis factor (hTNF)-driven transgenic mouse (Tg197) model of arthritis. METHODS: Gene and protein expression of sPLA2-IIA, MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by real time PCR and ELISA respectively, in interleukin (IL)-1beta stimulated rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts cells treated with or without inhibitors of sPLA2 (PIP-18, LY315920) or MMPs (MMP Inhibitor II). Phosphorylation status of mitogen-activated protein kinase (MAPK) proteins was examined by cell-based ELISA. The effect of PIP-18 was compared with that of celecoxib, methotrexate, infliximab and antiflamin-2 in Tg197 mice after ip administration (thrice weekly for 5 weeks) at two doses (10, 30 mg/kg), and histologic analysis of ankle joints. Serum sPLA2 and cytokines (tumor necrosis factor (TNF)alpha, IL-6) were measured by Escherichia coli (E coli) assay and ELISA, respectively. RESULTS: PIP-18 inhibited sPLA2-IIA production and enzymatic activity, and suppressed production of MMPs in IL-1beta-induced RA and OA SF cells. Treatment with PIP-18 blocked IL-1beta-induced p38 MAPK phosphorylation and resulted in attenuation of sPLA2-IIA and MMP mRNA transcription in RA SF cells. The disease modifying effect of PIP-18 was evidenced by significant abrogation of synovitis, cartilage degradation and bone erosion in hTNF Tg197 mice. CONCLUSIONS: Our results demonstrate the benefit that can be gained from using sPLA2 inhibitory peptide for RA treatment, and validate PIP-18 as a potential therapeutic in a clinically relevant animal model of human arthritis.

Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity: solution structure and molecular modeling.

Secretory phospholipase A2 (sPLA2) and matrix metallopreoteinases (MMPs) are key enzymes involved in rheumatoid arthritis (RA), and their modulation thus represents a potential therapeutic option. On the basis of Escherichia coli radioassay, synthetic peptides were designed and screened for sPLA2 inhibition. The linear peptide, 10f (PIP-18), inhibited the recombinant human synovial sPLA2 activity with an IC50 of 1.19 microM. Not only did the peptide interfere with the function of sPLA2, but it also appeared to inhibit mRNA expression of sPLA2 and various MMPs in IL-1beta-stimulated RA synovial fibroblast (RASF) cultures and thereby the production of the corresponding proteins (>80% inhibition). Nuclear magnetic resonance (NMR), modeling, and docking studies indicate that in solution the peptide exhibits a beta-turn at residues Trp-Asp-Gly-Val and possibly binds to the hydrophobic channel of sPLA2. The results strongly suggest that the modulatory action of peptide 10f may play a major role in counteracting the development of RA.

Predictability of simple clinical tests to identify shoulder pain after stroke.

OBJECTIVE: To identify simple diagnostic musculoskeletal tests that can be performed early after stroke to predict patients' likelihood of reporting early signs of hemiplegic shoulder pain. DESIGN: Case control. SETTING: Multicenter acute care hospitals. PARTICIPANTS: A total of 152 adults after a first episode of stroke, of whom 135 met the inclusion criteria. Thirty patients were assigned to the experimental group because they reported moderate intensity of hemiplegic shoulder pain at rest. The remaining 105 patients made up the control group. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Therapists measured the performance of combined upper-limb movement including the hand-behind-neck (HBN) maneuver, passive pain-free ranges of shoulder motion, 3 musculoskeletal tests, and the strength of deltoid muscles during each patient's hospital stay. The numeric rating scale (NRS) identified those who reported moderate or greater intensities of hemiplegic shoulder pain during rest and during assessment. RESULTS: In our study, 22.2% (95% confidence interval, 15.5-30.2) of the patients reported hemiplegic shoulder pain, on average 1 week after the onset of stroke. Positive Neer test (NRS score >or=5) during the HBN maneuver and a difference of more than 10 degrees of passive range of external rotation between shoulders had a 98% probability of predicting the presence of hemiplegic shoulder pain (receiver operating characteristic, .994; sensitivity, 96.7%; specificity, 99.0%; positive predictive value, 96.7%; negative predictive value, 99.0%; P<.001). CONCLUSIONS: Three diagnostic clinical tests that can be performed during a bedside evaluation increase the likelihood of determining those who complain of hemiplegic shoulder pain after an acute episode of stroke.

Functional units within the latissimus dorsi muscle based on Sihler technique.

The latissimus dorsi is the largest dorsally located pectoral girdle muscle. The anatomic basis for splitting this muscle is based on dissection studies. These dissection studies have outlined the extramuscular innervation of the muscle. The intramuscular innervation, on the other hand, has been studied by using radiographs of intramuscular nerves labeled by fine wire. This technique, however, is limited by the level of microdissection that can be performed. Sihler staining technique renders the muscle translucent, stains the myelin in the nerve a dark blue and the hemoglobin in the vessels a dark brown. The intramuscular course and branching of the nerve and vessels is thus revealed without any surgical disruption of the anatomy. We use this technique to study the intramuscular neurovascular anatomy of the latissimus dorsi flap in 6 fresh human cadavers to determine the degree to which the muscle could be separated for functional muscle transfer.

Case report: the split flexor carpi ulnaris as a local muscle flap.

The flexor carpi ulnaris is a useful local muscle flap in the forearm and elbow. It is, however, an important palmar flexor and ulnar deviator of the wrist, and functional loss may arise from the use of this muscle in its entirety. The flexor carpi ulnaris is made up of two distinct neuromuscular compartments. This arrangement allows for splitting of the muscle and the potential use of the larger ulnar compartment as a local muscle flap while maintaining the humeral compartment as an ulnar deviator and palmar flexor of the wrist. We report two cases illustrating the clinical use of the split flexor carpi ulnaris as a local muscle flap.